Chest-2012-美国胸科医师协会血栓防治指南
DOI 10.1378/chest.11-2293 2012;141;e89S-e119S Chest
and Jeffrey I. Weitz John W. Eikelboom, Jack Hirsh, Frederick A. Spencer, Trevor P. Baglin
Evidence-Based Clinical Practice Guidelines
American College of Chest Physicians
and Prevention of Thrombosis, 9th ed: Antiplatelet Drugs : Antithrombotic Therapy
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CHEST / 141 / 2 / FEBRUARY , 2012 SUPPLEMENT e 89S
P latelets are vital components of normal hemostasis and key participants in atherothrombosis by virtue
of their capacity to adhere to the injured blood vessel
wall; recruit additional platelets to the site of injury; release vasoactive and prothrombotic mediators that trigger vasoconstriction and promote coagulation, respectively; and form aggregates that affect primary hemostasis. 1 Although platelet adhesion, activation, and aggregation can be viewed as a physiologic repair response to the sudden ? ssuring or rupture of an ath-erosclerotic plaque, uncontrolled progression of such a process through a series of self-sustaining ampli? -cation loops can lead to intraluminal thrombus for-mation, vascular occlusion, and subsequent ischemia or infarction. Currently available antiplatelet drugs
interfere with one or more steps in the process of
platelet release and aggregation 2 and produce a mea-surable reduction in the risk of thrombosis that cannot
be dissociated from an increased risk of bleeding. 3
W hen considering antiplatelet drugs, it is impor-tant to appreciate that ?10 11 platelets are produced each day under physiologic circumstances, a level of production that can increase up to 10-fold at times of
increased need. 4 Platelets are anucleated blood cells
that form by fragmentation of bone marrow megakar-yocyte cytoplasm and have a maximum circulating life span of ? 10 days. Regulation of platelet produc-tion is mediated by thrombopoietin, which is pro-duced primarily in the liver as well as in the bone marrow and the kidney and cleared by binding to
T
he article de scribe s the me chanisms of action, pharmacokine tics, and pharmacodynamics of aspirin, dipyridamole, cilostazol, the thienopyridines, and the glycoprotein IIb/IIIa antagonists. The relationships among dose, ef? cacy, and safety are discussed along with a mechanistic over-view of results of randomized clinical trials. The article does not provide speci? c management re comme ndations but highlights important practical aspe cts of antiplate le t the rapy, including optimal dosing, the variable balance between bene? ts and risks when antiplatelet therapies are used alone or in combination with other antiplatelet drugs in different clinical settings, and the implications of persistently high platelet reactivity despite such treatment. C HEST 2012; 141(2)(Suppl):e89S–e119S
A bbreviations: A CE 5 angiotensin-converting enzyme; A CS 5 acute coronary syndrome; ACTIVE 5 Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events; ADP 5 adenosine diphosphate; AMP 5 adenosine monophosphate; CAPRIE 5 Clopidogrel vs Aspirin in Patients at Risk for Ischemic Events; COMMIT 5 Clopidogrel and Metoprolol Myocardial Infarction Trial; COX 5 cyclooxygenase; CURE 5 Clopidogrel in Unstable Angina to Prevent Recurrent Events; CURRENT-OASIS 7 5 Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events/Organization to Assess Strategies for Ischemic Syndromes; CYP450 5 cytochrome P450; EPIC 5 Evaluation of 7E3 for the Prevention of Ischaemic Complications; ESPRIT 5 Aspirin Plus Dipyridamole Versus Aspirin Alone After Cerebral Ischaemia of Arterial Origin; ESPS 5 European Stroke Prevention Study; FDA 5 US Food and Drug Administration; GpIIb-IIIa 5 glycoprotein IIb/IIIa; H R 5 hazard ratio; IMPACT-II 5 Integrilin to Minimise Platelet Aggregation and Coronary Thrombosis-II; MI 5 myocardial infarction; NSAID 5 nonsteroidal antiin? ammatory drug; PCI 5 percutaneous
coronary intervention; PGH 2
5 prostaglandin H 2;PGI 2 5 prostacyclin; PLATO 5 Study of Platelet Inhibition and Patient Outcomes; PTCA 5 percutaneous transluminal coronary angioplasty; RR 5 rate ratio; TIA 5 transient ischemic attack;
TTP 5 thrombotic thrombocytopenic purpura; TXA 2 5 thromboxane A 2
A
ntithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines
J ohn W. E ikelboom ,M BBS ;J ack H irsh ,M D, FCCP ;F rederick A. S pencer ,M D ;T revor P . B aglin ,M BChB, PhD ;and J effrey I. W eitz ,M D ,F CCP
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T
he article on antiplatelet therapy in the American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition) reviewed the antiplatelet effects of traditional nonsteroidal antiin-? ammatory drugs (NSAIDs) and the cardiovascular effects of COX-2-selective NSAIDs. This topic will not be covered here, and interested readers are
referred to the previous article. 8
1.0 Aspirin A
spirin is the most widely studied antiplatelet drug. On the basis of . 100 randomized trials in high-risk patients, aspirin reduces vascular death by ?15% and
nonfatal vascular events by ?30%. 9,10
1.1 Mechanism of Action T he best-characterized mechanism of action of
aspirin is related to its capacity to permanently inhibit the COX activity of prostaglandin H -synthase-1 and prostaglandin H-synthase-2 (also referred to as
COX-1 and COX-2, respectively). 11-15COX isozymes
catalyze the ? rst committed step in prostanoid bio-synthesis, the conversion of arachidonic acid to prosta-glandin H 2(PGH 2)( F ig 1 ). PGH 2 is the immediate precursor of TXA 2 and PGI 2. T he molecular mechanism of permanent inhibition of COX activity by aspirin is related to blockade of the COX channel as a consequence of acetylation of a strategically located serine residue (Ser529 in COX-1, Ser516 in COX-2), thereby preventing substrate
access to the catalytic site of the enzyme. 16Complete
or near-complete inhibition of platelet COX-1 can be achieved with low doses of aspirin (75-150 mg) given once daily. In contrast, inhibition of COX-2-dependent pathophysiologic processes (eg, hyperalgesia, in? am-mation) requires larger doses of aspirin and a much shorter dosing interval because nucleated cells rap-idly resynthesize the enzyme. Thus, 10- to 100-fold higher daily doses of aspirin are required when the drug is used as an antiin? ammatory agent rather than as an antiplatelet agent. The bene? t/risk pro? le of aspirin depends on dose because its GI toxicity is dose dependent (discussed in section 1.3 “The Optimal Dose of Aspirin”). H uman platelets and vascular endothelial cells process PGH 2 to produce primarily TXA 2 and PGI 2,respectively. 12TXA 2 induces platelet aggregation and
vasoconstriction, whereas PGI 2inhibits platelet aggre-gation and induces vasodilation. 12Because TXA 2is largely derived from COX-1 (mostly from platelets), it is highly sensitive to aspirin inhibition. In contrast, although vascular PGI 2 can be derived from COX-1, its major source is COX-2, even under physiologic conditions.17COX-1-dependent PGI 2production high-af? nity receptors on platelets and megakaryo-cytes.5 In the presence of a high-platelet mass, thrombopoietin levels are reduced, and platelet pro-duction falls, whereas in the presence of a low-platelet mass, thrombopoietin levels rise, thereby stimulating thrombopoiesis. Platelets provide a circulating source of chemokines, cytokines, and growth factors, which are preformed and packaged in storage granules. Acti-vated platelets can synthesize prostanoids, primarily
thromboxane A 2(TXA 2
), from arachidonic acid released from membrane phospholipids through rapid coor-dinated activation of phospholipases, cyclooxygenase (COX)-1, and TX synthase ( F ig 1 ). The inducible form of COX (COX-2) not only is found primarily in the vascular endothelium and in monocytes but is also expressed in newly formed platelets, particularly
in the setting of accelerated platelet production.
6 Although activated platelets are incapable of de novo protein synthesis, they can translate constitutive
mRNA into protein over the course of several hours. 7
Thus, platelets may play a part in in? ammation, angiogenesis, and wound healing, and antiplatelet therapies may have an impact on these processes by blocking platelet-derived protein signals for in? am-matory or proliferative responses.
N egative modulation of platelet adhesion and aggregation is exerted by a variety of physiologic mechanisms, including endothelium-derived prosta-cyclin (PGI 2
), nitric oxide, CD39/ecto-ADPase, and platelet endothelial cell adhesion molecule-1. Some drugs may interfere with these regulatory pathways, as exempli? ed by the dose-dependent inhibition of PGI 2 production by aspirin and other COX-1 and
COX-2 inhibitors. 3
R evision accepted August 31, 2011.
A f? liations: From the Department of Medicine (Drs Eikelboom, Hirsh, Spencer, and Weitz), McMaster University; Population Health Research Institute (Drs Eikelboom and Hirsh); and Thrombosis and Atherosclerosis Research Institute (Drs Eikelboom, Hirsh, Spencer, and Weitz), Hamilton, ON, Canada; and Department of Haematol-ogy (Dr Baglin), Addenbrooke’s NHS Trust, Cambridge, England.
F unding/Support: The Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines received support from the National Heart, Lung, and Blood Institute [R13 HL104758] and Bayer Schering Pharma AG. Support in the form of educa-tional grants was also provided by Bristol-Myers Squibb; P? zer, Inc; Canyon Pharmaceuticals; and sano? -aventis US.
D isclaimer: American College of Chest Physician guidelines are intended for general information only, are not medical advice, and do not replace professional medical care and physician advice, which always should be sought for any medical condition. The complete disclaimer for this guideline can be accessed at https://www.360docs.net/doc/666725975.html,/content/141/2_suppl/1S.
C orrespondence to: John W. Eikelboom, MBBS, McMaster Univer s ity, Hamilton General Site, 237 Barton St E, Hamilton, ON, L9K 1H8, Canada; e-mail: eikelbj@mcmaster.ca
? 2012 American College of Chest Physicians.Reproduction of this article is prohibited without written permission from the American College of Chest Physicians ( h ttp://https://www.360docs.net/doc/666725975.html,/site/misc/reprints.xhtml ).
D OI: 10.1378/che st.11-2293
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CHEST / 141 / 2 / FEBRUARY , 2012 SUPPLEMENT e 91S
evident within 1 h. In contrast, it can take 3 to 4 h to reach peak plasma levels after administration of enteric-coated aspirin. Therefore, if a rapid effect is required and only enteric-coated tablets are avail-able, the tablets should be chewed instead of swal-lowed intact. The oral bioavailability of regular aspirin
tablets is ? 40% to 50% over a wide range of doses. 24
A considerably lower bioavailability has been reported for enteric-coated tablets and for sustained-release,
microencapsulated preparations. 24 The lower bio-availability of some enteric-coated preparations and
their poor absorption from the higher pH environment of the small intestine may result in inadequate plate-let inhibition when these preparations are used at low
doses, particularly in heavier subjects. 25Both a controlled-release formulation 18 and a transdermal
patch 26 with negligible systemic bioavailability have been developed in an attempt to achieve selective inhi-bition of platelet TXA 2 production without suppress-ing systemic PGI 2 synthesis. The former was used
successfully in the Thrombosis Prevention Trial, 27but
it remains unknown whether the controlled-release formulation has any advantages over plain aspirin. T he plasma concentration of aspirin decays with a half-life of 15 to 20 min. Despite the rapid clearance
occurs transiently in response to agonist stimulation
(eg, bradykinin) 18 and is sensitive to aspirin inhibition. COX-2-mediated PGI 2 production occurs long term
in response to laminar shear stress 19 and is relatively
insensitive to low-dose aspirin, which may explain the substantial residual COX-2-dependent PGI 2biosyn-thesis that occurs with daily doses of aspirin in the
range of 30 to 100 mg,
20 despite transient suppression of COX-1-dependent PGI 2release. 18 It is not estab-lished that the greater suppression of PGI 2formation
produced by higher doses of aspirin is suf? cient to initiate or predispose to thrombosis. However, two lines of evidence suggest that PGI 2 is thromboprotective. First, mice lacking the PGI 2 receptor exhibit increased susceptibility to injury-induced thrombosis. 21Second, the cardiovascular toxicity associated with COX-2 inhibitors 22 also supports the concept that PGI 2is important for thromboresistance in the setting of
inadequate inhibition of platelet TXA 2biosynthesis. 23
1.2 Aspirin Pharmacokinetics A spirin is rapidly absorbed in the stomach and
upper intestine. Plasma levels peak 30 to 40 min after aspirin ingestion, and inhibition of platelet function is
F igure 1. Arachidonic acid metabolism and mechanism of action of aspirin. Arachidonic acid, a 20-carbon fatty acid containing four double bonds, is liberated from the sn2 position in membrane phos-pholipids by several forms of phospholipase, which are activated by diverse stimuli. Arachidonic acid is converted by cytosolic prostaglandin H synthases, which have both COX and HOX activity, to the unstable intermediate prostaglandin H 2
. The synthases are colloquially termed “ c yclooxygenases ” and exist in two forms, COX-1 and COX-2. Low-dose aspirin selectively inhibits COX-1, and high-dose aspirin inhibits both COX-1 and COX-2. Prostaglandin H 2 is converted by tissue-speci? c isomer-ases to multiple prostanoids. These bioactive lipids activate speci? c cell membrane receptors of the superfamily of G-protein-coupled receptors. COX 5 cyclooxygenase; DP 5 prostaglandin D 2receptor; EP 5 prostaglandin E 2 receptor; FP 5 prostaglandin F 2 a receptor; HOX 5 hydroperoxidase; IP 5 prostacyclin receptor; TP 5 thromboxane receptor.
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Antiplatelet Drugs
tion (MI) or death in patients with unstable angina 36
or chronic stable angina, 37 (2) reduce the risk of stroke
or death in patients with transient cerebral ischemia, 38
and (3) reduce the risk of stroke after carotid endarterectomy. 39 In the European Stroke Preven-tion Study (ESPS)-2, aspirin 25 mg bid reduced the risk of stroke and the composite outcome of stroke or death in patients with prior stroke or transient ischemic
attack (TIA). 40 In the European Collaboration on
Low-dose Aspirin in Polycythemia vera trial, 41aspirin
(100 mg/d) was effective in preventing thrombotic complications in patients with polycythemia vera, even in the face of higher-than-normal platelet counts. The lowest doses of aspirin demonstrated to be effective for these various indications are shown in T able 1 .
A spirin Dose Comparisons: T he clinical effects of different doses of aspirin have been directly com-pared in randomized controlled trials. 42-48In the United Kingdom-Transient Ischaemic Attack (UK-TIA) study that randomized 2,435 patients after a TIA or minor ischemic stroke to receive one of two doses of aspirin or placebo, aspirin doses of 300 and 1,200 mg/d were associated with a similar rate of MI, major stroke, or vascular death (20% and 20%, respectively;
OR, 1.03; 95% CI, 0.83-1.29). 42 In the Dutch TIA trial,
which randomized 3,131 patients after a TIA or minor ischemic stroke, aspirin doses of 30 and 283 mg/d
of aspirin from the circulation, the platelet-inhibitory
effects last the life span of the platelet 28because aspirin irreversibly inactivates platelet COX-1. 13,14
Aspirin also acetylates megakaryocyte COX-1, thereby inhibiting thromboxane production in newly released
platelets as well as those already in the circulation. 11,29-31
The mean life span of human platelets is ?10 days, which means that ? 10% to 12% of circulating platelets
are replaced every day. 32,33 The recovery of throm-boxane production and thromboxane-dependent plate-let aggregation after prolonged aspirin treatment is
stopped is faster than what would be predicted based
on the rate of platelet turnover 20possibly because
of the nonlinear relationship between inhibition of
platelet COX-1 activity and TXA 2biosynthesis 34 ,35
( F ig 2 ) and the capacity of small amounts of throm-boxane produced by nonaspirinated platelets to sus-tain thromboxane-dependent platelet aggregation.
1.3 The Optimal Dose of Aspirin E
ffectiveness of Low-Dose Aspirin:P lacebo-controlled randomized trials have shown that aspirin is an effective antithrombotic agent when used long term in doses ranging between 50 and 100 mg/d, and there are data to suggest that it is effective in doses as
low as 30 mg/d. 9,10 At a dose of 75 mg/d, aspirin was
shown to (1) reduce the risk of acute myocardial infarc-
F igure 2. Maximal capacity of human platelets to synthesize TXB 2 , rate of TXB 2 production in healthy subjects, and relationship between the inhibition of platelet cyclooxygenase activity and TXB 2biosynthe-sis in vivo. Left, The level of TXB 2
production stimulated by endogenous thrombin during whole-blood clotting at 37°C. 34, 35 Center, The metabolic fate of TXA 2 in vivo and the calculated rate of its production
in healthy subjects on the basis of TXB 2
infusions and measurement of its major urinary metabolite. Right, The nonlinear relationship between inhibition of serum TXB 2 measured ex vivo and the reduction in the
excretion of thromboxane metabolite measured in vivo. 31TXA 2 5 thromboxane A 2;TXB 2 5 thromboxane B 2.
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CHEST / 141 / 2 / FEBRUARY , 2012 SUPPLEMENT e 93S
been compared with an untreated control group in a number of thrombotic vascular disorders. The aspirin doses have ranged from 50 to 1,500 mg/d. Aspirin has been shown to be effective in the following conditions: unstable angina where the incidence of acute MI or death was signi? cantly reduced in four separate
studies using daily doses of 75, 36325,49650,50 or
1,300 mg
51 ; stable angina where a dose of 75 mg/d reduced the incidence of acute MI or sudden death 37
; aortocoronary bypass surgery where the incidence of early graft occlusion was similarly reduced with daily
doses of 100, 52325, 53975, 54 or 1,200 mg
54;thrombo-prophylaxis in patients with prosthetic heart valves who also received warfarin where the incidence of systemic embolism was reduced with daily doses of
100, 55500, 56 or 1,500 mg
57,58;thromboprophylaxis in long-term hemodialysis patients with arterial venous shunts where a dose of 160 mg/d was shown to be
effective 59
; acute MI in which a dose of 162.5 mg/d reduced 35-day mortality as well as nonfatal reinfarc-tion and stroke 60
; transient cerebral ischemia in which doses between 50 and 1,200 mg/d were
effective 38,40,42,61-63 ; acute ischemic stroke where doses of 160 to 300 mg/d were effective in reducing early
mortality and stroke recurrence 64,65;and polycythemia vera in which 100 mg/d,
41 but not 900 mg/d, 66was effective in reducing fatal and nonfatal vascular events. Thus, aspirin is an effective antithrombotic agent at doses between 50 and 1,500 mg/d. Based on the results of the Dutch TIA study, it is also possible that
30 mg/d is effective. 47 E
ffect of Aspirin Dose on GI Side Effects and Bleeding: T here is evidence that the GI side effects of aspirin are dose dependent. Thus, aspirin doses of ? 300 mg/d are associated with fewer GI side effects than doses of ?1,200 mg/d. 42 There is also evidence that aspirin doses ?100mg / d are associ-ated with fewer side effects than 300 mg/d. 47In an observational analysis in patients with ACS, the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) investigators demonstrated that aspi-rin ? 100 mg/d alone or in combination with clo-pidogrel was associated with lower rates of major or life-threatening bleeding complications than aspirin alone at a dose of ?200mg/d.67 In the randomized CURRENT-OASIS 7 trial, aspirin given at a dose of 75 to 100 mg/d produced less GI bleeding than a dose of 300 to 325 mg/d. The incidence of other types of major bleeding was not different between
the two groups. 48 In summary, the lack of a dose-response relationship for the ef? cacy of aspirin in
clinical studies and the dose dependence of GI bleed-ing support the use of lowest proven effective doses of aspirin as the most appropriate strategy to maxi-mize ef? cacy and minimize toxicity ( T able 1 ). 9
were associated with a similar rate of MI, stroke, or cardiovascular death (14.7% and 15.2%, respectively;
hazard ratio [H R], 0.91; 95% CI, 0.76-1.09). 47The
ASA and Carotid Endarterectomy (ACE) trial reported that the risk of stroke, MI, or death within 3 months of carotid endarterectomy was signi? cantly lower for patients taking aspirin 81 or 325 mg/d than for those taking 650 or 1,300 mg/d (6.2% vs 8.4%, P 5 .03). 46 The Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events/Organization to Assess Strategies for Ischemic Syndromes (CURRRENT-OASIS 7) trial, which included 25,086 patients with acute coronary syn d romes (ACSs), found that 30 days of treatment with aspirin 300 to 325 mg/d was no more effective than aspirin 75 to 100 mg/d for the prevention of stroke, MI, or cardiovascular death (4.2% and 4.4%, respectively; H R, 0.97; 95% CI, 0.86-1.09).48 Thus, on the basis of results from ran-domized studies comparing different doses of aspirin, there is no convincing evidence that higher doses are any more effective at reducing the risk of serious vas-cular events than lower doses. In fact, the indirect comparisons reported in the overview of the Anti-thrombotic Trialists’ Collaboration ( T able 2 ) and the results of several direct randomized comparisons are compatible with the reverse; that is, there is blunt-ing of the antithrombotic effect with higher doses of aspirin, a ? nding consistent with dose-dependent inhibition of PGI 2. T
he Range of Effective Aspirin Doses:T he anti-thrombotic effects of a range of doses of aspirin have
T able 1— V ascular Disorders for Which Aspirin Has Been Shown to Be Effective and Lowest Effective Dose
Disorder
Lowest Effective
Daily Dose, mg
Transient ischemic attack and ischemic stroke a 50Men at high cardiovascular risk 75Hypertension 75Stable angina
75Unstable angina a 75Severe carotid artery stenosis a 75Polycythemia vera
100Acute myocardial infarction a 160Acute ischemic stroke a 160
a
H igher doses have been tested in other trials and not found to confer any greater risk reduction.
T able 2— I ndirect Comparison of Aspirin Doses Reducing Vascular Events in High-Risk Patients
Aspirin Dose, mg/d No. Trials No. Patients Odds Reduction, %
500-1,50034
22,45119 ? 3160-3251926,51326 ? 375-150126,77632 ? 6
,753
3,655
13 ? 8
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Optimal Dose of Aspirin”). How do we explain this apparent paradox? T he most likely explanation is that the relationship between platelet reactivity and thrombotic risk is con-founded by comorbidities, such as smoking or diabetes, that affect both platelet function and cardiovascular risk. It is also possible that the laboratory tests used to measure platelet reactivity fail to monitor the mecha-nism by which aspirin reduces the risk of thrombotic events. Many of these tests use nonphysiologic stimuli to induce platelet aggregation, and none assess platelet interaction with the vessel wall or the effect of aspirin on COX-2-dependent PGI 2 production. Thromboxane production appears to be the most speci? c measure of the inhibitory effects of aspirin because thromboxane is the major biochemical end product of the platelet COX-1 biosynthetic pathway that is targeted by aspirin. However, serum thromboxane levels re? ect the max-imum capacity of platelets to produce thromboxane; urinary thromboxane is also produced from nonplate-let sources, and measures of thromboxane concen-tration do not capture the effect of aspirin on PGI 2 production.
G iven the multifactorial triggers of atherothrom-bosis and the likelihood that platelet activation and subsequent aggregation are not the sole mediators of vascular events, it is not surprising that only a fraction (usually one-fourth to one-third) of all vascular com-plications can be prevented by aspirin alone. There is no evidence that patients who experience a throm-botic event despite aspirin therapy bene? t from treatment with higher-dose aspirin. Concomitant administration of nonselective NSAIDs, such as ibuprofen, should be avoided because, as outlined previously, these drugs can interfere with the anti-platelet effect of aspirin. 16A pharmacodynamic interaction between naproxen and aspirin has also
been described, 81 but this does not appear to occur with rofecoxib, 82celecoxib, 83
or diclofenac, 82drugs endowed with variable COX-2 selectivity. 84The US
Food and Drug Administration (FDA) has issued a statement informing patients and health-care pro-fessionals that ibuprofen can interfere with the antiplatelet effect of low-dose aspirin (81 mg/d), potentially rendering aspirin less effective when used
for cardioprotection or stroke prevention. 85 1.5 Ef? cacy and Safety
(a) Prevention of Atherothrombosis:T he ef? cacy
and safety of aspirin are documented from analyses of . 100 randomized controlled trials that have included thousands of patients representing the entire spectrum of atherosclerosis, ranging from apparently healthy low-risk individuals to patients presenting with an acute MI or acute ischemic stroke. Trials have
1
.4 High On-Treatment Platelet Reactivity (Aspirin Resistance)
H igh platelet reactivity in patients prescribed aspi-rin has been associated with an increased risk of thrombotic events. Therefore, this phenomenon has been used as one de? nition of aspirin resistance. Observational studies demonstrate that about one-third of patients treated with aspirin demonstrate less-than-expected inhibition of agonist-induced platelet aggrega-tion and increased levels of urinary thromboxane.8-10 Estimates of the prevalence of high on-treatment platelet reactivity are affected by differences among the studies in patient characteristics (eg, age, female sex, diabetes), concomitant therapies (particularly NSAIDs, eg, ibuprofen), the laboratory test used to measure the antiplatelet effects of aspirin (light trans-mission or whole-blood aggregometry, shear stress-induced platelet activation, expression of activation markers on the platelet surface as measured by ? ow cytometry, inhibition of thromboxane production), the cutoff used to de? ne high on-treatment reactivity,
and patient compliance with aspirin therapy. 25Despite
these differences, high platelet reactivity in patients prescribed aspirin has been consistently associated with a twofold to fourfold higher risk of MI, stroke,
or death. 9,10,26,27 I f thrombotic events in aspirin-treated patients with high on-treatment platelet reactivity were solely attributable to reduced responsiveness to aspirin, strategies aimed at improving the response would be expected to reduce this risk. Observational stud-ies suggest that aspirin inhibits platelet function 68-72
and coagulation 73-79 in a dose-dependent manner;
a ? nding con? rmed in a randomized dose compari-son.80 Thus, in a randomized, double-blind, cross-over trial that included 125 patients with stable
coronary artery disease, Gurbel and colleagues 80dem-onstrated that at doses of 81, 162, or 325 mg/d, aspi-rin inhibited adenosine diphosphate (ADP) and
collagen-induced platelet aggregation, blocked shear-dependent platelet aggregation measured by the PFA-100 device, and reduced urinary thromboxane concentrations in a dose-dependent manner. Most of the patients included in this study demonstrated near-complete inhibition of arachidonic acid-induced platelet aggregation with the 81-mg/d dose of aspi-rin, but higher aspirin doses reduced the propor-tion of patients in whom arachidonic acid-induced
aggregation exceeded a cutoff value of 20%. 80H
ow-ever, the dose-dependent inhibition of platelet func-tion and thromboxane production by aspirin observed in this study does not ? t with the results of the CURRENT-OASIS 7 trial, which failed to demon-strate a reduction in the risk of thrombotic events with higher doses of aspirin (See section 1.3 “The
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F
or patients with various manifestations of ischemic cardiac or neurologic disease, there is consensus that the optimal dose of aspirin for prevention of MI, stroke, or vascular death lies within the narrow range of 75 to 160 mg/d. This concept is supported by an overview of all antiplatelet trials that showed no obvious aspirin dose dependence for the protective effects of aspirin based on direct and indirect com-parisons 10 as well as by the results of individual trials that randomized patients to treatment with low-dose aspirin or placebo or to two different doses of aspirin ( T able 3 ). As discussed earlier, there is no con-vincing evidence that the dose requirement for the antithrombotic effect of aspirin varies in different clinical settings.
(b) Primary Prevention: A mong most high-risk patient groups, the expected number of individuals avoiding a serious vascular event by using aspirin sub-stantially exceeds the number experiencing a major bleed. It is less certain, however, whether aspirin is of bene? t in apparently healthy people who are at inter-mediate risk for serious vascular events because they have well-established cardiovascular risk factors. The Antithrombotic Trialists’ Collaboration addressed this issue in an individual participant data meta-analysis of the results of large randomized trials of aspirin for
primary prevention of vascular events. 87The analysis
was based on the results of six primary prevention
trials that included 95,456 subjects
27,88-92 with a mean follow-up of 6.9 years and a median follow-up among survivors of 5.5 years, re? ecting the fact that the
Women’s Health Study, 91 which accounted for almost
one-half of the participants, had a mean follow-up of ? 10 years ( T able 4 ). The effects of aspirin for pri-mary prevention were compared with its effects in high-risk settings using the results of six trials among patients with a history of MI, nine trials among patients with a history of TIA or stroke, and one trial in patients
with moderately severe diabetic retinopathy. 10
T he results of the Antithrombotic Trialists’ Collab-oration individual patient meta-analysis indicated a 12% proportional reduction in the incidence of serious vascular events (rate ratio [RR], 0.88; 95% CI, 0.82-0.94; P 5 .0001) and an 18% proportional reduction in the incidence of major coronary events (RR, 0.82; 95% CI, 0.75-0.90; P , .0001). Most of the bene? t of aspirin was due to a 23% reduction in non-fatal MI (RR, 0.77; 95% CI, 0.67-0.89; P ,.0001); there was no apparent reduction in cardiovascular death (RR, 0.95; 95% CI, 0.78-1.15; P 5 .50). Aspirin was associated with a nonsigni? cant 10% reduction in nonhemorrhagic stroke (RR, 0.90; 95% CI, 0.80-1.01; P 5 .08).
A spirin had no signi? cant effect on the aggregate of all vascular causes of death (RR, 0.98; 95% CI,
evaluated aspirin therapy of only a few weeks dura-tion or as long as 10 years. 9,10 Although aspirin has
consistently been shown to be effective in preventing fatal and nonfatal vascular events in these trials, the absolute bene? ts depend on the clinical setting. I n Second International Study of Infarct Survival (ISIS-2), 59 a single 162.5-mg tablet of aspirin started within 24 h of the onset of symptoms of a suspected MI and continued at the same dose daily for 5 weeks produced highly signi? cant reductions in vascular mortality, nonfatal reinfarction, and nonfatal stroke (23%, 49%, and 46%, respectively). There was no associated increase in hemorrhagic stroke or GI bleed-ing with aspirin, although there was a small increase in minor bleeding. 59 Based on the results of this study, a 5-week course of aspirin treatment in 1,000 patients with suspected acute MI will prevent ?40 vascular events, 10 a proportional odds reduction of 30%.
T wo separate trials with a similar protocol tested the ef? cacy and safety of early aspirin use in acute
ischemic stroke. The Chinese Acute Stroke Trial 64
and the International Stroke Trial 65collectively ran-domized ? 40,000 patients within 48 h of the onset of
stroke symptoms to 2 to 4 weeks of daily aspirin therapy (at doses of 160 and 300 mg/d, respectively) or to placebo. An overview analysis of the results of both trials indicated an absolute bene? t of nine fewer deaths or nonfatal strokes per 1,000 patients in the
? rst month of aspirin therapy. 10The proportional
odds reduction in the risk of fatal or nonfatal vascular events was only 10% in this setting. Although the background risk of hemorrhagic stroke was threefold higher in the Chinese Acute Stroke Trial than in the International Stroke Trial, the absolute increase in this risk was similar in the two studies (an excess of
2/1,000 aspirin-treated patients). 64,65
L ong-term aspirin therapy confers a conclusive net bene? t on the risk of subsequent MI, stroke, or vas-cular death among subjects with a high risk of vascu-lar complications. These include patients with chronic
stable angina, 37prior MI,10unstable angina,36,49-51
history of TIA or minor stroke,
37,40,42,62,63,86and other high-risk categories. 10The proportional reduction in
vascular events with long-term aspirin therapy in these various clinical settings ranges from 20% to 25%
based on an overview of all of the randomized trials. 10
Estimates of relative bene? ts based on the results of individual trials vary from no statistically signi? cant bene? t in patients with peripheral arterial disease to an ? 50% risk reduction in patients with unstable
angina. 10 In terms of absolute bene?
t, the protective effects of aspirin translate into avoidance of a major vascular event in 50 of 1,000 patients with unstable angina treated with aspirin for 6 months to 36 of 1,000 patients with prior MI, stroke, or TIA treated with aspirin for ?30 months. 10
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vidual patient meta-analysis performed by the Anti-thrombotic Trialists’ Collaboration. 93-95A meta-analysis
of all nine primary prevention trials demonstrated a borderline signi? cant reduction in all-cause mortality with aspirin but no reduction in cardiovascular mor-tality, 96 a ?
nding that raises the possibility that aspirin also prevents nonvascular (cancer) mortality (Discussed in “Cancer Incidence and Mortality”). P revious meta-analyses of the effects of antiplate-let therapy in persons at high risk of occlusive vascu-lar disease 7 have shown that the bene?
ts of aspirin far exceed the bleeding risks. By contrast, the majority (92%) of participants in the primary prevention trials was at low absolute risk of coronary disease; on average, the annual risk of a vascular event in the pri-mary prevention trials was only about one-tenth of that in the high-risk trials. Although the proportional bene? ts of aspirin appeared broadly similar when used for primary or secondary prevention, the abso-lute bene? ts of aspirin in the primary prevention trials were very small. When used for primary pre-vention, fewer than one person of every 1,000 treated with aspirin would avoid an occlusive vascular event, whereas a comparably small number would experi-ence a major extracranial bleed. Until the bene? ts of aspirin can be de? ned more precisely, therefore, the possibility of a bene? t for vascular prevention does not seem to justify the potential for harms. However, these estimates do not take into account the bene? ts of aspirin for the prevention of cancer and cancer-related mortality, which might tip the balance in favor of aspirin use for primary prevention. Additional trials evaluating the utility of aspirin for primary preven-tion of cardiovascular disease in elderly patients 97,98
and in patients with diabetes 99 are ongoing. Readers
are referred to the prevention of cardiovascular disease
article in this supplement by Vandvik et al. 100 (c) Atrial Fibrillation: A nticoagulant therapy with
dose-adjusted warfarin (international normalized
ratio, 2.0-3.0), 101 the direct thrombin inhibitor dabig-atran etexilate, 102 or the direct factor Xa inhibitors
rivaroxaban and apixaban 103 is very effective in reducing
the risk of stroke in patients with nonvalvular atrial ? brillation. The ef? cacy of aspirin (in doses ranging from 75-1,200 mg/d) has been compared with that of
0.87-1.10; P not signi? cant), and there was no evi-dence of a protective effect on the two-thirds of vas-cular deaths due to coronary heart disease (RR, 0.95; 95% CI, 0.78-1.15; P 5 .5), the one-sixth due to stroke (RR, 1.21; 95% CI, 0.84-1.74; P 5 .2), or the remain-ing vascular causes of death (RR, 0.90; 95% CI, 0.65-1.26; P 5 .4). Aspirin had no signi? cant effect on nonvascular mortality (RR, 0.93; 95% CI, 0.85-1.02; P 5 .1) or unknown causes of death (RR, 0.95; 95% CI, 0.75-1.21; P not signi? cant) but increased the risk of major extracranial bleeds (RR, 1.55; 95% CI, 1.31-1.83; P ,.0001). T he absolute bene? ts of aspirin were summarized under the term ”occlusive vascular events,” that is, vascular events other than hemorrhagic stroke or fatal extracranial bleeds. Among low-risk individ-uals (annual risk of coronary heart disease ?1%), allocation to aspirin resulted in the avoidance of four (95% CI, 2-6) occlusive vascular events per 1,000 after 5 years, which was chie? y attributable to three (95% CI, 1-5) fewer major coronary events. This ben-e? t was offset by two (95% CI, 1-3) additional major extracranial bleeds per 1,000 over the same 5-year period, but there was no signi? cant excess risk of hemorrhagic stroke (0.1 [95% CI, 2 0.5 to 0.7] excess; P not signi? cant). Among the much smaller number of moderate-risk participants (yearly coronary heart disease risk . 1%), the net effect of aspirin over 5 years on occlusive vascular events was statistically uncertain (13 [95% CI, 2 3-29] fewer; P 5 .1) because despite a de? nite reduction in major coronary events (18 [95% CI, 5-30] fewer per 1,000), there was no signi? cant reduction in presumed ischemic stroke (one fewer per 1,000 [95% CI, nine more to 11 fewer]), and there was an excess of both hemorrhagic stroke (? ve [95% CI, 1-9] more per 1,000) and major bleeds (4 more per 1,000 [95% CI, one fewer to 10 more]). About one-half of the hemorrhagic strokes were fatal (and the remainder would be expected to result in moderate or severe disability), so this hazard substan-tially offsets any cardiac bene? ts in moderate-risk individuals. T he results of three subsequently completed primary prevention trials involving 7,165 patients with diabetes, peripheral arterial disease, or both
( T able 4 27,88-95 ) are consistent with those of the indi- T able 3— [Section 2.4] Dose and Time Dependence of the Effects of Aspirin on Platelets and In? ammatory Cells
Cellular Target Enzyme Single Dose, mg a
Duration of Prostanoid
Suppression, h
Cumulative Effects Upon
Repeated Dosing
Daily Dose, mg b
Platelets COX-1
100
24-48Yes 50-81
In? ammatory cells
COX-2
?6503-4
No
3,000-5,000
COX 5 cyclooxygenase. a
D ose causing complete or near-complete suppression of prostanoid formation and clinically detectable functional effect after single dosing. b R ange of doses shown clinically effective in long-term trials of cardiovascular protection or rheumatoid arthritis.
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CHEST / 141 / 2 / FEBRUARY , 2012 SUPPLEMENT e 97S
T a b l e 4— P r i m a r y P r e v e n t i o n T r i a l s
T r i a l
D a t e s o f
R e c r u i t m e n t Y e a r o f
P u b l i c a t i o n M e a n D u r a t i o n o f F o l l o w -u p , y T a r g e t P o p u l a t i o n
E l i g i b l e A g e R a n g e , y I n t e r v e n t i o n
R a n d o m i z e d F a c t o r i a l C o m p a r i s o n
P l a c e b o C o n t r o l
B r i t i s h D o c t o r s S t u d y 90
N o v e m b e r 1, 1978, t o N o v e m b e r 1, 19791988
5.6
M a l e p h y s i c i a n s
19-90500 m g /d
N o n e
N o
U S P h y s i c i a n s
92 A u g u s t 24, 1981, t o A p r i l 2, 19841988
5.0M a l e p h y s i c i a n s
45-73 (m e n )325 m g a l t e r n a t e d
b -
c a r o t e n e (a l t e r n a t e
d a y s ) v s p l a c
e b o Y e s
T h r o m b o s i s P r e v e n t i o n T r i a l 27
F e b r u a r y 6, 1989, t o M a y 18, 19941998
6.7M e n w i t h r i s k f a c t o r s
f o r C D 45-69
75 m g /d
W a r f a r i n v s p l a c e b o
Y e s
H y p e r t e n s i o n O p t i m a l T r e a t m e n t 89
O c t o b e r 12, 1992, t o M a y 7, 19941998
3.8M e n a n d w o m e n w i t h D B P 100-115 m m H g 31-75
75 m g /d
3 t a r g e t D B P s
( ,80,,85,,90)Y e s
P r i m a r y P r e v e n t i o n P r o j e c t 88
J u n e 8, 1993, t o A p r i l 21, 19982001
3.7M e n a n d w o m e n w i t h ?1 r i s k f a c t o r f o r C H D 45-94
100 m g /d
V i t a m i n E v s o p e n c o n t r o l N o
W o m e n ’s H e a l t h S t u d y 91
S e p t e m b e r 1992 t o M a y 19952005
10.1F e m a l e h e a l t h p r o f e s s i o n a l s
?45100 m g a l t e r n a t e d
V i t a m i n E v s p l a c e b o
Y e s
J a p a n e s e P r i m a r y P r e v e n t i o n o f A t h e r o s c l e r o s i s w i t h A s p i r i n f o r D i a b e t e s 93 D e c e m b e r 2002 t o M a y 2005
20084.4T y p e 2 d i a b e t e s w i t h o u t h i s t o r y o f a t h e r o s c l e r o t i c d i s e a s e 30-85
81 o r 100 m g /d
N o n e N o
P r e v e n t i o n o f P r o g r e s s i o n o f A r t e r i a l D i s e a s e a n d D i a b e t e s 94
N o v e m b e r 1997 t o J u l y 2001
20086.7D i a b e t e s a n d A B I ?0.99, n o s y m p t o m a t i c c a r d i o v a s c u l a r d i s e a s e
?40100 m g /d A n t i o x i d a n t v s p l a c e b o Y e s
A s p i r i n f o r A s y m p t o m a t i c
A t h e r o s c l e r o s i s s t u d y 95 A p r i l 1998 t o O c t o b e r 2008
20108.2
A B I ? 0.95, f r e e o f c l i n i c a l c a r d i o v a s c u l a r d i s e a s e
50-75
100 m g /d N o n e Y e s
T h e ? r s t s i x t r i a l s l i s t e d i n t h e t a b l e w e r e i n c l u d e d i n t h e A n t i t h r o m b o t i c T r i a l i s t s ’ C o l l a b o r a t i o n i n d i v i d u a l p a t i e n t m e t a -a n a l y s i s . A B I 5 a n k l e -b r a c h i a l i n d e x ; C H D 5 c o r o n a r y h e a r t d i s e a s e ; D B P 5 d i a s t o l i c B P .
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by the Antiplatelet Trialists’ Collaboration 109and by
Sandercock and colleagues 110 of antiplatelet trials in
patients with stroke.
W hen compared with warfarin, heparin, low-molecular-weight heparin, or danaparoid, aspirin was associated with similar or higher rates of DVT detected by screening ultrasound or venography; however, the
frequency of symptomatic events was low. 111A large
randomized controlled trial is required to compare the effectiveness of aspirin with that of anticoagulants for the prevention of fatal or symptomatic VTE events.
Readers are referred to Falck-Ytter et al 112in this guideline for further discussion of the use of antiplate-let therapy for prevention of VTE.
(e) Placental Insuf? ciency: P reeclampsia and fetal growth restriction are believed to be related to reduced placental blood ? ow, which is believed to be caused by constriction, thrombosis, or both of small
placental arteries. 113 The initial reports that low-dose
aspirin therapy reduces the risk of severe low birth
weight among newborns 114 and lowers the need for
cesarean section in mothers with pregnancy-induced hypertension 114 led to the widespread use of prophy-lactic aspirin for prevention of preeclampsia. Subse-quently, several larger trials reported no bene? cial
effects of aspirin.
115-121 However, a systematic review of data from 59 trials in 37,560 women con? rmed that antiplatelet therapy (mostly aspirin 60 mg/d) is bene? cial. Aspirin was associated with a 17% decrease in the risk of preeclampsia, an 8% reduction in the risk of preterm birth, a 14% reduction in the risk of fetal or neonatal death, and a 10% reduction in small-for-gestational age babies. 122 An individual patient
meta-analysis of 31 trials involving 32,217 patients who received antiplatelet therapy for primary pre-vention of preeclampsia revealed a consistent bene? t of aspirin for the prevention of eclampsia (overall 10% relative risk reduction) in all of the subgroups studied (? rst pregnancy with or without any high risk factor; second pregnancy with or without high risk factors or history of hypertensive disorder of preg-nancy; preexisting renal disease, diabetes, hyper-tension, or previous infant small for gestational age; maternal age; singleton or multiple pregnancy; and timing of starting of treatment or intended aspirin dose ? 75 mg/d or ?75 mg/d). 123 Aspirin given in doses ranging from 50 to 150 mg/d accounted for 98% of women included in this data set. Readers are
referred to Bates et al 124 in this guideline for further
discussion of the use of antithrombotic therapy during pregnancy.
(f) Cancer Incidence and Mortality: T here is com-pelling evidence from randomized controlled trials that aspirin reduces the incidence of colorectal cancer
placebo or no antiplatelet treatment in seven ran-domized trials that included 3,990 patients with non-valvular atrial ? brillation. 101 A pooled analysis revealed
a relative risk reduction of ? 19% with aspirin compared with placebo or no treatment (95% CI, 2 1%-35%), which is consistent with the 22% (95% CI, 6%-35%) relative risk reduction obtained when com-paring any antiplatelet therapy with placebo or no antiplatelet therapy for stroke prevention in
patients with nonvalvular atrial ? brillation. 101Pooled
analysis of 10 trials involving 4,620 patients with non-valvular atrial ? brillation revealed that dose-adjusted vitamin K antagonist therapy was signi? cantly more effective than aspirin, with a 39% relative risk
reduction (95% CI, 19%-53%).
104 Warfarin is also more effective than the combination of aspirin and clopidogrel. 105 T he ef? cacy of antiplatelet therapy for stroke pre-vention in atrial ? brillation has been con? rmed by the results of the Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE) A trial, which compared the combina-tion of aspirin plus clopidogrel with aspirin alone in
7,554 patients deemed ineligible for warfarin. 106Aspi-rin plus clopidogrel reduced the risk of major vascu-lar events, comprising the composite of stroke, MI,
non-CNS embolism, or death from vascular causes, by 11% compared with aspirin (95% CI, 2%-19%) primarily because of a 28% reduction in stroke (95% CI, 17%-38%). However, the combination of clopidogrel plus aspirin is less effective than warfarin
and is associated with a similar risk of bleeding. 105
Readers are referred to You et al 107 in this guide-line for further discussion of the use of antiplatelet
therapy for stroke prevention in patients with atrial ? brillation.
(d) VTE: T he Pulmonary Embolism Prevention (PEP) trial results demonstrated that aspirin is effec-tive in preventing VTE after major orthopedic sur-gery. 108 This double-blind, multicenter study included 13,356 patients undergoing surgery for hip fracture and an additional 4,088 patients undergoing elective hip or knee arthroplasty. Patients were randomized to receive aspirin (160 mg/d) or placebo for 5 weeks, with the ? rst dose administered prior to surgery. Other forms of prophylaxis were allowed, and either heparin or low-molecular-weight heparin was used in ?40% of the patients. Among the 13,356 patients undergoing surgery for hip fracture, aspirin produced a 36% reduction in symptomatic DVT or pulmonary embo-lism (absolute risk reduction, 0.9%; P 5 .0003). A similar relative risk reduction was observed in aspirin-treated patients who did or did not receive concomitant hep-arin or low-molecular-weight heparin. These results are consistent with those of meta-analyses performed
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CHEST / 141 / 2 / FEBRUARY , 2012 SUPPLEMENT e 99S
doses) inhibition of COX-1 in platelets. 6 Thus, it is not
surprising that the antithrombotic effect of aspirin can be dissociated, at least in part, from GI bleeding. Even
at low doses, aspirin causes serious GI bleeding. 40,47
Because of the underlying prevalence of gastric muco s al erosions related to concurrent use of other NSAIDs and H elicobacter pylori infection in the general pop-ulation, it should be expected that any dose of aspirin will cause more GI bleeding from preexisting lesions than placebo. Consistent with this mechanistic inter-pretation, the relative risk of hospitalization due to upper-GI bleeding and perforation associated with low-dose aspirin therapy (mostly 100-300 mg/d) is comparable to that with other antiplatelet drugs and anticoagulants (ie, 2.3 [95% CI, 1.7-3.2], 2.0 [95% CI, 1.4-2.7], and 2.2 [95% CI, 1.4-3.4], respectively, in a
large population-based observational study 128
).
I n the 2002 overview of randomized trials of aspi-rin for secondary vascular prevention performed by
the Antithrombotic Trialists’ Collaboration, 10infor-mation was available on 787 major extracranial hem-orrhages in 60 trials recording at least one such
hemorrhage. These were generally de? ned as hem-orrhages that were fatal or required transfusion; among them, 159 (20%) caused death. Overall, the proportional increase in risk of a major extracranial bleed with antiplatelet therapy was about one-half (OR, 1.6; 95% CI, 1.4-1.8), with no signi? cant differ-ence between the proportional increases observed in each of the ? ve high-risk categories of patients. A similar proportional increase in extracranial bleeding was obtained in the 2009 individual patient meta-analysis by the Antithrombotic Trialists’ Collabora-tion of six trials of aspirin for primary prevention that
and cancer mortality.
125,126 An individual patient meta-analysis of eight randomized controlled trials that included 25,570 subjects demonstrated that compared with no aspirin, daily aspirin for a scheduled mean treatment duration of at least 4 years reduced the odds of cancer deaths by 21% (95% CI, 8%-32%). The mor-tality bene? t appeared to be unrelated to aspirin dose, only became apparent after 5 years of follow-up, and the absolute bene? t increased over time. The greatest mortality bene? t was seen with adenocarcinoma. Among patients aged ? 65 years at the start of the trials, the absolute reduction in cancer deaths over
20 years was 7.1% (95% CI, 2.4%-11.7%). 126Separate
analyses based on individual patient data from four trials of 14,033 patients followed for a median of 18.3 years demonstrated that aspirin (at doses of 75-300 mg/d) also reduced the incidence of colorectal cancer. Furthermore, an analysis from the Dutch TIA trial suggested that the risk of fatal colorectal cancer was higher with aspirin doses of 30 mg/d than it was
with a dose of 283 mg/d. 126
(
g) Adverse Effects of Aspirin:A spirin-induced impairment of primary hemostasis cannot be sepa-rated from its antithrombotic effect and appears to be similar with all doses ?75 mg/d. 9The balance between preventing thrombotic events and causing bleeding with aspirin critically depends on the abso-lute thrombotic vs hemorrhagic risk of the patient. Thus, in individuals at low risk for vascular occlusion (eg, ? 1% per year), the very small reduction of vascu-lar events is probably offset by bleeding complications. In contrast, in patients at high risk of cardiovascular or cerebrovascular complications (eg, . 3% per year), the substantial absolute bene? t of aspirin prophylaxis clearly outweighs the harm ( T able 5 ). For example, the absolute excess of major bleeds (ie, those requiring transfusion) in patients with acute MI is ?1/100th the absolute number of major vascular events avoided
by aspirin therapy. 10
T he overall risk of major extracranial and intracra-nial hemorrhage associated with antiplatelet drugs is dif? cult to assess in individual trials because their incidence is , 1% per year. This makes detection of even a 50% to 60% relative increase in risk unrealistic in most trials of a few thousand patients.
A spirin-induced GI toxicity, as detected in random-ized clinical trials, appears to be dose-related, with
doses in the range of 30 to 1,300 mg/d. 127This conclu-sion is based on both indirect comparisons of different
trials and direct randomized comparisons of different aspirin doses, as reviewed previously in this article. The dose-response relationship for GI toxicity is believed to re? ect at least two COX-1-dependent components: dose-dependent inhibition of COX-1 in the GI mucosa and dose-independent (within the range of examined
T able 5— B ene? t and Harm of Antiplatelet Prophylaxis
With Aspirin in Different Settings
Clinical Setting Bene? ts, No. of Patients in Whom a Major Vascular Event Is Avoided per 1,000/y a Harm, No. of Patients in Whom a Major GI Bleeding Event Is Caused per
1,000/y b
Patients at low to high cardiovascular risk 1-21-2Essential hypertension 1-21-2Chronic stable angina 101-2Prior myocardial infarction 201-2Unstable angina
50
1-2
a
B ene? ts are calculated from randomized trial data reviewed in this article and depicted in F igure 3 . b E xcess of upper-GI bleedings are estimated from a background rate of one event per 1,000/y in the general population of nonusers and a relative risk of 2.0 to 3.0 associated with aspirin prophylaxis. Such an estimate assumes comparability of other risk factors for upper-GI bleeding, such as age and concomitant use of nonsteroidal antiin? ammatory drugs and may actually underestimate the absolute risk in an elderly population exposed to primary prevention.
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Similar conclusions were reached by a case-control
study using data from the UK General Practice
Research Database. 134
S uppressing acid secretion is believed to reduce the risk of ulcers associated with the regular use of NSAIDs. In patients who required continuous treat-ment with NSAIDs and who had ulcers or .10ero-sions in their stomach or duodenum, omeprazole healed and prevented ulcers more effectively than
did ranitidine. 135 In these patients, maintenance
therapy with omeprazole was associated with a lower rate of relapse and was better tolerated than miso-prostol. 136 In patients with a history of previous ulcer bleeding who took low-dose aspirin for 6 months, omeprazole and H pylori eradication were associated with similar rates of recurrent bleeding (0.9% and
1.9%, respectively), 137 although clinically important
differences between the two preventive strategies could not be excluded owing to the small sample size (n 5 250).
T wo relatively small studies 138,139have challenged
earlier guidelines that recommended the use of clo-pidogrel for patients who have major GI contraindica-tions to aspirin, principally recent signi? cant bleeding from a peptic ulcer or gastritis. Both studies enrolled patients who developed ulcer bleeding after the use
of low-dose aspirin. In a study by Chan et al, 138after
healing of ulcers and eradication of H pylori , if pres-ent, 320 patients were randomly assigned to receive either clopidogrel 75 mg/d or aspirin 80 mg/d plus esomeprazole 20 mg bid for 12 months. The cumula-tive incidence of recurrent bleeding was 8.6% (95% CI, 4.1%-13.1%) among patients who received clo p idogrel and 0.7% (95% CI, 0%-2.0%) among those who received aspirin plus esomeprazole ( P 5 .001). 138
In a study by Lai et al,
139 170 patients with prior ulcer bleeding were randomly assigned to treatment with clopidogrel 75 mg/d or aspirin 100 mg/d and esomep-razole 20 mg/d for 1 year. The cumulative incidence of recurrent ulcer complications was 13.6% and 0%, respectively (95% CI for the difference, 6.3%-20.9%; P 5 .0019). 139 The combination of esomeprazole and low-dose aspirin is superior to clopidogrel for the prevention of recurrent GI bleeding as is now rec-ommended by the 2008 guidelines of the American College of Cardiology/American College of Gastro-enterology/American Heart Association. 140
S ubstantially less information is available about the risk of intracranial hemorrhage associated with aspirin use. In the Nurses’ H ealth Study cohort of ? 79,000 women aged 34 to 59 years, infrequent use of aspirin (1-6 tablets per week) was associated with a reduced risk of ischemic stroke, whereas high frequency use ( ? 15 tablets per week) was associated with an increased risk of subarachnoid hemorrhage,
particularly among older or hypertensive women. 141
included 554 extracranial hemorrhages (OR, 1.5;
95% CI, 1.3-1.8).
87 A case-control study with hospital and community controls examined the risks of hospitalization for bleeding peptic ulcer associated with three differ-ent regimens of aspirin prophylaxis. 129 ORs were cal-culated for different doses of aspirin: 75 mg (2.3;
95% CI, 1.2-4.4), 150 mg (3.2; 95% CI, 1.7-6.5), and 300 mg (3.9; 95% CI, 2.5-6.3). Additional epidemi-ologic studies have found a dose-response relation-ship between aspirin prescription and upper-GI
complications, as reviewed by García Rodríguez et al. 130
It has been calculated that ? 900 of the 10,000 epi-sodes of ulcer bleeding occurring in persons aged . 60 years each year in England and Wales could be associated with and ascribed to prophylactic
aspirin use. 129 If the assumptions from indirect com-parisons are correct, a general change to lower doses
(75 mg/d) of aspirin would not eliminate the risk but would reduce it by ? 40% compared with a 300-mg dose and by 30% compared with a 150-mg dose.129 The mortality rate among patients who are hospitalized for NSAID-induced upper-GI bleeding
is 5% to 10%.
131,132 T he widely held belief that enteric-coated and buffered aspirin preparations are less likely to cause major upper-GI bleeding than plain tablets was eval-uated in a multicenter case-control study. 133The relative risks of upper-GI bleeding for plain, enteric-coated, and buffered aspirin at average daily doses of ? 325 mg were 2.6, 2.7, and 3.1, respectively. At doses . 325 mg, the relative risk was 5.8 for plain and 7.0 for buffered aspirin; there were insuf? cient data
to evaluate enteric-coated aspirin at this dose level. 133
F igure 3. The absolute risk of vascular complications is the major determinant of the absolute bene? t of antiplatelet prophylaxis. Data are plotted from placebo-controlled aspirin trials in different clinical settings. For each category of patients, the abscissa denotes the absolute risk of experiencing a major vascular event as recorded in the placebo arm of the trials. The absolute bene? t of antiplatelet treatment is reported on the ordinate as the number of subjects in whom an important vascular event (nonfatal MI, nonfatal stroke, or vascular death) is actually prevented by treating 1,000 subjects with aspirin for 1 year. MI 5 myocardial infarction.
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CHEST / 141 / 2 / FEBRUARY , 2012 SUPPLEMENT e 101S
tion) and blockade of the uptake of adenosine (which binds to A 2 receptors, stimulates platelet adenyl cyclase, and increases cyclic AMP) have been sug-gested. Moreover, direct stimulation of PGI 2synthe-sis and protection against its degradation have been reported, although the dipyridamole concentrations required to produce these effects far exceed the low-micromolar plasma levels achieved after oral administration of conventional doses (100-400 mg/d).148 Dipyridamole also differentially inhibits the expres-sion of critical in? ammatory genes by platelet-leukocyte aggregates. 149 2.2 Pharmacokinetics
T he absorption of dipyridamole from conven-tional formulations is quite variable and may result in low systemic bioavailability of the drug. A modi? ed-release formulation of dipyridamole with improved bioavailability has been developed in a combination
pill with low-dose aspirin.
150 Dipyridamole is highly protein bound to albumin, eliminated primarily by biliary excretion as a glucuronide conjugate, and is subject to enterohepatic recirculation. A terminal half-life of 10 h has been reported. This is consis-tent with the bid regimen used in recent clinical studies.
2.3 Ef? cacy and Safety
T he clinical ef? cacy of immediate-release dipyri-damole, alone or in combination with aspirin, was questioned on the basis of earlier randomized trials. 3,151 As a result, the reformulated extended-release prep-aration was evaluated in the more recent ESPS-2, Aspirin Plus Dipyridamole Versus Aspirin Alone After Cerebral Ischaemia of Arterial Origin (ESPRIT),
a nd Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) randomized trials. In ESPS-2, the new preparation of dipyridamole was eval-uated in 6,602 patients with prior stroke or TIA.
40 This study showed that the addition of modi? ed-release dipyridamole (200 mg bid) to aspirin (25 mg bid) was associated with a 22% relative risk reduction in major vascular events compared with aspirin alone. H eadache was the most common adverse effect of dipyridamole.
I n the ESPRIT trial, 152 2,739 patients within
6 months of a TIA or minor stroke of presumed arterial origin were randomized to receive aspirin (30-325 mg/d) with or without dipyridamole (200 mg bid). Compared with aspirin alone, the primary out-come (a composite of major vascular events or major bleeding complications) was reduced by 20% with the combined treatment. Patients on aspirin plus dipyridamole discontinued trial medication almost
In the 2002 overview of the Antithrombotic Trialists’ Collaboration, 10 the overall absolute excess of intra-cranial hemorrhage due to aspirin therapy was less than one per 1,000 patients per year in trials that involved patients at high risk for cardiovascular events, with a somewhat higher risk in patients with cere-brovascular disease. The 2009 individual patient meta-analysis of primary prevention trials indicated that aspirin was associated with ? ve additional hem-orrhagic strokes per 1,000 among moderate-risk par-ticipants (risk of coronary event, . 1% per year) over 5 years (ie, ? 1/1,000 per year) but substantially fewer
events in low-risk participants. 87
L ow-dose aspirin therapy has not been reported to affect renal function or BP control, 142consistent with its lack of effect on renal prostaglandins 143primarily derived from constitutively expressed COX-2 in the kidney.84 Moreover, aspirin 75 mg/d did not affect BP or the need for antihypertensive therapy in inten-sively treated patients with hypertension. 89The sug-gestion that the use of aspirin and other antiplatelet
agents is associated with reduced bene? t in enalapril-treated patients with left ventricular systolic dysfunc-tion 144 is not supported by the results of a large
meta-analysis of MI trials. 145 Similarly, no negative
interaction occurred between angiotensin-converting enzyme (ACE) inhibition and the cardiovascular bene? ts of low-dose aspirin in intensively treated
patients with hypertension. 146 The ACE Inhibitors
Collaborative Group performed a systematic overview of data from 22,060 patients included in six long-term randomized trials of ACE inhibitors to assess whether aspirin altered the effects of ACE inhibitor therapy
on major clinical outcomes. 147 Even though the results
from these analyses cannot rule out the possibility of an interaction, they show unequivocally that even if aspirin is given, the addition of ACE inhibitor therapy produces substantial additional benefit in all major vascular outcomes. Therefore, in the absence of clear contraindications, concomitant use of aspirin and ACE inhibitors should be considered in all patients who are at high risk of major vascular events.147
2.0 Dipyridamole
2.1 Mechanism of Action D
ipyridamole is a pyrimidopyrimidine derivative with vasodilator and antiplatelet properties. The mechanism of action of dipyridamole as an antiplate-let agent is controversial.
148 Both inhibition of cyclic nucleotide phosphodiesterase (the enzyme that degrades cyclic adenosine monophosphate [AMP]
to 5
9 -AMP , resulting in the intraplatelet accumula-tion of cyclic AMP , an inhibitor of platelet aggrega-
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food increases the rate and extent of drug absorption. Cilostazol is highly albumin bound and is extensively metabolized by cytochrome P450 (CYP450) enzymes, with excretion of metabolites in the urine. It has a half-life of 11 h, and the half-life is prolonged in patients with severe renal impairment. 3.3 Ef? cacy and Safety
M
eta-analyses of mainly small, open-label, placebo- and active-controlled trials have demonstrated that cilostazol (50 mg bid or 100 mg once daily) increases maximal and pain-free walking distance in patients
with intermittent claudication, 156prevents throm-botic events in patients with peripheral arterial
disease, 157 and prevents restenosis and target vessel revascularization in patients undergoing stenting of
coronary or peripheral arteries. 158
T he Cilostazol for Prevention of Secondary Stroke (CSPS-2) study evaluated the ef? cacy and safety of cilostazol (100 mg bid) compared with aspirin (81 mg/d) in 2,757 Japanese patients with recent
stroke, using a noninferiority study design. 159The
mean duration of follow-up was 29 months. In an on-treatment analysis, the annual rate of recurrent stroke was 2.8% in patients randomized to receive cilostazol and 3.7% in those randomized to receive aspirin (HR, 0.74; 95% CI, 0.56-0.98), which met the prespeci? ed criterion for noninferiority. Consistent with the results of the placebo-controlled comparisons, which demonstrated no increase in bleeding with cilostazol, the annual rate of bleeding with cilostazol was lower than that with aspirin (0.77 and 1.78%, respectively; H R, 0.46; 95% CI, 0.30-0.71), although bleeding rates were unexpectedly low in both groups. Head-ache, diarrhea, palpitation, dizziness, and tachycardia were more frequent with cilostazol than with aspirin and led to an almost twofold higher rate of discontin-uation of cilostazol (20% vs 12%).
4.0 Thienopyridines
T
iclopidine, clopidogrel, and prasugrel represent three generations of oral thienopyridines that selectively inhibit ADP-induced platelet aggregation. The ? rst-generation agent ticlopidine was limited by bone marrow toxicity and has largely been replaced by clopidogrel, which has become established as standard therapy across the spectrum of patients with ACS and in those undergoing percutaneous coronary intervention (PCI). However, clopidogrel also has limitations, including var-iable absorption; variable antiplatelet effects related, at least in part, to common polymorphisms in the genes that regulate the metabolic activation of clopidogrel; and a delayed onset and offset of action. Prasugrel, the third-generation thienopyridine, has a more rapid
three times more often than those on aspirin alone
mainly because of headache. 152 I n the PRoFESS trial, 153 20,332 patients with
recent ischemic stroke were randomized to receive the combination of aspirin (25 mg bid) plus extended-release dipyridamole (200 mg bid) or clopidogrel (75 mg once daily) for a mean of 2.5 years. The HR for the primary ef? cacy outcome (1.01; 95% CI, 0.92-1.11) failed to reach the prespeci? ed noninferi-ority margin. Major hemorrhages occurred more fre-quently in those given aspirin plus extended-release dipyridamole than in patients treated with clopidogrel (HR, 1.15; 95% CI, 1.00-1.32), and the combination was associated with an excess of intracranial hemor-rhage (HR, 1.42; 95% CI, 1.11-1.83). A meta-analysis of six randomized trials involving 7,648 patients with a history of TIA or stroke in which stroke was reported as an outcome demonstrated that compared with aspirin alone (dose range, 50-1,300 mg/d), the combination of aspirin (dose range, 50-1,300 mg/d) plus dipyridamole reduced stroke by 23% (RR, 0.77; 95% CI, 0.67-0.89), with no statistical
evidence of heterogeneity. 154Consistent estimates
were obtained from trials that used the immediate-release preparation of dipyridamole (four trials) and those that used the extended-release preparation. A Cochrane review of 29 randomized trials involving 23,019 patients con? rmed the superiority of the com-bination of aspirin plus dipyridamole over aspirin alone for prevention of vascular events in patients with a history of TIA or stroke but found no evidence of a bene? t of the combination in studies involving patients with a history of coronary or peripheral arte-rial disease or in other high-risk patients. 155
3.0 Cilostazol
3.1 Mechanism of Action C
ilostazol is a 2-oxoquinolone derivative that is reported to have vasodilatory and antiplatelet prop-erties as well as antiproliferative effects, reducing smooth muscle cell proliferation and neointimal hyper-plasia after endothelial injury. Cilostazol is a common cause of GI side effects, and headache occurs in up to one-fourth of patients within the ? rst 2 weeks of start-ing treatment. Cilostazol is contraindicated in patients with heart failure because of the potential to trigger ventricular tachycardia, an effect that has been attrib-uted to the increase in intracellular cyclic AMP, a mechanism that likely also accounts for the vasodila-tory effects of cilostazol. 3.2 Pharmacokinetics
T
here is substantial variability in the absorption of orally administered cilostazol. Coadministration of
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tions in patients with peripheral arterial disease. 167-169
The association of ticlopidine therapy with hypercho-lesterolemia and neutropenia (for which the reported rate of occurrence is 2.4% for a neutrophil count of , 1.2 310 9 /L and 0.8% for a count of , 0.45 310 9/L), and its comparative expense has reduced enthusiasm for this therapy as an alternative to aspirin in most situations. 171 Ticlopidine has also been associated with
thrombocytopenia, 171aplastic anemia, 172
and throm-botic thrombocytopenic purpura (TTP). 173Ticlopi-dine has been approved for clinical use in patients
with cerebral ischemia when aspirin has failed, cannot be tolerated, or is contraindicated, although this lim-itation does not apply in all countries where the drug is registered.
S everal studies have demonstrated the superiority of the combination of ticlopidine plus aspirin com-pared with aspirin alone or aspirin plus warfarin in preventing thrombotic complications after coronary
artery stent placement.
174,175 Ticlopidine was routinely used in combination with aspirin in patients receiving coronary artery stents, but the superior safety pro? le of clopidogrel has resulted in the replacement of ticlopidine by clopidogrel as the standard of care after
stent deployment. 176 The risk of TTP associated with
ticlopidine is estimated to be 0.02% in patients receiving the drug after stent placement. 177This com-pares with an incidence of 0.0004% in the general population. The mortality rate for this complication
exceeds 20%. 177
T he role of ticlopidine in the current therapeutic armamentarium is uncertain because of the toxicities presented. In most jurisdictions, it has been largely replaced by clopidogrel.
4.2 Clopidogrel
4.2.1 Pharmacokinetics: C lopidogrel is rapidly absorbed and metabolized through a two-step pro-cess to generate a highly labile active metabolite 178
that irreversibly binds to the platelet P2Y12 receptor
when platelets pass through the liver. 179The main systemic metabolite of clopidogrel is the inactive carboxylic acid derivative SR 26334, which has a half-life of ? 8 h. On repeated daily dosing of 50 to 100 mg of clo p idogrel in healthy volunteers, ADP-induced platelet aggregation was inhibited from the second day of treatment (25%-30% inhibition) and reached a steady state (50%-60% inhibition) after 4 to 7 days. Such a level of maximal inhibition was comparable to that achieved with ticlopidine (500 mg/d), although the antiplatelet effects of the latter was more delayed than that of clopidogrel. No appreciable differences in the maximum inhibitory effects pro-duced by 50, 75, or 100 mg of clopidogrel were noted
in this study. 180 As would be expected from these
onset of action, is more potent than clopidogrel, and produces more consistent platelet inhibition. All three thienopyridines are prodrugs that must undergo metabolic activation through the hepatic CYP450 system to generate the active metabolites that inhibit the platelet P2Y12 receptor. Permanent inhibition of the platelet P2Y12 receptor by thienopyridines is consis-tent with the time-dependent, cumulative inhibition of ADP-induced platelet aggregation that occurs with repeated daily dosing of the slower-acting thienopyri-dines ticlopidine and clopidogrel and with the slow
recovery of platelet function after drug withdrawal. 160
Although thienopyridines can also suppress platelet aggregation induced by arachidonic acid, collagen,
and thrombin,
161,162 these inhibitory effects are atten-uated or abolished by increasing the agonist concen-tration and are probably explained by blockade of ADP-mediated ampli? cation of the platelet response to other agonists. 4.1 Ticlopidine
4.1.1 Pharmacokinetics: U p to 90% of a single oral
dose of ticlopidine is rapidly absorbed. 160Plasma con-centrations peak 1 to 3 h after a single oral dose of
250 mg. More than 98% of absorbed ticlopidine is reversibly bound to plasma proteins, primarily albu-min. Ticlopidine is metabolized rapidly and exten-sively. A total of 13 metabolites have been identi? ed in humans. Of these, only the 2-keto derivative of ticlopidine is more potent than the parent compound
at inhibiting ADP-induced platelet aggregation. 160
The apparent elimination half-life of ticlopidine is 24 to 36 h after a single oral dose and up to 96 h
after 14 days of repeated dosing. 160The standard
dosing regimen of ticlopidine is 250 mg bid. 4.1.2 Ef? cacy and Safety: A s a single agent, ticlopi-dine has been evaluated in patients with stroke, 163
transient cerebral ischemia, 164unstable angina,165
MI, 166 and intermittent claudication
167-169 and in those undergoing aortocoronary bypass surgery. 170Ticlo-pidine was more effective than aspirin in reducing
stroke in patients with transient cerebral ischemia or
minor stroke 164 (although there was no statistically
signi? cant difference in the combined outcome of
stroke, MI, or death 10
); was as effective as aspirin in the treatment of patients with a recent MI 166;was
more effective than placebo in reducing the risk of the combined outcome of stroke, MI, or vascular
death in patients with thromboembolic stroke 163;was
more effective than conventional antianginal therapy in reducing vascular death or MI in patients with
unstable angina 165
; was more effective than placebo in reducing acute occlusion of coronary bypass grafts 170
; and was more effective than controls in improving
walking distance 168 and reducing vascular complica-
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4
.2.2 High On-Treatment Platelet Reactivity (Clo-pidogrel Resistance): N umerous studies have dem-onstrated variable levels of platelet P2Y12 receptor inhibition in patients treated with clopidogrel and an increased risk of thrombotic events in those with high
on-treatment platelet reactivity. 186H
igh on-treatment platelet reactivity is reported to occur in about one-third of those prescribed clopidogrel and has been associated with a 1.5-fold to ? vefold increased risk of thrombosis. E stimates of the prevalence of high platelet reac-tivity in patients prescribed clopidogrel vary accord-ing to comorbidities (eg, diabetes, dyslipidemia), concomitant therapies (lipophilic statins, eg, simva-statin and atorvastatin; proton pump inhibitors, eg, omeprazole; and calcium channel blockers), and the test and cutoffs used to de? ne high reactivity. Partic-ular attention has focused on the mechanisms respon-sible for insuf? cient active metabolite generation as an explanation for high platelet reactivity in patients prescribed clopidogrel. Variable levels of active metabolite generation can be caused by smoking, drugs that stimulate or inhibit CYP450 isoenzymes (2C19, 1A2, 2B6, 2C9, 3A4) involved in the conver-sion of clopidogrel to its active metabolite and genetic polymorphisms involving CYP450 isoenzymes and ABCB1, the p-glycoprotein ef? ux transporter gene
involved in GI absorption of clopidogrel. 186
A reduced laboratory response to clopidogrel has been observed following coadministration of CYP3A4-metabolized statins
187and CYP2C19-metabolized proton pump inhibitors,
188 but the clinical relevance of these pharmacodynamic interactions remains uncertain because observational studies and post hoc analyses of randomized trials have yielded con-? icting results.
189-194 In the COGENT (Clopidogrel and the Optimization of Gastrointestinal Events) trial, 3,861 patients with an indication for dual anti-platelet therapy were randomly assigned to receive
omeprazole or placebo.
191 Omeprazole reduced the rates of GI events, including GI bleeding, by .60%,but the primary vascular outcome, a composite of MI, revascularization, stroke, or cardiovascular death, occurred in a similar proportion of patients in each treatment group (HR, 0.99; 95% CI, 0.68-1.44). These results provide no evidence for a clinically important
interaction between omeprazole and clopidogrel. 191
M ultiple observational studies have demonstrated an association between loss-of-function polymor-phisms involving CYP2C19 and the risk of thrombotic events. In an individual patient meta-analysis of nine such studies involving 9,685 patients with ACS or
undergoing PCI, Mega and colleagues 195demonstrated
a signi? cantly increased risk of MI, stroke, or cardio-vascular death in carriers compared with noncarriers of one (HR, 1.55; 95% CI, 1.11-2.17) and two (HR, 1.76;
pharmacokinetic and pharmacodynamic features, a loading dose (eg, 300 mg) of clopidogrel results in more-rapid platelet inhibition than is achieved with
the 75-mg dose. 181 After loading with 600 mg of
clopidogrel, the full antiplatelet effect of the drug
was achieved after 2 to 4 h. 182 Moreover, a loading
dose of 600 mg resulted in higher plasma concen-trations of the active metabolite and the inactive carboxyl metabolite compared with a loading dose
of 300 mg. 183 Inhibition of ADP-induced platelet
aggregation was also signi? cantly greater with a 600-mg loading dose of clo p idogrel compared with
a 300-mg loading dose.
183-185 The incremental anti-platelet effect of 900 mg over 600 mg of clopidogrel
appears marginal 183,185 possibly because of limited drug absorption. 183
T he active metabolite of clopidogrel has a pharma-codynamic pattern similar to that of aspirin; there is cumulative inhibition of platelet function with repeated daily administration of low doses. Platelet function does not return to normal until 7 to 10 days after the last dose of clopidogrel. Both the cumulative nature of the inhibitory effects and the slow rate of recovery of platelet thromboxane production (aspirin) or ADP-induced platelet aggregation (clopidogrel) are consistent with permanent inhibition of COX-1 and the P2Y12 receptor, respectively, by the active moieties of aspirin and clopidogrel (active metabo-lite). This also justi? es a once-daily regimen for aspi-rin and clopidogrel in patients with normal rates of platelet turnover, despite the short half-life of both drugs in the circulation. It should be noted, however, that although aspirin currently is used at doses that represent a 2.5- to 10-fold excess over the 30-mg dose necessary to fully inactivate platelet COX-1 activity
on repeated daily dosing, 28,35 clopidogrel is used at
doses that produce only partial inhibition of the P2Y12 receptor. Thus, the main determinants of the interindividual variability in the antiplatelet effects of the two drugs are also likely to be substantially dif-ferent ( T able 6 ).
T able 6— M ain Determinants of the Interindividual Variability in the Antiplatelet Effects of Aspirin and
Clopidogrel
Determinant
Aspirin Clopidogrel
Dependence on systemic bioavailability No Yes Dependence on liver metabolism to active moiety
No Yes Ratio of recommended dose: minimum effective dose for full pharmacodynamic effect
2-3
1
Relevance of pharmacodynamic interactions at the target site
Yes ?Relevance of genetic polymorphisms
affecting drug absorption or metabolism No
Yes
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no evidence to support the use of platelet function or
genetic testing to individualize antiplatelet therapy. The Gauging Responsiveness With a Verify Now Assay-Impact on Thrombosis and Safety (GRAVITAS) trial found no evidence of reduced cardiovascular outcomes or stent thrombosis when double-dose clopidogrel was given to patients with high residual platelet reactivity after implantation of a drug-eluting
stent despite aspirin plus usual-dose clopidogrel. 199
Several trials currently under way are testing the hypothesis that adjusting therapy in response to the results of platelet function testing can improve clin-ical outcomes. 200 Ongoing trials are also evaluating
the possible bene? t of a genotype-guided strategy for the management of patients at risk for poor outcomes either because they have already had an adverse event (eg, stent thrombosis) or because of other high-risk characteristics, such as diabetes mellitus, chronic
renal failure, or angiographic high-risk features. 198 4.2.3 Ef? cacy and Safety: T he clinical development
of clopidogrel was unusual because the phase 2 studies were limited and its approval was based on a single, large phase 3 trial, which compared the ef? cacy and safety of clopidogrel (75 mg/d) with those of aspirin
(325 mg/d). 201 The Clopidogrel vs Aspirin in Patients at
risk for Ischemic Events (CAPRIE) trial included three groups of patients at increased risk of recur-rent ischemic events, with each group involving ? 6,400 patients: those who had experienced a recent stroke, those with a recent MI, and those with symp-tomatic peripheral arterial disease. Compared with aspi-rin in the overall CAPRIE study population of 19,185 high-risk patients, clopidogrel reduced the relative risk of MI, ischemic stroke, or vascular death by 8.7% (95% CI, 3%-65%) and the absolute risk by 0.51%. B oth clopidogrel and medium-dose aspirin therapy
were well tolerated in the CAPRIE study. 201The inci-dence of early permanent discontinuation of study
drug due to adverse events was 12% in both groups. Similarly, the overall incidence of hemorrhagic events was 9.3% in both groups. No excess neutropenia was found in the clopidogrel group, and the incidence of thrombocytopenia was identical in the clopidogrel and aspirin groups. On the basis of these ? ndings, clopidogrel has been approved for the reduction of atherosclerotic events in patients with recent stroke, recent MI, or established peripheral arterial disease. TTP is rare but can occur after the initiation of clo-pidogrel therapy; when TTP occurs, its onset is usu-ally within 2 weeks of initiation of treatment. 202
B ecause clopidogrel and aspirin act on distinct and complementary pathways of platelet activation, combi-nation therapy has been evaluated in high-risk clinical
settings. 203-208 The CURE trial 208randomly assigned 12,562 patients with ACS without ST-segment elevation
95% CI, 1.24-2.50) reduced-function CYP2C19 alleles. The greatest effect of carriage of the loss-of-function alleles was on the incidence of stent thrombosis. Overall, 71.5% of subjects included in the trials were noncarriers, 26.3% had one reduced-function CYP2C19 allele, and 2.2% had two reduced-function CYP2C19 alleles. I n contrast to the ? ndings of observational studies, 195 genetic analyses of three randomized trials, Study of Platelet Inhibition and Patient Outcomes (PLATO) and CURE in patients with ACS and ACTIVE A in patients with atrial ? brillation, did not demonstrate an interaction between CYP2C19 loss-of-function carrier status and randomized clopidogrel treatment
of any outcome, including stent thrombosis.
196,197In the PLATO genetics study involving 10,285 patients with ACS randomized to receive ticagrelor or clopid-ogrel, estimates of relative risk for primary outcome of MI, stroke, or cardiovascular death were similar irre-spective of CYP2C19 genotype (interaction P 5 .46), and likewise, no interaction was found for ABCB1 genotype or for the gain-of-function CYP2C19*17 allele.196 In the CURE genetics study involving 5,059 patients with ACS randomized to receive clo-pidogrel or placebo, the effect of clopidogrel in reducing the rate of the primary ef? cacy outcome of MI, stroke, or cardiovascular death was similar in patients who were heterozygous or homozygous for loss-of-function alleles and in those who were not car-riers of these alleles. 197 In contrast, carriers of gain-of-function alleles derived more bene? t from clopidogrel
treatment compared with placebo than did noncar-riers, although this ? nding was only nominally signif-icant (interaction P 5 .02). Among 1,156 genotyped patients with atrial ? brillation in the ACTIVE A trial, there was no evidence of an interaction with respect to either ef? cacy or bleeding between CYP2C19
genotype and study treatment. 197
O ne proposed explanation for the discrepant ? nd-ings of observational and randomized clopidogrel genetic studies is that only 14.5% of patients in the CURE trial underwent PCI, and the ACTIVE A trial enrolled patients with AF at relatively low risk of
thrombotic events. 198 However, this explanation cannot
account for lack of a signi? cant interaction between CYP2C19 loss-of-function polymorphisms and ran-domized clopidogrel treatment in the PLATO trial, which included high-risk patients with ACS of whom
two-thirds underwent PCI. 196 An alternative potential
explanation is that the association between carriage of a loss-of-function allele and outcome is confounded or that loss-of-function alleles have pleiotropic effects (ie, independent of their effects on the levels of the active metabolite of clopidogrel) on clinical outcome. A s is the case for high on-treatment platelet reac-tivity in patients prescribed aspirin, there currently is
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600-mg loading dose on day 1 followed by 150 mg/d for 6 days and 75 mg/d thereafter) or standard-dose clopidogrel (a 300-mg loading dose and 75 mg/d there-after) and either higher-dose aspirin (300-325 mg/d) or lower-dose aspirin (75-100 mg/d). The results of the aspirin dose comparison have been reviewed earlier. In the clopidogrel dose comparison, the rates of the primary outcome of MI, stroke, or vascular death were similar in patients receiving double-dose com-pared with standard-dose clopidogrel (4.2% vs 4.4%; H R, 0.94; 95% CI, 0.83-1.06; P 5 .30), but in the 17,263 patients who underwent PCI, double-dose clopidogrel reduced stent thrombosis (1.6% vs 2.3%; HR, 0.68; 95% CI, 0.55-0.85; P 5 .001) at the cost of an increase in major bleeding (2.5% vs 2.0%; H R,
1.24; 95% CI, 1.05-1.46). 209These results suggest that
there is a bene? t of more rapid and complete platelet inhibition with double-dose clopidogrel during the acute phase in patients presenting with ACS. I n contrast to the consistent ? nding of a favorable bene? t/risk pro? le of dual antiplatelet therapy in
patients with ACS,
204,206,208 the same strategy was not proven successful when compared with aspirin alone in stable patients at high risk for atherothrombotic events 203 or with clopidogrel alone in patients after a
recent ischemic stroke or TIA. 205Although there
might be mechanistic reasons underlying this apparent heterogeneity in treatment effects, it is important to emphasize that the size of the additional bene? t associated with dual antiplatelet therapy compared with aspirin alone in patients with ACS is only a frac-tion (about one-third) of the bene? t associated with aspirin compared with no antiplatelet therapy in this population. Perhaps more importantly, both the
CURE 208 and the COMMIT
204investigators tested realistic hypotheses of relative risk reduction (17% and 10%, respectively) and observed reductions (20% and 9%, respectively) that were consistent with these conservative estimates. In contrast, both the Man-agement of Atherothrombosis With Clopidogrel in
High Risk Patients (MATCH) 205 and the Clopidogrel
for High Atherothrombotic Risk and Ischemic Stabili-zation, Management, and Avoidance (CHARISMA) 203 investigators tested overly optimistic expectations of risk reduction and actually observed only a fraction (approximately one-third to one-half) of the expected bene? t.
T he combination of clopidogrel and aspirin has also been compared with oral anticoagulation with a
vitamin K antagonist 105 and with aspirin alone
106in the ACTIVE trial program. The primary outcome in both trials was the composite of stroke, non-CNS systemic embolism, MI, or vascular death. The 6,706-patient ACTIVE W trial was stopped early by the data monitoring committee because of clear evi-dence of superiority of warfarin over the combination
who presented within 24 h of symptom onset to receive clopidogrel (300-mg loading dose followed by 75 mg once daily) or placebo in addition to aspirin (75-325 mg/d) for 3 to 12 months. After a mean duration of treatment of 9 months, the primary outcome (a com-posite of cardiovascular death, nonfatal MI, or stroke) occurred in 9.3% of the patients in the clopidogrel group and 11.4% of those given placebo (RR, 0.80; 95% CI, 0.72-0.90; P , .001). The bene? t of clopidogrel was apparent within the ? rst 30 days after randomization and remained constant during the 12 months of the study. There were signi? cantly more patients with major bleeding in the clopidogrel group than in the placebo group (3.7% vs 2.7%; P 5 .001). T he clinical bene? t of dual antiplatelet therapy over aspirin alone has been con? rmed in patients undergoing PCI (Clopidogrel for the Reduction of
Events During Observation [CREDO]) 207 and in those
presenting with an acute ST-segment elevation MI within 12 h (Clopidogrel and Metoprolol Myocardial
Infarction Trial [COMMIT]) 204 to 24 h (Clopidogrel
as Adjunctive Reperfusion Therapy [CLARITY] trial) 206 after the onset of symptoms. In the COMMIT trial, 204 the addition of clopidogrel (75 mg/d) to aspi-rin (162 mg/d) reduced mortality and major vascular events in the hospital by 9% (95% CI, 3%-14%), cor-responding to nine fewer events per 1,000 patients with MI treated for ? 2 weeks. Overall, when all transfused, fatal, or cerebral bleeds were considered, there was no signi? cant excess risk associated with the use of clopidogrel during the scheduled treat-ment period (0.58% clopidogrel plus aspirin vs 0.55% aspirin alone, P 5 .59), nor was there any excess of major bleeds in patients aged . 70 years or in those
given ? brinolytic therapy before randomization. 204
Clopidogrel, however, was associated with a small, but signi? cant excess of 4.7 (95% CI, 1.4-8.0) minor bleeds per 1,000 patients treated. Taking major and minor bleeds together, there was no apparent trend
with respect to age in the excess risk of bleeding.
204 Factors that may have contributed to the remarkable safety of dual antiplatelet therapy in the COMMIT trial include the lack of a loading dose of clopidogrel, the uniform use of low-dose aspirin (162 mg/d), and the short duration of treatment.
E vidence for a more rapid onset of action and greater platelet inhibition with the use of a 600-mg
rather than a 300-mg loading dose of clopidogrel 185
and growing concern about the possibility that a sub-stantial proportion of patients achieve suboptimal inhibition of platelet function with conventional doses of clopidogrel prompted the CURRENT-OASIS 7 trial. This two-by-two factorial study, which enrolled 25,086 patients with ACS who were referred for an invasive management strategy, randomized such patients to receive either double-dose clopidogrel (a
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CHEST / 141 / 2 / FEBRUARY , 2012 SUPPLEMENT e 107S
trial, which involved 13,608 patients with ACS
scheduled to undergo PCI, prasugrel (60-mg loading dose followed by 10 mg/d) was compared with standard-dose clopidogrel (300-mg loading dose followed by 75 mg/d). Compared with clopidogrel, prasugrel reduced the composite primary outcome of MI, stroke, or cardiovascular death (9.9% vs 12.1%; HR, 0.81; 95% CI, 0.73-0.90) as well as stent throm-bosis (1.1% vs 2.4%, P , .001) but did not reduce over-all mortality and increased major, life-threatening, and fatal bleeding. Secondary analyses suggested that the greatest bene? ts of prasugrel occurred in patients with ST-segment-elevation MI, a setting in which rapid and complete platelet inhibition is critical, and in those with diabetes, a patient population consistently documented to have high on-treatment platelet reactivity despite therapy with both aspirin and clopidogrel. The excess of bleeding with pras-ugrel re? ects its more rapid onset of action; its higher potency; and, possibly, its more consistent anti-platelet effects. The FDA approval of prasugrel came with a boxed warning regarding the risk of signi? cant or fatal bleeding. The drug is contraindi-cated in patients with active bleeding or with a his-tory of stroke. The Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes (TRILOGY ACS) trial is evaluating whether a more favorable bene? t/risk ratio
can be obtained by reducing the dose of prasugrel. 215
5.0 Glycoprotein IIb/IIIa Antagonists T he pharmacologic characteristics of the three
approved IV glycoprotein IIb/IIIa (GpIIb-IIIa) inhibitors abciximab, tiro? ban, and epti? batide are summarized in T able 7 . 5.1 Abciximab
A
bciximab is a humanized version of a Fab fragment of a murine antibody directed against GpIIb-IIIa. Blockade of GpIIb-IIIa with abciximab produces a
of clopidogrel plus aspirin for the prevention of major vascular events (3.9% vs 5.6% per year; RR, 1.44; 95% CI, 1.18-1.76), with similar rates of major bleeding. 105 The ACTIVE A trial, which included patients with atrial ? brillation who were deemed ineligible for warfarin therapy, demonstrated superi-ority of the combination of clopidogrel plus aspirin over aspirin alone for the prevention of major vascu-lar events (6.8% vs 7.6% per year; RR, 0.89; 95% CI, 0.81-0.98). The difference was primarily due to a 28% relative reduction in the rate of stroke with clopidogrel, but this was achieved at a cost of an increase in major bleeding (2.0% vs 1.3% per year; RR, 1.57; 95% CI, 1.29-1.92), including a two per
1,000 per year increase in intracranial bleeding. 106
The results of the ACTIVE trial program con? rm the superiority of anticoagulants over antiplatelet therapy for stroke prevention in patients with atrial ? brilla-tion but at the same time establish the superiority of dual antiplatelet therapy with clopidogrel plus aspirin over aspirin alone for this indication, thereby sup-porting a mechanistic role of platelets in cardioembo-lic stroke. 4.3 Prasugrel
4.3.1 Pharmacokinetics: P rasugrel is rapidly absorbed after oral ingestion and is rapidly converted to its active metabolite, which reaches peak concen-trations within 30 min of dosing. Absorption is unaf-fected by food. The active metabolite has a half-life of ? 4 h, and renal excretion is the major route for elim-ination of the metabolites. 210 The prasugrel active metabolite is converted to inactive metabolites by S-methylation and cysteine conjugation.
I nitial pharmacological studies with prasugrel in healthy individuals 211 and in patients with stable coro-nary artery disease 212 showed that prasugrel has a more
rapid onset of action than clopidogrel and achieves more consistent and complete inhibition of ADP-induced platelet aggregation. 211,212 The more rapid
onset of action of prasugrel may in part re? ect the hepatic conversion to its active metabolite by CYP450 enzymes in a single step, which contrasts with that of clopidogrel, which undergoes a two-step hepatic con-version process. 213 No evidence exists that polymor-phisms in CYP2C19 or the concomitant use of proton
pump inhibitors interfere with the metabolism of
prasugrel. 211,214 4.3.1 Ef? cacy and Safety:T he ef? cacy and safety
of prasugrel have been compared with those of clopidogrel in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocar-dial Infarction 38 (TRITON-TIMI 38). 214In this T able 7— C omparison of Glycoprotein IIb/IIIa
Inhibitors in Clinical Use
Abciximab
Tiro? ban
Epti? batide
Structure
Antibody Fab fragment
Nonpeptide Cyclic
heptapeptide
Molecular weight 48 kDa ,1 kDa ,1 kDa Onset Rapid Rapid Rapid Reversibility of platelet inhibitory effects Slow Rapid Rapid Drug half-life 10-30 min 2 h
2.5 h
Excretion Unknown
40%-70% renal
50% renal
深静脉血栓指南(中华医学会骨科)邱贵兴
中国骨科大手术静脉血栓栓塞症预防指南 中华医学会骨科学分会 通信作者：邱贵兴E-mail: qguixing@https://www.360docs.net/doc/666725975.html, 骨科大手术后静脉血栓栓塞症（venous thromboembolism，VTE）发生率较高，是患者围手术期死亡的主要原因之一，也是医院内非预期死亡的重要原因。对骨科大手术患者施以有效的预防方法，不仅可以降低发生静脉血栓栓塞症的风险，减轻患者痛苦，大量的医药经济学研究证实还可降低医疗费用[1]。为提高与骨科相关的静脉血栓栓塞症的预防水平、规范预防方法，特制订“中国骨科大手术静脉血栓栓塞症预防指南”。本指南中的“骨科大手术”特指人工全髋关节置换术（total hip replacement，THR）、人工全膝关节置换术（total knee replacement，TKR）和髋部周围骨折手术（hip fractures surgery，HFS）[2]。本指南仅为学术性指导意见，具体实施时必须依据患者的医疗情况而定。 一、概述 1. 静脉血栓栓塞症：指血液在静脉内不正常地凝结，使血管完全或不完全阻塞，属静脉回流障碍性疾病[3]。包括两种类型：深静脉血栓形成（deep vein thrombosis，DVT）和肺动脉血栓栓塞症（pulmonary thromboembolism，PTE），即静脉血栓栓塞症在不同部位和不同阶段的两种临床表现形式。 2. 深静脉血栓形成：可发生于全身各部位静脉，以下肢深静脉为多，常见于骨科大手术后。下肢近端（腘静脉或其近侧部位）深静脉血栓形成是肺栓塞血栓栓子的主要来源，预防深静脉血栓形成可降低发生肺动脉血栓栓塞症的风险。 3. 肺动脉血栓栓塞症：指来自静脉系统或右心的血栓阻塞肺动脉或其分支导致的肺循环和呼吸功能障碍疾病[4,5]，是骨科围手术期死亡的重要原因之一。 4. 骨科大手术后静脉血栓栓塞症的流行病学：国外骨科大手术后静脉血栓栓塞症的发生率如表1所示[2]。一项亚洲7个国家19个骨科中心407例人工全髋、人工全膝关节置换及髋关节周围骨折手术后深静脉血栓形成发生率调查研究[6]表明，经静脉造影证实深静脉血栓形成发生率为43.2%（120/278）。国内邱贵兴等[7]的一项多中心研究结果显示，关节置换术后深静脉血栓形成的发生率在未预防组为30.8%（16/52）、预防组为11.8%（8/68）。余楠生等[8]报告髋关节置换术后深静脉血栓形成的发生率为20.6%（83/402），膝关节置换术后为58.2%（109/187）。吕厚山等[9]报告髋关节和膝关节置换术后深静脉血栓形成发生率为47.1%（24/51）。陆芸等[10]报告股骨干骨折术后深静脉血栓形成的发生率为30.6%，髋部骨折术后为1 5.7%。 二、静脉血栓栓塞症的危险因素 任何引起静脉损伤、静脉血流停滞及血液高凝状态的原因都是静脉血栓栓塞症的危险因素，其中骨科大手术是静脉血栓栓塞症的极高危因素[11,12]其他常见的继发性危险因素包括老龄、创伤、既往静脉血栓栓塞症病史、肥胖、瘫痪、制动、术中应用止血带、全身麻醉、恶性肿瘤、中心静脉插管、慢性静脉瓣功能不全等。少见的原发性危险因素有抗凝血酶缺乏症等。危险因素越多，发生静脉血栓栓塞症的风险就越大，当骨科大手术伴有其他危险因素时，危险性更大。骨科手术的静脉血栓栓塞症危险分度如表2所示[13,14]。 三、预防骨科大手术深静脉血栓形成的措施 对接受骨科大手术患者需常规进行静脉血栓预防。预防方法包括基本预防、物理预防和药物预防。 1. 基本预防措施[15,16]：（1）手术操作尽量轻柔、精细，避免静脉内膜损伤；（2）规范使用止血带；（3）术后抬高患肢，防止深静脉回流障碍；（4）常规进行静脉血栓知识宣教，鼓励患者勤翻身、早期功能锻炼、下床活动、做深呼吸及咳嗽动作；（5）术中和术后适度
(美国胸科医师学会)ACCP第三版指南精要之肺部小结节的评估
ACCP第三版指南精要之肺部小结节的评估 南京军区南京总医院呼吸内科姚艳雯宋勇 肺癌是目前致死率第一位的肿瘤[1]。究其原因，许多病人在诊断已发生转移是其中一重要因素。若能在早期即进行诊断，必定能降低肺癌的死亡率[2]。而肿瘤的最初起病可能就只表现为肺部的结节，临床医生或患者本身稍一疏忽，可能便会延迟肺癌的诊断。在临床中，我们不难发现，体检发现的肺部小结节并不少见，但这样的肺部结节是否是肺癌？如何对肺部结节进行评估？这是临床上的难点也是重点[2]。最新的第三版ACCP（美国胸科医师学会）指南，单独分出一部分来详述肺部结节的评估，由此为临床应用提供很大帮助[3]。 目前国内外公认的肺部结节的定义是：小的、成灶的、圆形、实质或混合性的影像学不透明影[4]。其中一部分为孤立性肺结节：单一的、边界清楚的、影像不透明的、直径小于或等于3cm、周围完全由含气肺组织所包绕的病变，没有肺不张、肺门增大或胸腔积液表现的肺部结节[5]。直径大于3cm的肺部局灶性改变被称为肺部团块，并且被认为是支气管源性的肿瘤可能大，因讨论的较多，这里略去不谈[6]。另外，因弥漫性的肺部结节或大于10个的肺部结节通常伴随着症状，并提示着肺外恶性疾病的转移或急性感染或炎症，因此也不再进一步讨论[3, 7]。此篇主要讨论的是无症状的肺部结节的评估。 ACCP指南所提出的肺部结节的评估全部是针对无法确定良恶性的结节[3]。因为直径小于等于8mm的结节恶性程度相对较低，因此将这部分结节从肺部结节中单独分类出来。另外就性质而言，实质性结节和亚实质性结节也分类开来，亚实质性结节进一步被分为纯磨玻璃样影或部分实质混合。在评估病人的肺部结节时，应将重点放在结节的大小、形态及恶性疾病的危险因素和是否合适进行后续治疗这些方面。 当胸部X平片或胸部CT提示可见性的不明性质的结节时，应首先回顾该病人的既往影像学资料[8]。如果影像学提示不明性质的实质性结节稳定2年以上，则不需做进一步的诊断检查。若该结节为胸部X平片所发现，则需要作进一步的胸部CT检查，以帮助明确结节性质[9]。 大于8mm的实质性结节 根据先前所述的肺部结节分类，对大于8mm的实质性结节，临床医生应对结节的检测前恶性概率进行评价，或者通过临床判断进行定性分析，或者通过经过认证的模型进行定量分析[3, 10]。当评估认为大于8mm的实质性结节的恶性概率低（5%-65%）时，可进行功能影像检查，推荐PET，来定义结节的性质。而对恶性概率较高（>65%）的大于8mm的实质性结节而言，可利用PET进行恶性结节的治疗前分期，但不能通过功能影像分析结节特征，此时需要临床医生对后续的不同诊断策略的获益和风险进行权衡，并且要注重患者的本身意愿[9]。 后续处理策略主要包括三个部分：CT扫描监测、非手术性的活检、外科诊断[3, 4, 11]。对于大于8mm 的实质性结节而言，CT扫描监测将应用于以下情况：1.临床恶性概率很低（<5%）时；2.临床恶性概率低（30%-40%以下），并且功能影像阴性（如，PET上代谢不高或动态增强CT上增强不超过15个hounsfield 单位）提示检测后恶性概率很低时；3.细针活检无法诊断并且PET上代谢不高时；4.向患者全面告知病情后患者自己选择该项非侵入性处理方案时。以上情况下，CT扫描监测应选用非增强的低剂量扫描，频率在3到6个月，9到12个月及18到24个月时[12]。当结节在监测扫描时提示具有明显的恶性增长时，除非特殊紧急，否则需要考虑行非手术性的活检和/或外科手术切除以帮助诊断[13, 14]。
美国最佳医生心胸外科CraigJ.Baker.
美国心胸外科最佳医生 Craig J. Baker医学博士 克雷格·贝克医学博士（Dr.Craig J. Baker，MD），现任洛杉矶县南加州大学医学中心(LA County USC Medical Center)心脏外科主任医师，并兼任南加州大学凯克医学院(USC, Keck School of Medicine)的临床外科教授。他于杜兰大学人文科学学院(Tulane University, College of Arts and Sciences)获得生物学学士学位，继而进入华盛顿乔治城大学医学院(Georgetown University, School of Medicine)获得医学博士学位，毕业后在南加州大学凯克医学院实习，完成了长达7年的医学训练，其中包括3年的心胸外科住院医师训练。此外，他还在在洛杉矶儿童医院(CHLA)完成了儿童心胸外科专科临床培训。 贝克教授擅长心胸外科手术、心血管疾病、胸外科手术，并专精于儿童和成人先天性心脏病（Pediatric And Adult Congenital cardiac Disease）、心脏移植（Cardiac Transplantation）、冠状动脉搭桥术，（Coronary Artery Bypass Grafting）、心脏瓣膜修复和更换（Valve Repair And Replacement），以及所有类型的复杂成人心脏手术（包括微创心脏瓣膜手术）等领域。
贝克教授是美国普通外科医学委员会(American Board of General Surgery)和美国胸外科医学委员会(American Board of Thoracic Surgery)双重认证的专科医师，亦是包括胸外科医师协会(Society of Thoracic Surgeons)在内的多个医学专业组织协会的资深研究员。他在成人和小儿心脏手术方面发表了大量的同行审阅性质医学论文和教科书章节，为许多权威医学专业期刊杂志和医学院所收录。 贝克教授目前执业于南加州大学医院（USC University Hospital）、洛杉矶儿童医院（Childrens Hospital Los Angeles）和南加州大学医疗保健咨询中心-2（USC Healthcare Consultation Center II）。临床治疗包括：先天性心脏病、心脏移植、冠状动脉旁路移植（冠脉搭桥手术）、心脏瓣膜修复和更换、微创瓣膜手术、复杂的成人心脏手术（所有类型）。 贝克教授于2012年获得美国医学界最高奖项之一的“卡斯尔康诺利最佳医师奖”(Castle Connolly's Top Doctors )，他在心脏外科手术领域拥有近20年临床经验，代表了当前世界级心脏外科手术的一流水平。
美国胸科医师协会第九版抗栓治疗及血栓预防指南静脉血栓栓塞性疾病最新进展
美国胸科医师协会第九版抗栓治疗及血栓预防指南静脉血栓栓塞性疾病最新进展 周玉杰， 杨士伟（首都医科大学附属北京安贞医院 心内科12病房，北京 100029） 通讯作者：周玉杰 E-mail：jackydang@https://www.360docs.net/doc/666725975.html, 静脉血栓栓塞性疾病（venous?thromboembolism ，VTE ）包括深静脉血栓（deep?venous?thrombosis ，DVT ）和肺栓塞（pulmonary?embolism ，PE ）。近日，美国胸科医师协会（American?College?of?Chest?Physicians ，ACCP ）在Chest 杂志上公布了第9版《抗栓治疗及血栓预防指南》（ACCP-9）[1-4]。此版指南在第8版基础上，结合最新循证医学证据，对抗栓治疗进行了全面细致的推荐。本文将结合ACCP-9对VTE 的最新进展进行阐述。1 病因与诱因 Virchow 于1856年提出了导致静脉血栓形成的三因素假说：静脉血流淤滞、血管损伤和高凝状态。经过大量试验证实，该假说目前已得到了公认。许多参与上述过程的临床情况均可诱发静脉血栓形成，主要包括： （1）肢体制动：各种疾病导致的长时间卧床或肢体制动，如急性心肌梗死、主要脏器功能衰竭、脑卒中、大型手术后等； （2）静脉受压：如股动脉或静脉穿刺术后压迫止血导致下肢静脉回流受阻，妊娠、腹腔巨大肿瘤或大量腹水导致盆腔静脉或下腔静脉回流受阻等；（3）静脉曲张：主要是指深静脉曲张，浅静脉曲张一般不会导致血栓形成； （4）静脉损伤：如外伤或手术累及静脉、静脉穿刺、静脉炎等； （5）高凝状态：各种遗传性或获得性血栓形成倾向，如抗凝因子缺乏（抗凝血酶Ⅲ、C 蛋白或S 蛋白最常见）、弥漫性血管内凝血（disseminated? intravascular?coagulation ，DIC ）、抗磷脂综合征、肾病综合征、恶性肿瘤、大量呕吐或腹泻导致的脱水、药物因素（长期口服避孕药、激素或抗肿瘤药物）等； （6）其他：如高龄、吸烟、肥胖等。2 病理与病理生理 以上因素往往不是孤立的，而是多种因素同时存在，相互影响，有时很难明确始动因素，但静脉损伤通常是导致血栓形成的关键环节。内膜损伤以后迅速激活内源性和（或）外源性凝血途径，在损伤部位形成血栓（thrombosis ）。 血栓的起始部（即头部）主要由血小板及少量纤维蛋白构成，称为白血栓（pale?thrombus ）；血栓头部形成以后，下游血流缓慢和出现涡流，此时除血小板聚集以外，还有大量红细胞填充在纤维蛋白形成的网状结构内，称为混合血栓（mixed?thrombus ）；当混合血栓阻塞管腔以后，远端血流完全停止，血液凝固，此时血栓主要由纤维蛋白和红细胞构成，称为红血栓（red?thrombus ）。白血栓与血管壁结合紧密，不易脱落；而红血栓与血管壁黏附力差，容易脱落，形成栓塞（embolism ）。血液中存在凝血系统与抗凝血系统，凝血系统激活的同时抗凝血系统也被激活。因此在早期，血栓形成与溶解是一个动态过程，这一阶段血栓也最容易脱落而导致栓塞。如果促凝因素持续存在或血栓溶解不完全，未脱落的血栓可发生机化，血栓被肉芽组织取代。较大的血栓约2周可以完全机化，此时，血栓与血管壁紧密结合不易脱落，栓塞危险显著降
ACOG临床指南深静脉血栓和肺栓塞的预防
ACOG临床指南——深静脉血栓和肺栓塞的预防（84号，2007年8月） 2011年更新：本指南由ACOG临床指南学术委员会编写。本指南的内容用于协助妇产科临床医生在工作中处理相应的临床问题。本指南并非唯一的临床处理流程。在具体临床实施过程中，应根据患者的个体情况、本身经济情况，以及医疗机构的具体条件，对本指南内容进行相应的变化。 深静脉血栓和肺栓塞的预防 尽管对于静脉血栓栓塞症的预防、诊断、治疗都有所进展，但它依旧是导致术后或住院患者致残或致死的主要原因之一（1-3）。静脉血栓通常表现为深静脉血栓（DVT，deep venous thrombosis）或肺栓塞（PE，pulmonary）。除急诊情况以外，静脉血栓栓塞症还导致某些慢性病症，如血栓后症状、静脉缺血和肺动脉高压。本指南根据目前关于妇产科患者血栓预防的文献，为临床决策提供有循证基础的建议。 背景 流行病学及目前研究现状 深静脉血栓（DVT）和PE均属于静脉血栓栓塞症的范畴。接受大的妇科手术患者DVT的发生率为15-40%（4）。无症状DVT与发生临床症状显著的肺栓塞高度相关（5）。大多数死于肺栓塞患者躲在发
病30分钟内死亡，可供医疗干预的时间非常有限。因此，临床医生应该主要关注对高危患者的确定，以及制定统一、有效的血栓预防方案，由此来减少这种多发的，通常情况下可以预防的死亡原因。 美国每年诊断DVT的患者达20,00,000，这些患者中约1/3将发展成肺栓塞，每年导致约60,000例患者死亡（6）。每年每1,000人中约1-2人首次发生静脉血栓栓塞症（7,8）。肺栓塞的病人死亡率为11-12%，该比率在年轻患者稍低，而肿瘤患者更高（8,9）。此外，卧床患者发生静脉血栓栓塞症的概率增加约9倍（10）。住院和手术均增加血栓发生风险，其OR值分别为和（10）。 最近一项研究，针对2,000例以上接受手术的癌症患者，结果显示，尽管80%以上住院患者应用血栓预防措施，但仍有2%的患者发生临床上静脉血栓栓塞症（11）。术后35天内总死亡率为%。尽管有预防措施，仍有46%患者死于静脉血栓栓塞性疾病。鉴于这种情况，确定高危患者非常重要，因为通过积极的预防血栓措施能够降低潜在的致死性血栓栓塞性疾病的风险。高危因素如下： 静脉血栓栓塞性疾病的高危因素 手术 创伤（大范围的或下肢的） 瘫痪
美国儿科学会母乳喂养和母乳使用的政策陈述
美国儿科学会关于母乳喂养和母乳使用的政策陈述 （武汉市疾病预防控制中心） 摘要：母乳喂养和人奶是婴儿喂养和营养供给的标准规范。因为母乳喂养在神经系统发育及其他的健康方面具有短期和长期的优势，所以婴儿营养应该是一项公共卫生的问题，而不是单纯的喂养方式的选择。 美国儿科学会重申：推荐6个月的纯母乳喂养，6个月添加辅食后继续母乳喂养，并可根据母婴双方的需要喂养至一年或一年以上。 母乳喂养在医学上的禁忌症很少。婴儿的生长发育应参考世界卫生组织（the World Health Organization，WHO）生长发育标准曲线，避免对婴儿低体重或发育迟缓的误诊。 医疗单位需根据美国儿科学认可的WHO/UNICEF“母乳喂养成功实现十步骤”来鼓励和支持初始的和持续的母乳喂养。美国卫生总署（US Surgeon General）的“行动呼吁”计划、美国疾病预防与控制中心（CDC）和美国医疗机构评鉴联合会（The Joint Commission）所支持的国家战略中，也涉及到在美国医院和社区中推广母乳喂养方面的行动。 儿科医生作为母乳喂养的倡导者在其执业过程和社区活动中对母乳喂养起到了重 要作用，所以儿科医生应知道非母乳喂养的健康风险，母乳喂养在社会经济上的益处，以及实现和支持母乳喂养所需要的技能。“职场母乳喂养”详细讲述了职场妈妈怎样维持哺乳喂养，以及支持母乳喂养对雇主们的好处。 关键词：母乳喂养；辅食添加；婴儿营养；哺乳；母乳；护理 缩略词：AAP——美国儿科学会 AHRQ——美国医疗保健研究与质量局 CDC——疾病预防控制中心 CI——可信区间 CMV——巨细胞病毒 DHA——二十二碳六烯酸 NEC——坏死性小肠结肠炎 OR——比值比
深静脉血栓形成的诊断和治疗指南第三版
深静脉血栓形成的诊断和治疗指南（第三版） 2017-10-11 摘自：中华普通外科杂志2017 年9 月第32 卷第9 期 作者：中华医学会外科学分会血管外科学组 深静脉血检形成（DVT)是血液在深静脉内不正常凝结引起的静脉回流障碍性疾病，常发生于下肢。血栓脱落可引起肺动脉栓塞（PE)，DVT与PE统称为静脉血栓栓塞症（VTE)，是同种疾病在不同阶段的表现形式。DVT的主要不良后果是PE和血栓后综合征（PTS)，它可以显著影响患者的生活质量，甚至导致死亡。因此，为了提高我国DVT的诊治水平，指导和规范各级医院对DVT的诊治工作，特制订本指南。 DVT的主要原因是静脉壁损伤、血流缓慢和血液高凝状态。危险因素包括原发性因素（表1)和继发性因素（表2)。DVT多见于大手术或严重创伤后、长期卧床、肢体制动、肿瘤患者等。
根据发病时间，DVT分为急性期、亚急性期和慢性期。急性期是指发病14天以内；亚急性期是指发病15～30天；发病30天以后进人慢件期；早期DVT包括急性期和亚急性期。 急性下肢DVT主要表现为患肢的突然肿胀、疼痛等，体检患肢呈凹陷性水肿、软组织张力增高、皮肤温度增高，在小腿后侧和/或大腿内侧、股三角区及患侧髂窝有压痛。发病1～2周后，患肢可出现浅静脉显露或扩张。血栓位于小腿肌肉静脉丛时，Homans征和Neuhof征呈阳性。 Homans征:患肢伸直，足被动背屈时，引起小腿后侧肌群疼痛，为阳性。 Neuhof征:压迫小腿后侧肌群，引起局部疼痛，为阳性。严重的下肢DVT,患者可出现股青肿，是下肢DVT中最严重的情况，由于髂股静脉及其属支血栓阻塞，静脉回流严重受阻，组织张力极高，导致下肢动脉受压和痉挛，肢体缺血。临床表现为下肢极度肿胀、剧痛、皮肤发亮呈青紫色、皮温低伴有水疱，足背动脉搏动消失，全身反应强烈，体温升高。如不及时处理，可发生休克和静脉件坏疽。 静脉血栓一旦脱落，可随血流漂移、堵塞肺动脉主干或分支，根据肺循环障碍的不同程度引起相应PE的临床表现。
美国临床肿瘤学会癌症患者静脉血栓栓塞防治指南
解读美国临床肿瘤学会癌症患者静脉血栓栓塞防治指南癌症患者发生静脉血栓栓塞（VTE）的风险极高，并且早期死亡率高。由于药物的毒副作用及循证证据结果的多样化，因此针对这类人群有效安全的预防VTE面临巨大的挑战。2007年美国临床肿瘤学会颁布了最新关于癌症患者VTE的防治指南，进一步规范了癌症患者的抗凝治疗。（J Clin Oncol. 2007,25:5490） 癌症患者VTE的发生率高 VTE为癌症患者的主要并发症，发生率为4%~20%，并且可导致死亡。VTE包括深静脉血栓形成（DVT）及肺栓塞（PE）。癌症患者DVT的风险增加数倍，住院的癌症患者及正接受药物治疗的患者发生DVT的风险更大。基于人群的研究发现，癌症患者血栓形成的风险增加4.1倍，接受化疗的患者风险增加6.5倍。其实目前癌症患者VTE发生率（4%~20%）的报道远远低于尸解的发现，后者发生率为50%。 存在VTE的癌症患者死亡率高 一项回顾性观察研究提示，接受化疗的癌症患者，静脉和动脉血栓栓塞占死亡原因的9%。在发生VTE同时诊断癌症，或在发生VTE 1年内诊断的患者，1年时死亡率增加3倍。癌症患者接受外科手术，术后发生致命性PE的风险是接受同样手术非癌症患者的3倍。 癌症患者存在多个VTE危险因素 癌症患者发生VTE的危险因素因肿瘤的种类及自然病史的不同而异。恶性肿瘤诊断初期，VTE的风险最高。已有报道，某些部位的肿瘤，如胰腺、胃部、脑部、卵巢、肾脏、肺部肿瘤及已出现转移的肿瘤与VTE发生相关。最新研究提示，恶性血液系统疾病，特别是淋巴瘤与VTE发生显著相关。 接受活性药物治疗的癌症患者，VTE发生风险明显增加。使用新的抗肿瘤药物特别是抗血管再生的药物，VTE发生率较高。激素治疗特别是他莫西酚（tamoxifen）的应用及促红细胞刺激因子等可增加VTE的风险。癌症患者住院时VTE的风险明显增加。与非癌症患者相比，癌症患者接受外科手术，术后DVT风险增加2倍，致命性PE风险增加3倍。 其他可能的危险因素包括：化疗前血小板数量>350×109/L和存在致血栓的基因突变等（表1）。 表1 癌症患者VTE的危险因素 患者相关因素 高龄 种族 并存疾病（肥胖、感染、肾脏疾病、肺部疾病、动脉血栓栓塞） 既往VTE病史 化疗前血小板数量增加 遗传性致栓基因突变 肿瘤相关因素 原发肿瘤的部位（消化道、脑、肺、生殖系、肾脏、血液） 诊断后的最初3~6个月 肿瘤近期转移 治疗相关因素 近期接受大手术 正在住院 接受化疗 接受激素治疗 目前或近期接受抗血管再生治疗（thalidomide, lenalidomide）
深静脉血栓指南 ACCP指南解读
深静脉血栓指南 ACCP指南解读 推荐总则 1.4.3 我们推荐,机械性预防血栓方法主要应用于出血高风险的患者(1C级)或作为抗凝剂预防血栓的辅助方法(2A级)。我们推荐使用机械性装置必须谨慎,以确保正确和最佳的使用(1C 级)。 1.4.4 我们推荐,对于任何患者,都反对单独使用阿司匹林来预防血栓(1A级)。 1.4.5.1 对于每一种抗血栓药物,我们推荐,临床医师必须考虑生产厂家的剂量使用指南(1C 级)。 1.4.5.2 我们推荐,在决定低分子量肝素、合成戊糖(fondaparinux)、凝血酶直接抑制剂和其他抗血栓药物等由肾脏清除的药物剂量时,特别是对老年患者和有出血高风险的患者,应考虑其对肾功能的损害(1C级)。 1.5.1 我们推荐,对于接受神经轴麻醉或镇痛患者,使用抗凝剂预防时要特别小心(1C 级)。 2.0 普通外科手术、血管外科手术、妇产科手术和泌尿外科手术 2.1 普通外科手术 2.1.1 接受小手术、年龄小于40岁和无其他危险因素的低危普通外科患者,我们推荐,除早期和坚持活动外,不需特殊的预防(1C级)。 2.1.2 对于中度危险的普通外科患者,即年龄在40~60岁,而且接受非大型手术,或者有其他危险因素的患者,以及对于年龄在40岁以下、接受大手术而且无其他危险因素的患者,我们推荐,低剂量普通肝素5000 U,每天2次,或低分子量肝素≤3400 U,每天1次(1A级)。 2.1.3 对于接受非大型手术而且年龄大于60岁或者有其他危险因素,以及对于接受大型手术而且年龄大于40岁或有其他危险因素的更高危险普外科患者,我们推荐,低剂量普通肝素5000 U,每日3次,或低分子量肝素≥3400 U,每天1次(1A级)。
金贝口服液有望挽救肺纤维化患者
金贝口服液有望挽救肺纤维化患者 2019年12月18日济南日报记者刘文忠 发病率近年来不断上升的特发性肺纤维化（业内英文简称IPF），诊断后的平均生存期只有2.8年，不可逆+高死亡率，让它成了医学界公认的“不是癌症的癌症”。 服用进口西药，价格昂贵，毒副作用多，患者认可度不高；肺移植手术又面临供体、高额费用等问题。 中医药能否为治疗这种罕见病提供新的解决方案？传承精华，守正创新，来自济南的名老中医和制药企业宏济堂制药集团，正在加快技术攻关，组织有益尝试。 病因不明的“肺炎” “医生，我最近总是干咳，稍微活动一下，就感觉要窒息一样，喘不过气来。你给我看看，这是得了啥病了？”在某医院呼吸科，一位老年患者向医生诉说着自己的症状。 经过进一步观察、询问，这位患者不仅有干咳、呼吸困难、呼吸急促等外部表征，而且经常感到疲倦乏力，食欲不振，体重下降；手指、足趾末端还出现增生、肥厚现象，呈杵状膨大。 “经验不足的医生，很可能把它当成普通肺炎来治疗。因为从影像学检查或组织病理看，这些症状都是普通间质性肺炎的表现。”宏济堂中医院外聘专家陶凯教授说，“事实上，这是一种好发于中老年人的慢性、进行性、纤维化性间质性肺疾病，医学上叫做特发性肺纤维化（IPF）。” 国际上至今尚未查明IPF病因，其发病机制亦未完全阐明。医学界普遍认为，足够证据表明IPF与免疫炎症损伤有关，吸入物刺激与特定的遗传因素会增加IPF的患病风险，发病率男性高于女性，发病年龄通常在50-70岁之间。绝大多数IPF患者早期临床表现不典型，漏诊和延误诊断现象普遍，也易被误诊为慢阻肺、哮喘和充血性心力衰竭或其他肺部疾病。 2000年，美国胸科学会、欧洲呼吸学会、美国胸科医师协会首次确认IPF为一种独立的临床疾病。去年5月国家卫健委等5部门联合制定的《第一批罕见病
2019年深静脉血栓形成的诊断和治疗的指南
深静脉血栓形成的诊断和治疗指南 中华医学会外科学分会血管外科学组 第二届中国静脉论坛会议期间，由中华外科学分会血管外科学组责成安贞医院吴庆华教授负责制定我国的“DVT诊治指南”，后与第三届静脉论坛轮值主席董国祥共同承担本指南的制定，由吴庆华和罗小云执笔。本草案的制定历时两年余，经多次专家会议讨论修改。2 006年3月在三亚的第三届静脉论坛工作会议上形成初稿，后经200 5年11月26日和2007年6月11日北京医学会血管外科专业委员会会议以及2007年8月25日第三届中国静脉论坛预备会议等反复认真研究修改，2007年9月在北京举行的第三届中国静脉论坛的会议上全体通过。当然仍有不尽完美之处，也存在一定的意见分歧，留待以后不断修改，完善。我国血管外科著名专家(按姓氏拼音字母顺序排列)陈翠菊、陈忠、陈学明、董宗俊、董国祥、段志泉、符伟国、管珩、郭伟、谷涌泉、顾福杭、景在平、蒋米尔、姜维良、李大军、李俊海、李建新、李晓强、栗力、刘昌伟、刘鹏、刘长建、刘增庆、罗小云、马杰、潘松龄、钱水贤、时德、沈来根、王嘉桔、汪忠镐、王玉琦、王深明、吴庆华、吴丹明、辛世杰、苑超、余波、张柏根、张建、张福先、张纪蔚、张强、张静菊、赵春起等先后参加本指南的制定。
深静脉血栓形成(deep venous thrombosis，DVT)是血液在深静脉内不正常凝结引起的病症，多发生于下肢，血栓脱落可引起肺栓塞(p ulmonary embolism，PE)，合称为静脉血栓栓塞症(venous throboe mbolism，VTE)。DVT是常见的一种病症，后果主要是肺栓塞和DVT 后综合征，严重者可导致死亡和显著影响生活质量。国内临床对于D VT的诊断和治疗缺乏统一认识，疗效差异较大。为提高我国对DVT 的诊治和预防水平，我们制订了DVT诊治指南。 一、流行病学和危险因素目前国内还缺乏关于DVT发病率的准确统计资料。DVT的主要原因是静脉壁损伤、血流缓慢和血液高凝状态。其危险因素包括原发性因素(表1)和继发性因素(表2)。DVT多见于大手术或创伤后、长期卧床、肢体制动、晚期肿瘤患者或有明显家族史者。 表1 DVT的原发危险因素 表2 DVT的继发危险因素
美国意思协会-CKD指南
Screening,Monitoring,and Treatment of Stage 1to 3Chronic Kidney Disease:A Clinical Practice Guideline From the American College of Physicians Amir Qaseem,MD,PhD,MHA;Robert H.Hopkins Jr.,MD;Donna E.Sweet,MD;Melissa Starkey,PhD;and Paul Shekelle,MD,PhD,for the Clinical Guidelines Committee of the American College of Physicians* Description:The American College of Physicians (ACP)developed this guideline to present the evidence and provide clinical recom-mendations on the screening,monitoring,and treatment of adults with stage 1to 3chronic kidney disease. Methods:This guideline is based on a systematic evidence review evaluating the published literature on this topic from 1985through November 2011that was identified by using MEDLINE and the Cochrane Database of Systematic Reviews.Searches were limited to English-language publications.The clinical outcomes evaluated for this guideline included all-cause mortality,cardiovascular mor-tality,myocardial infarction,stroke,chronic heart failure,composite vascular outcomes,composite renal outcomes,end-stage renal dis-ease,quality of life,physical function,and activities of daily living.This guideline grades the evidence and recommendations by using ACP’s clinical practice guidelines grading system. Recommendation 1:ACP recommends against screening for chronic kidney disease in asymptomatic adults without risk factors for chronic kidney disease.(Grade:weak recommendation,low-quality evidence) Recommendation 2:ACP recommends against testing for protein-uria in adults with or without diabetes who are currently taking an angiotensin-converting enzyme inhibitor or an angiotensin II–receptor blocker.(Grade:weak recommendation,low-quality evidence) Recommendation 3:ACP recommends that clinicians select phar-macologic therapy that includes either an angiotensin-converting enzyme inhibitor (moderate-quality evidence)or an angiotensin II–receptor blocker (high-quality evidence)in patients with hyperten-sion and stage 1to 3chronic kidney disease.(Grade:strong recommendation) Recommendation 4:ACP recommends that clinicians choose statin therapy to manage elevated low-density lipoprotein in patients with stage 1to 3chronic kidney disease.(Grade:strong recommenda-tion,moderate-quality evidence) Ann Intern Med.2013;159:https://www.360docs.net/doc/666725975.html, For author affiliations,see end of text. This article was published online first at https://www.360docs.net/doc/666725975.html, on 22October 2013. C hronic kidney disease (CKD)is nearly always asymp-tomatic in its early stages (1).The most commonly accepted de?nition of CKD was developed by Kidney Dis-ease:Improving Global Outcomes (KDIGO)(2)and the Kidney Disease Outcomes Quality Initiative (KDOQI)(3)as abnormalities of kidney structure or function,present for more than 3months,with implications for health.Cri-teria for CKD include markers of kidney damage (albu-minuria,as indicated by an albumin excretion rate of 30mg/24h or greater and an albumin–creatinine ratio of 3mg/mmol or greater [?30mg/g]);urine sediment abnor-malities;electrolyte and other abnormalities due to tubular disorders;abnormalities detected by histologic examina-tion;structural abnormalities detected by imaging;history of kidney transplantation or presence of kidney damage;or kidney dysfunction that persists for 3or more months,as shown by structural and functional abnormalities (most often based on increased albuminuria,as indicated by a urinary albumin–creatinine ratio of 3mg/mmol or greater [?30mg/g])or a glomerular ?ltration rate (GFR)less than 60mL/min/1.73m 2for 3or more months. Traditionally,CKD is categorized into 5stages that are based on disease severity de?ned by GFR (3)(Table 1);stages 1to 3are considered to be early-stage CKD.People with early stages of the disease are typically asymptomatic,and the diagnosis is made by using laboratory tests or im-aging.In 2013,KDIGO revised CKD staging to consider both 5stages of GFR as well as 3categories of albuminuria to de?ne CKD severity (2). *This paper,written by Amir Qaseem,MD,PhD,MHA;Robert H.Hopkins Jr.,MD;Donna E.Sweet,MD;Melissa Starkey,PhD;and Paul Shekelle,MD,PhD,was developed for the Clinical Guidelines Committee of the American College of Physicians.Individuals who served on the Clinical Guidelines Committee from initiation of the project until its approval were Paul Shekelle,MD,PhD (Chair );Roger Chou,MD;Molly Cooke,MD;Paul Dallas,MD;Thomas D.Denberg,MD,PhD;Nick Fitterman,MD;Mary Ann Forciea,MD;Robert H.Hopkins Jr.,MD;Linda L.Humphrey,MD,MPH;Tanveer P.Mir,MD;Douglas K.Owens,MD,MS;Holger J.Schu ¨nemann,MD,PhD;Donna E.Sweet,MD;and Timothy Wilt,MD,MPH.Approved by the ACP Board of Regents on 17November 2012. See also: Print Summary for Patients.......................I-28Web-Only CME quiz
下肢深静脉血栓的正规治疗方案
下肢深静脉血栓的正规治疗方案 沃德医疗中心首席血管专家强访谈录记者：教授您好！从您的学生们和很多医学同行的口中得知，您是一位德艺双馨的血管外科专家。强：不敢当，不敢当。我只是愿意做一名病人喜欢的医生而已。为病人解除病痛的同时，自己身心也会得到愉悦。记者：我知道您平时很忙。今天想占用您的一点时间，给大家谈谈下肢深静脉血栓的话题好吗？强：没问题。我最愿意和大家聊医学上的东西。记者：前段时间，媒体上关于的某位教授在腰椎手术后出现意外死亡的话题引发了医务人员对静脉血栓的重视。据说，这位教授是因为下肢深静脉的血栓脱落后流到肺动脉，造成肺梗死而离开人世的。下肢深静脉血栓是怎么一回事呢？强：我也在一直在关注这个事件。这个悲剧给广大医务人员敲了警钟：一定要重视下肢深静脉血栓的预防。所谓下肢深静脉血栓形成，英文名为DVT（deep venous thrombosis），是指静脉管腔由于各种原因形成血凝块。下肢深静脉血栓形成的典型临床表现往往是单侧下肢（左下肢多见）出现肿胀、疼痛。但是血栓形成早期可以没有明显症状，这是静脉血栓容易被忽略的原因之一。记者：我的一位朋友母亲患了下肢静脉血栓，辗转多家医院。他抱怨每家医院的治疗方案和说法都不一样，令人无所适从。请问教授，怎么会出现这种情况呢？
强：下肢深静脉血栓在欧美国家称为DVT，在60年代就开始引起重视。很多普通老百姓也知道一些关于DVT的知识。我国真正重视DVT还是在近几年的事情。过去由于信息的闭塞和医疗界的一些错误认识，下肢深静脉血栓被漏诊、误诊的比例很高。每个医疗机构对下肢深静脉血栓的认识水平不同、理念上的差异，造成治疗方案的不同。记者：根据您的临床经验来看，有哪些认识方面的差异呢？强：首先是在发病时间的判断上。由于静脉系统存在大量的侧枝循环，早期的血栓形成并不会妨碍静脉血的顺利回流。只有血栓蔓延到一定长度，堵塞侧枝循环近远端开口的时候，才在临床上表现出下肢肿胀。所以说，一般临床上出现下肢肿胀才得到诊断的病例，往往发病时间已经超过数天。记者：发病时间的判断对治疗方案有什么指导意义吗？强：非常重要。静脉血栓就像水泥，及早可以冲洗掉，但是一旦结成凝块就无法溶解。这个比喻虽然不甚恰当，但是静脉血栓在形成数十小时之后就开始部分机化却是事实。机化的静脉血栓就很难用溶栓的方法去解决。手术取栓也很不适合，由于机化的血栓紧粘在静脉管壁上，强行取栓会导致静脉壁损伤造成更大围的血栓形成。因此，早期诊断非常重要。记者：那怎么样可以早期诊断下肢深静脉血栓呢？强：虽然早期深静脉血栓形成没有明显的症状，但是对于有经验的医生来说，还是可以通过仔细的体检发现一些蛛丝马迹的。比如，挤压小腿
美国外科住院医师培养简介
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