Disease : Antithrombotic Therapy and Prevention of ... · CHEST Supplement CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e669S ANTITHROMBOTIC THERAPY AND PREVENTION OF THROMBOSIS, 9TH

DOI 10.1378/chest.11-2307 2012;141;e669S-e690SChest

SpencerVandvik, Maarten G. Lansberg, Gordon H. Guyatt and Frederick A.Anand, Randolph Guzman, Michael H. Criqui, Elie A. Akl, Per Olav Pablo Alonso-Coello, Sergi Bellmunt, Catherine McGorrian, Sonia S. Clinical Practice Guidelines

Evidence-BasedCollege of Chest Physicians Prevention of Thrombosis, 9th ed: AmericanDisease : Antithrombotic Therapy and Antithrombotic Therapy in Peripheral Artery

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CHEST Supplement

www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e669S

ANTITHROMBOTIC THERAPY AND PREVENTION OF THROMBOSIS, 9TH ED: ACCP GUIDELINES

Background: This guideline focuses on antithrombotic drug therapies for primary and secondary prevention of cardiovascular disease as well as for the relief of lower-extremity symptoms and critical ischemia in persons with peripheral arterial disease (PAD). Methods: The methods of this guideline follow those described in Methodology for the Develop-ment of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement. Results: The most important of our 20 recommendations are as follows. In patients aged � 50 years with asymptomatic PAD or asymptomatic carotid stenosis, we suggest aspirin (75-100 mg/d) over no therapy (Grade 2B) for the primary prevention of cardiovascular events. For secondary prevention of cardiovascular disease in patients with symptomatic PAD (including patients before and after peripheral arterial bypass surgery or percutaneous transluminal angio-plasty), we recommend long-term aspirin (75-100 mg/d) or clopidogrel (75 mg/d) (Grade 1A). We recommend against the use of warfarin plus aspirin in patients with symptomatic PAD (Grade 1B). For patients undergoing peripheral artery percutaneous transluminal angioplasty with stenting, we suggest single rather than dual antiplatelet therapy (Grade 2C). For patients with refractory claudication despite exercise therapy and smoking cessation, we suggest addition of cilostazol (100 mg bid) to aspirin (75-100 mg/d) or clopidogrel (75 mg/d) (Grade 2C). In patients with crit-ical limb ischemia and rest pain unable to undergo revascularization, we suggest the use of pros-tanoids (Grade 2C). In patients with acute limb ischemia due to acute thrombosis or embolism, we recommend surgery over peripheral arterial thrombolysis (Grade 1B). Conclusions: Recommendations continue to favor single antiplatelet therapy for primary and secondary prevention of cardiovascular events in most patients with asymptomatic PAD, symp-tomatic PAD, and asymptomatic carotid stenosis. Additional therapies for relief of limb symptoms should be considered only after exercise therapy, smoking cessation, and evaluation for periph-eral artery revascularization. CHEST 2012; 141(2)(Suppl):e669S–e690S

Abbreviations: ABI 5 ankle brachial index; CAD 5 coronary artery disease; CAPRIE 5 Clopidogrel vs Aspirin in Patients at risk for Ischemic Events; MI 5 myocardial infarction; MWD 5 maximum walking distance; PAD 5 peripheral arterial disease; PTA 5 percutaneous transluminal angioplasty; RCT 5 randomized controlled trial; RR 5 risk ratio; rt-PA 5 recombinant tissue-type plasminogen activator

Antithrombotic Therapy in Peripheral Artery Disease Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

Pablo Alonso-Coello , MD , PhD ; Sergi Bellmunt , MD ; Catherine McGorrian , MBBCh , BAO ; Sonia S. Anand , MD , PhD ; Randolph Guzman , MD, RVT ; Michael H. Criqui , MD , MPH ; Elie A. Akl , MD , MPH , PhD ; Per Olav Vandvik , MD , PhD ; Maarten G. Lansberg , MD , PhD ; Gordon H. Guyatt , MD, FCCP ; and Frederick A. Spencer, MD


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e670S Antithrombotic Therapy in Peripheral Artery Disease

value preventing an MI substantially higher than avoiding a GI bleed, if they are in the moderate or high cardiovascular risk group, will be more likely to choose aspirin.

3.1-3.4. For secondary prevention patients with symptomatic PAD, we recommend one of the two following antithrombotic regimens to be contin-ued long term over no antithrombotic treat-ment: aspirin 75 to 100 mg daily or clopidogrel 75 mg daily (all Grade 1A) . We suggest not to use dual antiplatelet therapy with aspirin plus clopid-ogrel (Grade 2B) . We recommend not to use an antiplatelet agent with moderate-intensity war-farin (Grade 1B) .

4.1-4.4. For patients with intermittent claudi-cation refractory to exercise therapy (and smoking cessation), we suggest the use of cilostazol in addition to previously recommended antithrom-botic therapies (aspirin 75-100 mg daily or clopid-ogrel 75 mg daily) (Grade 2C) ; we suggest against the use of pent oxifylline, heparinoids, or pros-tanoids (Grade 2C) .

5.1. For patients with symptomatic PAD and critical leg ischemia/rest pain who are not can-didates for vascular intervention, we suggest the use of prostanoids in addition to previously recommended antithrombotic therapies (aspirin 75-100 mg daily or clopidogrel 75 mg daily) (Grade 2C) .

Values and preferences: Patients who do not value uncertain relief of rest pain and ulcer healing greater than avoidance of a high likelihood of drug-related side effects will be disinclined to take prostanoids.

6.1-6.3. In patients with acute limb ischemia due to arterial emboli or thrombosis, we sug-gest immediate systemic anticoagulation with unfractionated heparin over no anticoagula-tion (Grade 2C) ; we suggest reperfusion therapy (surgery or intraarterial thrombolysis) over no reperfusion therapy (Grade 2C) ; we recom-mend surgery over intraarterial thrombolysis (Grade 1B) . In patients undergoing intraarterial thrombolysis, we suggest recombinant tissue-type plasminogen activator (rt-PA) or urokinase over streptokinase (Grade 2C) .

7.1. For patients undergoing peripheral artery percutaneous transluminal angioplasty (PTA) with or without stenting, we recommend long-term aspirin (75-100 mg/day) or clopidogrel (75 mg/day) (Grade 1A) . For patients undergoing peripheral artery PTA with stenting, we suggest

Revision accepted August 31, 2011. Affi liations: From the Iberoamerican Cochrane Centre (Dr Alonso-Coello), CIBERESP-IIB Sant Pau, Barcelona, Spain; Angiology (Dr Bellmunt), Vascular and Endovascular Surgery Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; The Heart House (Dr McGorrian), Mater Misericordiae University Hospital, Dublin, Ireland; Departments of Medicine and Clinical Epidemiology and Biostatistics (Drs Anand and Guyatt), McMaster University, Hamilton, ON, Canada; Section Vascular Surgery (Dr Guzman), University of Manitoba, St Boniface Hospital, Winnipeg, MB, Canada; Department of Family and Preventive Medicine (Dr Criqui), University of California San Diego School of Medicine, La Jolla, CA; Department of Medicine (Dr Akl), State University of New York at Buffalo, Buffalo, NY; Norwegian Knowledge Centre for the Health Services and Department of Medicine Gjøvik (Dr Vandvik), Innlandet Hospital Trust, Gjøvik, Norway; Stanford Stroke Center (Dr Lansberg), Stanford Univer-sity Medical Center, Palo Alto, CA; and Department of Medicine (Dr Spencer), McMaster University, Hamilton, ON, Canada. Funding/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 were also provided by Bristol-Myers Squibb; Pfi zer, Inc; Canyon Pharmaceuticals; and sanofi -aventis US. Disclaimer: 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 http://chestjournal.chestpubs.org/content/141/2_suppl/1S. Correspondence to: Frederick A. Spencer, MD, Department of Medicine, McMaster University, St Joseph’s Health Care, 50 Charlton Ave E, Hamilton, ON, L8N 4A6, Canada; e-mail: [email protected] © 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians ( http://www.chestpubs.org/site/misc/reprints.xhtml ). DOI: 10.1378/chest.11-2307

Summary of Recommendations

Note on Shaded Text: Throughout this guideline, shading is used within the summary of recommenda-tions sections to indicate recommendations that are newly added or have been changed since the pub-lication of Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Rec-ommendations that remain unchanged are not shaded.

2.1. For persons with asymptomatic peripheral arterial disease (PAD), we suggest aspirin 75 to 100 mg daily over no aspirin therapy (Grade 2B) .

Remarks: Aspirin slightly reduces total mortality regardless of cardiovascular risk profi le if taken over 10 years. In people at moderate to high risk of cardio-vascular events, the reduction in myocardial infarc-tion (MI) is closely balanced with an increase in major bleeds. Whatever their risk status, people who are averse to taking medication over a prolonged time period for very small benefi ts will be disinclined to use aspirin for primary prophylaxis. Individuals who


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events and mortality. The patient-important outcomes (ie, total mortality, nonfatal MI, nonfatal stroke, major nonfatal extracranial bleed) are the same outcomes considered for recommendations for CAD and stroke. However, we review the effects of antithrombotic therapy on outcomes specifi c to PAD (eg, rest pain of the limbs, quality of life, or amputation).

Studies evaluating antithrombotic therapy imme-diately following peripheral bypass graft surgery or percutaneous endovascular procedures generally have used graft patency or reocclusion as the primary end point. These outcomes are surrogates for patient-important outcomes of quality of life and limb ampu-tation, which are seldom reported.

We consider the desirable and undesirable con-sequences of antithrombotic therapy in the follow-ing populations or patient groups: (1) persons with asymptomatic PAD, (2) patients with symptomatic PAD (including those with claudication or critical [chronic] limb ischemia and rest pain or prior periph-eral arterial revascularization), (3) patients with acute limb ischemia and threatened limb loss, (4) patients following peripheral arterial revascularization, and (5) persons with asymptomatic and symptomatic carotid stenosis. Table 1 and Table S1 describe both the question defi nition (ie, population, intervention, comparator, and outcome) and the study types con-sidered for each question. (Tables that contain an “S” before the number denote supplementary tables not contained in the body of the article and avail-able instead in an online data supplement. See the “Acknowledgments” for more information.)

High-quality evidence supports an effect of aspi-rin on vascular mortality. In addition, a recent meta-analysis provided moderate-quality evidence that long-term use of aspirin reduces mortality from spe-cifi c cancer types. 1 In a population of patients with symptomatic vascular disease, vascular disease and cancer are the leading causes of death. Therefore, we have chosen total mortality over a 10-year period as the main outcome of interest. When data are avail-able, we included fatal intracranial or extracranial bleeding with vascular death or total mortality under the general category of antithrombotic therapy-related deaths. Nonfatal hemorrhagic strokes and ischemic strokes are included together as nonfatal strokes. Although the former is a complication and decrease in the latter is a benefi cial effect of antithrombotic therapy, their impact on patient morbidity is similar.

1.0 Methods

Estimation of Baseline Risks and Absolute Effects of Treatment

In order to estimate absolute benefi ts and harms associated with a given therapy, we performed the following steps. First,

single rather than dual antiplatelet therapy (Grade 2C) .

Values and preferences: Patients who place a high value on an uncertain reduction in the risk of limb loss and a relatively low value on avoiding a defi nite increased risk of bleeding are more likely to choose to use dual antiplatelet therapy.

8.1-8.4. We recommend one of the following antithrombotic regimens to be continued long-term following peripheral artery bypass graft surgery over no antithrombotic treatment: aspi-rin 75 to 100 mg daily or clopid ogrel 75 mg daily (all Grade 1A) . We recommend single antiplatelet therapy over antiplatelet therapy and warfarin (Grade 1B) . In patients undergoing below-knee bypass graft surgery with prosthetic grafts, we suggest clopidogrel 75 mg/d plus aspirin (75-100 mg/d) over aspirin alone for 1 year (Grade 2C) . For all other patients, we suggest single over dual antiplatelet therapy (Grade 2B) .

9.1. For persons with asymptomatic carotid ste-nosis, we suggest aspirin 75 to 100 mg daily over no aspirin therapy (Grade 2B) .

Remarks: Aspirin slightly reduces total mortality regardless of cardiovascular risk profi le if taken over 10 years. In people at moderate to high risk of car-diovascular events, the reduction in MI is closely balanced with an increase in major bleeds. What-ever their risk status, people who are averse to taking medication over a prolonged time period for very small benefi ts will be disinclined to use aspirin for primary prophylaxis.

9.2-9.3. In patients with symptomatic carotid ste-nosis (including recent carotid endarterectomy), we recommend long-term antiplatelet therapy with clopidogrel (75 mg once daily) or aspirin-extended-release dipyridamole (25 mg/200 mg bid) or aspirin (75-100 mg once daily) over no antiplatelet therapy (Grade 1A) . We suggest either clopidogrel (75 mg once daily) or aspirin-extended-release dipyridamole (25 mg/200 mg bid) over aspirin (75-100 mg) (Grade 2B) .

This article focuses on the use of antithrombotic drugs in patients with peripheral arterial disease

(PAD). PAD is associated with a high prevalence of atherosclerosis in other vascular beds. The leading causes of morbidity and mortality in patients with PAD are myocardial infarction (MI) and stroke; therefore, as in patients with coronary artery disease (CAD), the primary benefi t of antithrombotic therapy in this patient population is prevention of vascular





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the lower limb to that of the arm. This relatively simple clinical test was originally used to confi rm the diagnosis of PAD and assess its severity. Low ABI ( , 0.90) has been shown to be an independent predictor of MI, stroke, and vascular mortality inde-pendent of other cardiovascular risk factors. 5-9 The ABI, therefore, has been promoted as a simple, inex-pensive, noninvasive screening tool for the assess-ment of future cardiovascular risk. In a meta-analysis of � 48,000 healthy men and women, ABI , 0.90 at baseline was associated with an approximate dou-bling of the 10-year mortality, cardiovascular mor-tality, and major coronary event rate after adjusting for the Framingham risk score. 10

Therefore, when evaluating a patient for primary prevention with aspirin, we suggest using a risk strat-ifi cation tool such as the Framingham risk score, which provides estimates of low ( , 10%), moderate (10%-20%), and high risk ( . 20%) of cardiovascular events over 10 years. If, in addition, the patient has an ABI , 0.90, we suggest doubling this score, thus possibly increasing the patient’s risk from a low to moderate or a moderate to high category. 10

2.1 Aspirin

We consider the evidence for aspirin therapy for the primary prevention of CAD (see section 1.1 in Vandvik et al 4 in this supplement) applicable to patients with asymptomatic PAD. On the basis of an individual participant data meta-analysis, 11 aspi-rin would be expected to prevent 19 and 31 nonfatal MIs and lead to 16 and 22 major extracranial bleeding events per 1,000 moderate- and high-risk patients treated, respectively (Table S2). In addition, long-term aspirin use has been associated with a signifi cant decrease in cancer mortality, 12 likely contributing to the decrease in total mortality associated with long-term aspirin therapy observed in another meta-analysis. 13 On the basis of these data and regardless of vascular risk, aspirin use in 60-year-old men would also result in six fewer deaths (12 fewer to 0 fewer) per 1,000 patients treated for 10 years. The overall quality of evidence is moderate given the impreci-sion in the estimates for total mortality.

The relative effect of aspirin on prevention of vas-cular events, bleeding, and total mortality are likely similar in patients with cardiovascular risk factors, asymptomatic PAD, and asymptomatic carotid ste-nosis. Our recommendations for primary prevention in asymptomatic patients with PAD are therefore identical to those described in Vandvik et al. 4

Recommendation

2.1. For persons with asymptomatic PAD, we suggest aspirin 75 to 100 mg daily over no aspi-rin therapy (Grade 2B) .

we generated relative effect estimates (relative risks) from the highest-quality published meta-analysis of randomized con-trolled trials (RCTs). If no such meta-analyses were available or were out of date, we conducted our own meta-analyses of relevant RCTs or used relative risk estimates from single RCTs in the absence of other relevant RCTs.

Ideally, in order to approximate the benefi t of a given therapy in the real world, estimates of baseline risk (control group risks) would be derived from population-based observational studies. Unfortunately, for most of our clinical questions, we were unable to identify observational studies of suffi cient quality that reported all relevant outcomes. In such cases, we derived control group risk estimates from a representative control arm of a relevant meta-analysis or RCT and adjusted them to our specifi ed time frame. Detailed explanations of our choices are presented in each section.

Values and Preferences

The relative weight given to outcomes (eg, an extracranial bleed compared with an MI or a stroke) greatly affects the trade-offs between desirable and undesirable consequences of antithrombotic therapy. Unfortunately, limited data guide us with respect to the relative impact of these events on a patient’s quality of life. 2 As described in Guyatt et al, 3 in this supplement we have used ratings from participating guideline panelists’ estimates of patient valuation of the outcomes of interest. The ratings sug-gest that nonfatal major extracranial bleeding (which is usually readily treated and with few long-lasting consequences) carries only slightly less weight than a nonfatal MI (which also often has limited long-term consequences) but substantially less weight than a stroke (which often is associated with long-term disability). Our decisions are based on a disutility or negative weight of stroke of three times the disutility of a major extracranial bleed.

Trade-offs between desirable and undesirable consequences of alternative management strategies sometimes represent close-call situations. In making recommendations in such situations, we have taken a primum non nocere (fi rst do no harm) approach, placing the burden of proof with those who would claim a benefi t of treatment. In other words, when a treatment is associated with uncertain benefi t and an appreciable probability of impor-tant harm, we recommend against such treatment.

We identifi ed the relevant evidence for our clinical ques-tions with the assistance of a team of methodologists and med-ical librarians as outlined in Guyatt et al. 3 Systematic literature searches for systematic reviews and original studies were per-formed until the date of January 15, 2010. After that date, we scanned the literature regularly, although this was not performed as systematic literature searches.

2.0 Primary Prevention of Cardiovascular Events in Patients With Asymptomatic PAD

As in the article by Vandvik et al 4 of this supplement, primary prevention refers to the use of an interven-tion to prevent events prior to any clinically manifested disease. Hence, even though nearly every 70-year-old man or woman has signifi cant vascular changes, they are candidates for primary (as opposed to secondary) prevention unless they have clinically manifested vascu-lar disease (ie, claudication; history of peripheral vascu-lar procedures; known history of CAD, MI, or stroke).

Most asymptomatic patients with PAD will be iden-tifi ed through ankle-brachial index (ABI) screening. The ABI is the ratio of the highest systolic BP in




domized trial that directly compared clopidogrel and aspirin in secondary prevention of cardiovascular events, and we consider this trial to be the most cred-ible source of evidence. 15 More than 19,000 patients with atherosclerotic vascular disease manifested as a recent stroke, recent MI, or symptomatic PAD received clopidogrel or aspirin. After a mean follow-up of 1.9 years, clopidogrel was associated with a pos-sible reduction in nonfatal MI and nonfatal extracra-nial bleeding and little or no effect on total mortality. Table S4 summarizes the quality of evidence and main fi ndings of the CAPRIE trial. The results indi-cate no effect of clopidogrel on total mortality com-pared with aspirin. These results are consistent with a meta-analysis of 10 studies examining the effects of thienopyridine derivatives (eg, clopidogrel, ticlopi-dine) vs aspirin in patients at high vascular risk. 16

3.3 Dual Antiplatelet Therapy With Clopidogrel and Aspirin vs Single Antiplatelet Therapy

A Cochrane systematic review evaluated short- and long-term dual antiplatelet therapy in patients with established CAD. 17 Only one large-scale RCT, the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoid-ance (CHARISMA) trial, has evaluated the long-term effi cacy of clopidogrel and aspirin vs aspirin alone. 18 This trial followed 15,603 patients with established vascular disease or multiple risk factors for a mean period of 28 months. Table S5 summarizes the qual-ity of evidence and fi ndings from this trial. Results of the study failed to demonstrate or exclude an effect of dual antiplatelet therapy relative to aspirin on total mortality or nonfatal MI. Dual antiplatelet therapy was associated with a possible reduction in nonfatal stroke and a possible increase in nonfatal extracranial bleeding. We considered the quality of evidence to be moderate because of imprecise effect estimates for all outcomes. Although this study included patients with other vascular diseases, we considered its fi nd-ings directly applicable to patients with symptomatic PAD. We did not deem subgroup analyses suggesting different effects of dual antiplatelet therapy in symp-tomatic vs asymptomatic patients to be credible. 14

3.4 Warfarin Plus Aspirin vs Aspirin Alone

Although studies comparing warfarin to placebo or aspirin have been conducted in patients with PAD, these have been small in size and focused on PAD-specifi c outcomes (eg, lower-extremity pain, bypass graft patency) rather than on rates of subsequent stroke, MI, or vascular death. Subsequent sections summarize these studies.

Of the available trials of patients with asymptom-atic CAD comparing warfarin plus aspirin to aspirin

Remarks: Aspirin slightly reduces total mortality regardless of cardiovascular risk profi le if taken over 10 years. In people at moderate to high risk of car-diovascular events, the reduction in MI is closely balanced with an increase in major bleeding events. Whatever the risk status, people averse to taking medication over a prolonged time period for very small benefi ts will be disinclined to use aspirin for primary prophylaxis. Individuals who value prevent-ing an MI substantially higher than avoiding a GI bleed, if they are in the moderate or high cardiovas-cular risk strata, will be more likely to choose aspirin.

3.0 Secondary Prevention of Cardiovascular Events in Patients With Symptomatic PAD

3.1-3.3 Antiplatelet Therapies for Secondary Prevention of Cardiovascular Events in Patients With Symptomatic PAD

Because antiplatelet therapy would be expected to result in similar relative reductions in vascular events such as MI or stroke in patients with PAD or CAD, we considered RCTs enrolling patients with PAD, CAD, or both to support our recommen-dations for both conditions. Although many of the included studies conducted post hoc analyses limited to patients enrolled for symptomatic PAD, we did not fi nd these subgroup analyses credible based on criteria proposed by Sun et al. 14 Therefore, our rec-ommendations for antiplatelet therapy as secondary prevention of cardiovascular events in symptomatic patients with PAD are identical to those described in sections 2.1.1, 2.1.2, 2.1.3, and 2.1.5 of Vandvik et al. 4 For the reader’s interest, we briefl y review the perti-nent evidence in the following sections.

3.1 Aspirin

Table S3 summarizes the quality of evidence and main fi ndings from a meta-analysis of individual participant data from 16 randomized trials with 17,000 patients with established vascular disease (six trials of patients with previous MI and 10 of patients with previous transient ischemic attack or stroke). 11 In this population at high risk for a serious vascular event (8.2% yearly risk), aspirin signifi cantly reduced total mortality, nonfatal MI, and nonfatal stroke but increased nonfatal extracranial bleeding events. The number of vascular events and total deaths prevented was far greater than the number of bleeding events that resulted from aspirin.

3.2 Clopidogrel vs Aspirin

The Clopidogrel vs Aspirin in Patients at Risk for Ischemic Events (CAPRIE) trial is the only ran-





directly and often used walking distance as a surrogate. We make inferences regarding quality of life based on these data, inferences that are less certain because of indirectness. Because these therapies have not been shown to have an impact on cardiovascular events, they are considered only as possible additions to previously recommended antiplatelet treatments.

Patients with intermittent claudication have lower-extremity discomfort with walking, thereby limiting activity. In general, claudication itself is not associ-ated with limb loss and is responsive to smoking ces-sation and exercise therapy. Cessation of tobacco use can signifi cantly reduce lower-extremity symp-toms and progression of PAD. 22,23 One systematic review suggested that structured exercise programs can improve maximal walking distance (MWD). 24 Therefore, additional drug therapy should be con-sidered only in patients who have troubling limi-tations even after smoking cessation and exercise therapy.

Selection of Baseline Risk

For the three comparisons of cilostazol, pentoxifyl-line, and prostanoids vs placebo, because controlled trials showed large improvements in walking test distance in patients in placebo groups, for the surro-gate outcome of MWD, we used a control response rate of 80%; that is, we assumed that 80% of untreated patients would show improvements in quality of life. We calculated the standardized mean differences, and when needed, we imputed SDs from other trials. We then converted standardized mean differences into risk differences 25,26 and present the results as the proportion of patients who experience an important benefi t in quality of life (inferred from MWD). For evaluation of bleeding risk associated with cilostazol compared with no cilostazol or placebo, we used the control group risk estimate from a systematic review of 10 RCTs evaluating cilostazol in addition to dual antiplatelet therapy in coronary percutaneous trans-luminal angioplasty (PTA) and stenting. 27

4.1 Cilostazol

Cilostazol is a phosphodiesterase III inhibitor of platelet activation and relaxes vascular smooth muscle. Ten RCTs that compared cilostazol 100 mg bid to placebo have been located in two systematic reviews. 28,29 Pooling data from seven studies com-paring cilostazol vs placebo suggested that regard-ing health-related quality of life (as inferred from MWD), patients receiving cilostazol are more likely to experience an important benefi t than those receiving placebo (79 more per 1,000 [55 more to 100 more]) ( Table 3 , Table S7). Changes in quality of life were evaluated directly in four of the studies

alone, all were in the setting of a recent acute coro-nary syndrome, and a number had only short-term follow-up. It is unknown whether the response to warfarin therapy, particularly with respect to bleed-ing, might differ in patients with symptomatic CAD vs symptomatic PAD. Therefore, we used only RCTs specifi cally enrolling patients with symptomatic PAD for our evaluation of warfarin therapy.

For the comparison of warfarin plus aspirin vs aspi-rin alone for nonfatal vascular outcomes, we used the event rates from participants taking aspirin in a meta-analysis of 16 RCTs evaluating aspirin use vs no aspi-rin use in patients with vascular disease adjusted to a 5-year time interval as our baseline risk estimate. 10 Because this meta-analysis does not provide data on total mortality or nonfatal major extracranial bleeds, we derived baseline risk estimates from the aspirin arm in the CHARISMA trial (total mortality) and CAPRIE trial (major nonfatal extracranial bleeding events). 15,18

We identifi ed three RCTs evaluating warfarin (international normalized ratio, 2.0-3.0) plus aspirin vs aspirin alone in 3,048 patients with established PAD. 19-21 Table 2 and Table S6 provide details about the qual ity of evidence and fi ndings from our meta-analysis of the three included studies. Results failed to demonstrate or exclude an effect of warfarin plus aspirin vs aspirin alone on mortality, nonfatal MI, or nonfatal stroke. However, there was a signifi cant increase in major bleeding events with warfarin plus aspirin compared with aspirin alone. The overall qual-ity of evidence is low.

Recommendation

3.1-3.4. For secondary prevention in patients with symptomatic PAD, we recommend one of the two following antithrombotic regimens to be continued long term over no antithrombotic treatment: aspirin 75 to 100 mg daily or clopid-ogrel 75 mg daily (all Grade 1A) . We suggest not to use dual antiplatelet therapy with aspirin plus clopidogrel (Grade 2B) . We recommend not to use an antiplatelet agent with moderate-intensity warfarin (Grade 1B) .

4.0 Antithrombotic Therapy for the Management of Patients With Claudication

In the previous section, we recommended aspi-rin or clopidogrel for the prevention of nonfatal MI, nonfatal stroke, or vascular death for all patients with symptomatic PAD. In this section, we evaluate other therapies with antiplatelet and antithrombotic properties (eg, cilostazol, pentoxifylline, prostanoids) for their effect on quality of life. Unfortunately, most studies have not evaluated quality of life as an outcome




Tabl

e 2—

[Sec

tion

3.1

-3.4

] Su

mm

ary

of F

indi

ngs:

Mod

erat

e-In

tens

ity

War

fari

n (I

NR

2.0

-3.0

) P

lus

Asp

irin

vs

Asp

irin

Alo

ne f

or S

econ

dary

Pre

vent

ion

of

Car

diov

ascu

lar

Eve

nts

in P

atie

nts

Wit

h Sy

mpt

omat

ic P

AD

20,2

1,22

Out

com

esPa

rtic

ipan

ts (S

tudi

es),

Fol

low

-up

Qua

lity

of th

e E

vide

nce

(GR

AD

E)

Rel

ativ

e E

ffec

t (95

% C

I)

Ant

icip

ated

Abs

olut

e E

ffec

ts O

ver

5 y

Ris

k W

ith A

spir

inR

isk

Diff

eren

ce W

ith

War

fari

n +

Asp

irin

(95%

CI)

Tota

l mor

talit

y3,

048

(3 R

CT

), 35

-60

mo

Low

due

to im

prec

isio

n a an

d in

cons

iste

ncy b

RR

1.1

1 (0

.79-

1.55

)12

0 pe

r 1,

000 c

13 m

ore

per

1,00

0 (f

rom

25

few

er to

66

mor

e)M

I no

nfat

al e

vent

s3,

048

(3 R

CT

), 35

-60

mo

Mod

erat

e du

e to

im

prec

isio

n a R

R 0

.95

(0.6

4-0.

1.41

)80

per

1,0

00 d

4 fe

wer

per

1,0

00 (f

rom

28

few

er to

32

mor

e)St

roke

, inc

ludi

ng n

onfa

tal

isch

emic

and

hem

orrh

agic

st

roke

s e

3,04

8 (3

RC

T),

35-6

0 m

oM

oder

ate

due

to

impr

ecis

ion a

RR

0.9

2 (0

.64-

1.33

)11

0 pe

r 1,

000 d

8 fe

wer

per

1,0

00 (f

rom

39

few

er to

36

mor

e)

Maj

or e

xtra

cran

ial b

leed

no

nfat

al e

vent

s2,

994

(2 R

CT

), 35

-60

mo

Hig

hR

R 2

.39

(1.5

0-3.

82)

40 p

er 1

,000

f 55

mor

e pe

r 1,

000

(fro

m 2

0 m

ore

to

112

mor

e)B

urde

n of

trea

tmen

tN

/A g

Hig

hW

arfa

rin

. as

piri

nW

arfa

rin:

dai

ly m

edic

atio

n, d

ieta

ry a

nd

activ

ity r

estr

ictio

ns, f

requ

ent b

lood

te

stin

g/m

onito

ring

, inc

reas

ed

hosp

ital/c

linic

vis

its d

Asp

irin

: dai

ly m

edic

atio

n on

ly

CA

PRIE

5 C

lopi

dogr

el v

s A

spir

in i

n Pa

tient

s at

Ris

k fo

r Is

chem

ic E

vent

s; C

HA

RIS

MA

5 C

lopi

dogr

el f

or H

igh

Ath

erot

hrom

botic

Ris

k an

d Is

chem

ic S

tabi

lizat

ion,

Man

agem

ent,

and

Avo

idan

ce;

GR

AD

E 5

Gra

des

of R

ecom

men

datio

ns, A

sses

smen

t, D

evel

opm

ent,

and

Eva

luat

ion;

IN

R 5

inte

rnat

iona

l nor

mal

ized

rat

io; N

/A 5

not

app

licab

le; R

CT

5 ra

ndom

ized

con

trol

led

tria

l; R

R 5

risk

rat

io. S

ee

Tabl

e 1

lege

nd fo

r ex

pans

ion

of o

ther

abb

revi

atio

ns.

a The

95%

CI

for

abso

lute

eff

ect i

nclu

des

bene

fi t a

nd h

arm

. b E

xces

s ca

ncer

dea

ths

in o

ne s

tudy

with

war

fari

n an

d as

piri

n. c C

ontr

ol g

roup

ris

k es

timat

es fo

r to

tal m

orta

lity

com

e fr

om th

e as

piri

n ar

m o

f the

CH

AR

ISM

A tr

ial.

d Con

trol

gro

up r

isk

estim

ates

for

nonf

atal

MI

and

nonf

atal

str

oke

(isch

emic

, hem

orrh

agic

, and

unk

now

n ca

use)

com

e fr

om o

bser

ved

even

ts in

a m

eta-

anal

ysis

of 1

6 R

CTs

in s

econ

dary

pre

vent

ion.

11

e Of t

otal

non

fata

l str

okes

, tw

o of

48

(4%

) with

asp

irin

and

17

of 5

0 (3

4%) w

ith w

arfa

rin

plus

asp

irin

wer

e he

mor

rhag

ic.

f Con

trol

gro

up r

isk

estim

ates

for

maj

or b

leed

s co

me

from

the

obse

rved

eve

nts

in th

e as

piri

n-al

one

arm

of t

he C

APR

IE tr

ial. 15

g A

s fa

r as

we

are

awar

e, n

o st

udie

s ha

ve e

valu

ated

diff

eren

ces

in b

urde

n of

trea

tmen

t bet

wee

n pa

tient

s w

ith P

AD

taki

ng w

arfa

rin

vs a

spir

in. T

here

are

stu

dies

eva

luat

ing

qual

ity o

f life

in p

atie

nts

duri

ng

war

fari

n tr

eatm

ent (

with

dis

para

te fi

ndin

gs),

but t

hese

are

lim

ited

by s

mal

l sam

ple

size

, lac

k of

com

para

tor,

and

othe

r de

sign

issu

es.





Tabl

e 3—

[Sec

tion

4.1

-4.4

] Su

mm

ary

of F

indi

ngs:

Cil

osta

zol

vs P

lace

bo

in P

atie

nts

Wit

h Sy

mpt

omat

ic P

AD

and

Cla

udi

cati

on28

Out

com

esPa

rtic

ipan

ts (S

tudi

es),

Fol

low

-up

Qua

lity

of th

e E

vide

nce

(GR

AD

E)

Rel

ativ

e E

ffec

t (95

% C

I)

Ant

icip

ated

Abs

olut

e E

ffec

ts

Ris

k W

ithou

t Cilo

staz

olR

isk

Diff

eren

ce W

ith C

ilost

azol

(95%

CI)

Tota

l mor

talit

y1,

439

(1 R

CT

30 ),

34 m

oL

ow d

ue to

bia

s a and

impr

ecis

ion b

RR

0.9

4 (0

.64-

1.39

)68

per

1,0

00 c

4 fe

wer

per

1,0

00 (f

rom

27

few

er to

26

mor

e)M

I no

nfat

al e

vent

s…

……

……

Stro

ke, i

nclu

ding

non

fata

l isc

hem

ic

and

hem

orrh

agic

str

okes

……

……

…

Maj

or e

xtra

cran

ial b

leed

2,27

3 (6

RC

T),

1-6

mo

Low

due

to in

dire

ctne

ss d a

nd

inco

nsis

tenc

y e R

R 0

.89

(0.4

6-1.

73)

44 p

er 1

,000

c 5

few

er p

er 1

,000

(fro

m 2

4 fe

wer

to

32 m

ore)

Qua

lity

of li

fe a

s in

ferr

ed fr

om

max

imum

wal

king

dis

tanc

e (im

port

ant o

utco

me)

1,89

0 (7

RC

T),

3-6

mo

Low

due

to b

ias,

f inc

onsi

sten

cy g

and

indi

rect

ness

h 1.

09 (1

.06-

1.12

)80

0 pe

r 1,

000

79 m

ore

per

1,00

0 (5

5 m

ore

to 1

00 m

ore)

i

See

Tabl

e 1

and

2 le

gend

s fo

r ex

pans

ion

of a

bbre

viat

ions

. a U

ncle

ar c

once

alm

ent o

f allo

catio

n. b C

I in

clud

es im

port

ant b

enefi

t an

d ha

rm; o

nly

101

even

ts.

c Con

trol

gro

up r

isk

estim

ates

com

e fr

om o

bser

ved

even

ts r

epor

ted

in p

lace

bo a

rms

of in

clud

ed s

tudi

es.

d Dat

a fr

om s

tudi

es c

ompa

ring

cilo

staz

ol v

s pl

aceb

o in

add

ition

to a

spir

in a

nd c

lopi

dogr

el fo

llow

ing

perc

utan

eous

cor

onar

y in

terv

entio

n. e C

Is in

clud

e pr

otec

tive

effe

ct a

nd h

arm

. f U

ncle

ar c

once

alm

ent o

f allo

catio

n in

four

of s

even

stu

dies

. g M

oder

ate

hete

roge

neity

( I 2 5

69%

). h U

se o

f sur

roga

te e

nd p

oint

(wal

king

dis

tanc

e fo

r qu

ality

of l

ife).

i Cal

cula

ted

from

poo

led

stan

dard

ized

mea

n di

ffer

ence

s, c

onve

rted

into

ris

k di

ffer

ence

(ass

umed

con

trol

res

pons

e ra

te o

f 80%

).




an important risk of publication bias; thus, the overall quality of the evidence was deemed to be low.

4.3 Heparins (Including Low-Molecular Weight Heparins)

A Cochrane systematic review of the use of hep-arin products in patients with intermittent claudica-tion 37 identifi ed fi ve eligible studies (Table S8). 38-42 In the pooled data, there were no deaths, no bleed-ing events, and nine cardiovascular events with no signifi cant differences between heparins and placebo. Effects of heparin on walking distance were only eval-uable from one RCT in which heparin 12,500 units subcutaneously daily or placebo were administered for two 3-month periods followed by 6 months of observation in a crossover design. Aspirin was admin-istered throughout the 18-month period. 38 Results failed to establish or exclude benefi t or harm from heparin (112 more with improvement in quality of life per 1,000 [58 fewer to 149 more]) (Table S8).

4.4 Prostanoids

Prostaglandins (prostaglandin E1, prostaglandin I2, and their derivatives) are potent inhibitors of plate-let activation, adhesion, and aggregation and have vasodilatory and antithrombotic effects. A meta-analysis of fi ve studies (1,636 patients) suggested that with regard to quality of life as inferred from MWD, patients receiving prostaglandins are more likely to experience an important benefi t than those receiving placebo (79 more per 1,000 [58 more to 98 more]) but have a higher risk of adverse events (RR, 2.61; 95% CI, 1.40-4.85). 43 There was substan-tial heterogeneity between study results ( I 2 5 64%). Results failed to demonstrate or exclude an effect of prostaglandins vs placebo on nonfatal stroke, nonfatal MI, revascularization, or death. The overall quality of the evidence is low due to risk of bias and imprecision and for quality of life, indirectness (Table S9).

Recommendation

4.1-4.4. For patients with intermittent claudica-tion refractory to exercise therapy and smoking cessation, we suggest the use of cilostazol in addition to previously recommended anti-thrombotic therapies (aspirin 75-100 mg daily or clopidogrel 75 mg daily) (Grade 2C) ; we sug-gest against the use of pentoxifylline, hepari-noids, or prostanoids (Grade 2C) .

5.0 Critical Limb Ischemia

Patients with critical limb ischemia have inade-quate resting blood fl ow to the lower limbs, resulting

comparing cilostazol 100 mg bid to placebo. 31-34 All four trials reported results consistent with our infer-ences from MWD: a signifi cant improvement in the physical health subscale of the SF-36 (Short Form Health Survey ), suggesting an improvement in over-all physical function. However, the overall health-related quality of life was not improved, with no changes in the mental health components (eg, social functioning, role-emotional subscale). In the largest of the trials, the results failed to demonstrate or exclude an effect of cilostazol on total mortality. 30

Regarding quality of life (as inferred from MWD), patients receiving cilostazol 100 mg bid were more likely to experience an important benefi t than those receiving pentoxifylline. 35 There were no signifi cant differences in total mortality or adverse events (any adverse event or serious adverse events).

A separate review of a pharmaceutical safety database included eight RCTs of patients with symptomatic PAD. 36 The authors did not list the individual trials included in this database. There were 1,374 participants randomized to cilostazol (475 patient-years exposure) and 973 randomized to placebo (357 patient-years exposure). Although a formal meta-analysis does not appear to have been undertaken, the review reported no difference in rates of MI (1.0% vs 0.8%), stroke (0.5% vs 0.5%), or death (0.6% vs 0.5%) between patients with symptom-atic PAD taking cilostazol or those taking placebo. 36 Major or minor bleeding rates were not reported.

As we considered whether to add cilostazol to existing antithrombotic therapy, we relied on bleed-ing data from studies comparing cilostazol to no cil-ostazol in patients undergoing coronary stenting (and already taking aspirin and clopidogrel) to estimate bleeding risk associated with this therapy. A system-atic review of cilostazol in patients undergoing per-cutaneous coronary intervention included 10 RCTs (2,809 patients) comparing triple therapy with aspi-rin, clopidogrel, and cilostazol to aspirin plus clopid-ogrel. 27 Results failed to demonstrate or exclude an effect of cilostazol on major bleeding (risk ratio [RR], 0.89; 95% CI, 0.46-1.73).

4.2 Pentoxifylline

Pentoxifylline was compared with placebo in six small RCTs in patients with intermittent claudication. A pooled analysis of these trials failed to demon-strate a difference between pentoxifylline and pla-cebo in quality of life as inferred from MWD (31 more per 1,000 [47 less to 94 more]). 29 Pentox-ifylline was associated with more adverse events (96 more per 1,000 [21 more to 181 more]). The studies included had limitations in design and exe-cution and showed marked variability, and there was





80% of peripheral emboli originate in the heart (eg, left atrial appendage, left ventricular apex, native and prosthetic cardiac valves). In the remaining cases, emboli originate from the aorta or peripheral vessels themselves or are of venous origin (paradoxical with migration through patent foramen ovale and atrial septal defect). Thrombotic occlusion is most com-monly associated with advanced atherosclerosis, with slow progression of disease. 47 The limb typically has developed a collateral blood supply, and the fi nal occlusion of the stenotic vessel often is not immedi-ately limb threatening. 45,47

6.1 Anticoagulation for Acute Limb Ischemia

Regardless of the cause and level of acute limb ischemia, patients usually receive short-term anti-coagulation treatment with therapeutic doses of heparin to reduce the extent of ischemic injury by preventing clot propagation and further embolism. Although the logic of this approach is widely accepted, there are no formal studies demonstrating improved outcomes with anticoagulation. The expected adverse effect of preoperative anticoagulant therapy is an increased risk of bleeding, including wound hema-tomas. To our knowledge, there are no randomized trials directly comparing unfractionated heparin with other anticoagulants in this setting.

6.2 Thrombolysis vs Surgery for Acute Limb Ischemia

Treatment of acute limb ischemia is directed at restoration of fl ow to the occluded artery, which is now commonly accomplished by either surgery or catheter-directed intraarterial thrombolysis. Although no formal data support either reperfusion therapy over anticoagulation alone or supportive care, the high risk of limb loss (and subsequent associated morbidity and mortality) without blood fl ow restora-tion has led to widespread use of both modalities.

Table 5 and Table S11 summarize the results from a meta-analysis that provides the best evidence regarding the comparative benefi ts and harms of intraarterial thrombolysis vs surgery. 48 This meta-analysis presented data from fi ve randomized trials of 1,180 patients. 49-53 We provide absolute effect estimates based on control (surgical arm) event rates from these trials. In summary, thrombolysis com-pared with surgery appeared to have little or no effect on limb salvage but was associated with an increase risk in stroke (10 per 1,000 treated) and major bleeding (16 per 1,000 treated) at 30 days. Results failed to demonstrate or exclude an effect of thrombolysis vs surgery on amputation or death. We consider the overall quality of evidence to be moderate because of inconsistency and imprecision.

in rest pain, ulceration, and eventually gangrene and limb loss. Such patients are candidates for prompt revascularization. Pertinent outcomes include relief of pain, quality of life, and limb salvage.

5.1 Prostanoids

Investigators have also administered prostaglan-dins to patients with critical limb ischemia in hopes of relieving rest pain and healing ischemic ulcers. A Cochrane systematic review identifi ed 13 studies comparing prostanoids to placebo in patients with critical limb ischemia without chance of rescue or reconstructive intervention. 44 These studies mea-sured outcomes in different ways. The authors of the review dealt with this variability by dichoto-mizing the continuous results. Pain relief was defi ned as any improvement on a validated pain scale. Ulcer healing was defi ned as any decrease in lesion surface area and presence of granulation tissue. The overall quality of the evidence is low because of limitations in design, imprecision, and inconsistency.

Prostanoids improved rest pain and ulcer healing (77 and 136 patients per 1,000 treated, respectively) but did not signifi cantly prevent amputations or decrease mortality ( Table 4 , Table S10). Prostanoids were poorly tolerated, with � 75% of subjects experi-encing at least one adverse event compared with 31% of controls (the most commonly reported adverse effects were headache, nausea, vomiting, diarrhea, and facial fl ushing). A sensitivity analysis restricted to the eight highest-quality studies found similar results with respect to the fi ve outcome variables.

Recommendation

5.1. For patients with symptomatic PAD and critical leg ischemia/rest pain who are not can-didates for vascular intervention, we suggest the use of prostanoids in addition to previously recommended antithrombotic therapies (aspi-rin 75-100 mg daily or clopidogrel 75 mg daily) (Grade 2C) .

Values and preferences: Patients who do not value uncertain relief of rest pain and ulcer healing greater than avoidance of a high likelihood of drug-related side effects will be disinclined to undergo prostanoid therapy.

6.0 Acute Limb Ischemia

Acute limb ischemia results from a sudden inter-ruption of blood fl ow to an extremity. 45 The most common causes of nontraumatic acute arterial occlu-sion are embolism and thrombosis. 45-47 Approximately




Tabl

e 4—

[Sec

tion

5.1

] Su

mm

ary

of F

indi

ngs:

Pro

stan

oids

vs

Pla

ceb

o in

Pat

ient

s W

ith

Cri

tica

l L

imb

Isc

hem

ia I

neli

gib

le f

or R

evas

cula

riza

tion

44

Out

com

esPa

rtic

ipan

ts (S

tudi

es),

Fol

low

-up

Qua

lity

of th

e E

vide

nce

(GR

AD

E)

Rel

ativ

e E

ffec

t (95

% C

I)

Ant

icip

ated

Abs

olut

e E

ffec

ts

Ris

k W

ithou

t Pro

stan

oids

Ris

k D

iffer

ence

With

Pro

stan

oids

(95%

CI)

Tota

l mor

talit

y1,

391

(5 R

CT

), 32

wk

Low

due

to r

isk

of b

ias,

a in

cons

iste

ncy,

b and

impr

ecis

ion c

RR

1.0

7 (0

.65-

1.75

)12

1 pe

r 1,

000 d

8 m

ore

per

1,00

0 (f

rom

42

few

er to

90

mor

e)M

I no

nfat

al e

vent

s...

......

......

Stro

ke, i

nclu

ding

non

fata

l isc

hem

ic

and

hem

orrh

agic

str

okes

......

......

...

Maj

or e

xtra

cran

ial b

leed

......

......

...R

est p

ain

relie

f (an

y im

prov

emen

t on

val

idat

ed s

cale

)1,

116

(9 R

CT

), 21

.4 w

kM

oder

ate

due

to r

isk

of b

ias a

RR

1.3

2 (1

.1-1

.57)

243

per

1,00

0 d 77

mor

e pe

r 1,

000

(fro

m 2

4 m

ore

to

138

mor

e)U

lcer

hea

ling

(any

dec

reas

e in

siz

e or

gra

nula

tion

tissu

e)1,

132

(8 R

CT

), 17

.5 w

kL

ow d

ue to

ris

k of

bia

s a and

in

cons

iste

ncy e

RR

1.5

4 (1

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1.96

)25

3 pe

r 1,

000 d

136

mor

e pe

r 1,

000

(fro

m 5

5 m

ore

to

242

mor

e)A

mpu

tatio

ns (m

ajor

or

min

or

ampu

tatio

ns)

1,79

0 (9

RC

T),

23.1

wk

Low

due

to r

isk

of b

ias a a

nd

impr

ecis

ion f

RR

0.8

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.76-

1.04

)31

3 pe

r 1,

000 d

34 fe

wer

per

1,0

00 (f

rom

75

few

er to

12

mor

e)A

dver

se e

vent

s71

6 (8

RC

T),

14.4

mo

Mod

erat

e du

e to

ris

k of

bia

s a R

R 2

.35

(1.9

9-2.

78)

77 p

er 1

,000

g 10

3 m

ore

per

1,00

0 (f

rom

76

mor

e to

13

7 m

ore)

394

per

1,00

0 g 53

1 m

ore

per

1,00

0 (f

rom

390

mor

e to

70

1 m

ore)

See

Tabl

e 1

and

2 le

gend

s fo

r ex

pans

ion

of a

bbre

viat

ions

. a U

ncle

ar a

lloca

tion

of c

once

alm

ent a

nd b

lindi

ng c

once

rns.

b I 2 5

40%

. c C

Is in

clud

e bo

th im

port

ant b

enefi

t an

d ha

rm. S

mal

l num

ber

of e

vent

s (1

45).

d Con

trol

gro

up r

isk

estim

ates

com

e fr

om m

edia

n co

ntro

l gro

up r

ates

or

repr

esen

tativ

e co

ntro

l gro

up r

isk

of th

e in

clud

ed s

tudi

es.

e I 2 5

44%

. f C

Is in

clud

e im

port

ant b

enefi

t an

d ha

rm.

g Rep

rese

ntat

ive

cont

rol g

roup

ris

k.





Tabl

e 5—

[Sec

tion

6.1

-6.3

] Su

mm

ary

of F

indi

ngs:

Thr

omb

olys

is v

s Su

rger

y fo

r th

e T

reat

men

t of

Acu

te L

imb

Isc

hem

ia48

Out

com

esPa

rtic

ipan

ts (S

tudi

es),

Fol

low

-up

Qua

lity

of th

e E

vide

nce

(GR

AD

E)

Rel

ativ

e E

ffec

t (95

% C

I)

Ant

icip

ated

Abs

olut

e E

ffec

ts

Ris

k W

ith S

urge

ryR

isk

Diff

eren

ce W

ith T

hrom

boly

sis

(95%

CI)

Tota

l mor

talit

y at

1 y

a 76

8 (3

RC

Ts), b 1

2 m

oL

ow d

ue to

impr

ecis

ion c

and

inco

nsis

tenc

y d R

R 0

.74

(0.3

5-1.

58)

169

per

1,00

0 e 43

few

er p

er 1

,000

(fro

m 1

09 fe

wer

to

98 m

ore)

MI

nonf

atal

eve

nts

......

......

...St

roke

s at

30

d in

clud

es n

onfa

tal i

sche

mic

an

d he

mor

rhag

ic s

trok

es f

1,18

0 (5

RC

Ts), b,

g 1-1

2 m

oM

oder

ate

due

to

impr

ecis

ion h

0.01

(0.0

0-0.

02) i

0 pe

r 1,

000 e

10 m

ore

per

1,00

0 (f

rom

0 fe

wer

to

20 m

ore)

Maj

or e

xtra

cran

ial b

leed

at 3

0 d

1,07

0 (4

RC

Ts), b 1

-12

mo

Mod

erat

e du

e to

im

prec

isio

n j R

R 2

.34

(1.3

2-4.

14]

12 p

er 1

,000

e 16

mor

e pe

r 1,

000

(fro

m 3

mor

e to

37

mor

e)L

imb

salv

age

at 1

y65

4 (2

RC

Ts), b 1

2 m

oL

ow d

ue to

impr

ecis

ion c

and

inco

nsis

tenc

y k R

R 1

.00

(0.8

6-1.

17)

754

per

1,00

0 e 0

few

er p

er 1

,000

(fro

m 1

06 fe

wer

to

128

mor

e)A

mpu

tatio

n at

1 y

768

(3 R

CTs

), a 12

mo

Mod

erat

e du

e to

im

prec

isio

n c R

R 1

.10

(0.8

8-1.

38)

190

per

1,00

0 e 19

mor

e pe

r 1,

000

(fro

m 2

2 fe

wer

to

72 m

ore)

See

Tabl

e 1

and

2 le

gend

s fo

r ex

pans

ion

of a

bbre

viat

ions

. a O

urie

l et a

l 48 r

epor

ted

that

one

of 5

4 de

aths

in th

e th

rom

boly

sis

grou

p w

as fr

om in

trac

rani

al h

emor

rhag

e, w

here

as n

one

of 4

6 in

the

surg

ery

grou

p w

ere

from

intr

acra

nial

hem

orrh

age.

b For

one

stu

dy u

sing

thre

e di

ffer

ent d

oses

of t

he th

rom

boly

tic a

gent

, onl

y th

e op

timal

dos

e is

use

d fo

r co

mpa

riso

n w

ith s

urge

ry. C

ontr

ol g

roup

ris

k es

timat

es c

ome

from

con

trol

eve

nt r

ates

in th

e m

edia

n st

udy

(aft

er a

rran

ging

ris

ks in

incr

easi

ng o

rder

). c T

he 9

5% C

I fo

r ab

solu

te e

ffec

t inc

lude

s im

port

ant b

enefi

t an

d ha

rm.

d I 2 5

80%

. e C

ontr

ol r

isk

estim

ates

from

med

ian

or r

epre

sent

ativ

e co

ntro

l gro

up r

isk

of in

clud

ed s

tudi

es.

f Of r

epor

ted

nonf

atal

str

okes

, all

happ

ened

in th

e th

rom

boly

sis

grou

p, a

nd a

ll w

ere

intr

acra

nial

hem

orrh

ages

(eig

ht o

f eig

ht [1

00%

]).

g Wea

ver

et a

l 53 in

clud

ed p

atie

nts

with

bot

h ac

ute

and

chro

nic

limb

isch

emia

. h T

he 9

5% C

I fo

r ab

solu

te e

ffec

t inc

lude

s im

port

ant b

enefi

t an

d ha

rm; l

ow n

umbe

r of

eve

nts

(eig

ht).

i Poo

led

risk

diff

eren

ce p

rese

nted

inst

ead

of r

elat

ive

risk

. j T

he 9

5% C

Is a

re w

ide,

low

num

ber

of e

vent

s (6

0).

k I 2 5

49%

.




dures. Current practice is very heterogeneous and often is based on indirect evidence from studies in patients undergoing coronary stenting.

7.1 Antithrombotic Therapy Following PTA With and Without Stent Procedures

A Cochrane review 59 pooled data from two early studies, including 356 patients undergoing lower-extremity PTA without stent placement, and found a possible reduction in reocclusion at 6 months in patients taking aspirin plus dipyridamole compared with placebo (OR, 0.69; 95% CI, 0.44-1.10). 60,61 Two other studies failed to demonstrate or exclude an effect of aspirin and dipyridamole vs phenprocoumon (vitamin K antagonist) in reocclusion at 6 months following PTA (OR, 0.78; 95% CI, 0.43-1.41). 62,63 One study failed to demonstrate or exclude an effect on 12-month reocclusion in patients taking ticlopidine compared with phenprocoumon (OR, 0.71; 95% CI, 0.37-1.36). 64 An additional study randomized 179 patients following PTA (pelvic or lower extremity) complicated by extensive dissection to IV unfraction-ated heparin vs subcutaneous nadroparin (a low-molecular-weight heparin) administered for 1 week postprocedure (followed by 6 months of aspirin in each arm). 65 Nadroparin was associated with a reduction in vessel restenosis/occlusion at 6 months (OR, 0.35; 95% CI, 0.19-0.65) but failed to demonstrate or exclude an effect on amputation (OR, 1.0; 95% CI, 0.20-5.10).

We have identifi ed no RCTs comparing anti-thrombotic agents post-PTA with stent placement. Indeed, it remains unclear whether PTA with stent placement is superior to PTA alone with respect to patient-important outcomes. In a recent meta-analysis of 10 RCTs, PTA plus routine stenting for superfi cial femoropopliteal arterial disease was asso-ciated with a possible reduction in restenosis (RR, 0.85; 95% CI, 0.69-1.06) compared with PTA without routine stenting but failed to demonstrate or exclude an effect on need for target vessel revascularization (RR, 0.98; 95% CI, 0.78-1.23). 66

Nevertheless, stenting is performed frequently. Despite low-quality evidence regarding thienopyri-dines in patients undergoing PTA with stent place-ment for PAD, many interventionists provide a loading dose of clopidogrel in addition to aspirin pre-procedure and then continue dual antiplatelet ther-apy for 1 to 3 months post-PTA (particularly if a stent is placed in a small peripheral vessel). The rationale for this practice is based on the results from coro-nary artery stenting trials (see section 3 of Vandvik et al 4 in this supplement).

We are skeptical about extrapolating these data to all patients with PAD given differences in the

6.3 Comparison of Intraarterial Thrombolytic Agents for Acute Limb Ischemia

In the past, thrombolysis for acute limb ischemia was administered by IV; now this strategy has been replaced by catheter-directed thrombolysis. Evi-dence comparing the effi cacy of different intraarte-rial thrombolytic agents for acute limb ischemia is limited. However, in a Cochrane systematic review, Robertson et al 54 identifi ed four randomized trials comparing recombinant tissue-type plasminogen activator (rt-PA), urokinase, or streptokinase for the management of acute lower-limb ischemia. 55-58 Included was one small RCT comparing intraarte-rial streptokinase to intraarterial rt-PA in 40 patients with acute limb ischemia. 55 With streptokinase, there was an increased rate of amputation at 30 days (seven of 20 vs one of 20; RR, 7.0; 95% CI, 0.95-51.80). Results failed to demonstrate or exclude an effect of streptokinase vs intraarterial rt-PA on asymptomatic limb salvage, major hemorrhage, or death.

Initially, streptokinase was the most widely used agent, but since this study 55 and because of other safety concerns (eg, allergic reactions), it has largely been replaced by urokinase and rt-PA. 54 Three RCTs compared intraarterial urokinase to rt-PA for acute peripheral arterial occlusion. 56-58 The overall quality for this comparison is low because of imprecision in outcome estimates as well as limitations in design and execution. Results failed to demonstrate or to exclude an effect of intraarterial rt-PA vs intraarterial uroki-nase on amputation, limb salvage, major hemorrhage, or death (Table S12).

Recommendation

6.1-6.3. In patients with acute limb ischemia due to arterial emboli or thrombosis, we sug-gest immediate systemic anticoagulation with unfractionated heparin over no anticoagula-tion (Grade 2C) ; we suggest reperfusion therapy (surgery or intraarterial thrombolysis) over no reperfusion therapy (Grade 2C) ; and we recom-mend surgery over intraarterial thrombolysis (Grade 1B) . In patients undergoing intraarterial thrombolysis, we suggest rt-PA or urokinase over streptokinase (Grade 2C) .

7.0 Endovascular Revascularization in Patients With Symptomatic PAD

Patients with refractory claudication, rest pain, and ischemia often require revascularization for symp-tomatic relief and limb salvage. Increasingly, patients are undergoing PTA with or without stent placement. Few studies guide clinicians regarding type and dura-tion of antithrombotic therapy following such proce-





that evaluated the impact of aspirin and dipyridamole vs placebo in patients postinfrainguinal (venous or prosthetic) bypass graft surgery (for refractory clau-dication and limb salvage). The relative effects of aspirin plus dipyridamole vs aspirin alone have not been evaluated.

The overall quality of the evidence is low because of indirectness (loss of graft patency being a surro-gate for amputation) and bias ( Table 6 , Table S13). Aspirin plus dipyridamole may result in 22 fewer graft occlusions per 1,000 patients (32 fewer to 12 fewer) treated for 12 months. Only one study pro-vided data on amputation rates wherein aspirin plus dipyridamole compared with placebo for 12 months was associated with a possible reduction in amputa-tions (34 fewer amputations per 1,000 patients treated [51 fewer to one more]). Pooled data from three studies reporting other vascular outcomes suggested that treatment with aspirin plus dipyridamole was associated with a possible reduction in nonfatal MI but failed to demonstrate or exclude an effect on nonfatal stroke. Aspirin plus dipyridamole was associ-ated with a possible increase in bleeding (eight more major bleeding events per 1,000 treated [one fewer to 30 more]).

8.2 Aspirin With or Without Dipyridamole vs Other Agents

The same Cochrane review presented evidence from studies comparing aspirin with or without dipyri-damole to other agents. 68 These other agents included low-molecular-weight heparin, indobufen, pentox-ifylline, and prostaglandins. All these studies failed to demonstrate or exclude an effect of these agents compared with aspirin with or without dipyridam-ole in long-term graft patency or major extracranial bleeding. Individual studies were underpowered for assessment of treatment differences in MI, stroke, or mortality.

8.3 Clopidogrel Plus Aspirin vs Aspirin Alone

The Clopidogrel and Acetylsalicyclate Acid in Bypass Surgery for Peripheral Arterial Disease (CASPAR) study randomized 851 patients under-going unilateral below-knee bypass graft surgery for PAD to clopidogrel (75 mg/d) plus aspirin (75-100 mg/d) vs placebo plus aspirin. 75 In the overall cohort, aspirin and clopidogrel failed to demon-strate or exclude an effect on limb amputation, non-fatal extracranial bleeding, or total mortality compared with aspirin alone (Table S14).

Randomization of patients in this trial was strati-fi ed according to graft type (venous or prosthetic), and the investigators undertook prespecifi ed analy-sis of these subgroups. In the subgroup of patients

risk of stent thrombosis (lower in stenting of larger-caliber peripheral arteries compared with smaller coronary arteries), difference in stent types, and dif-fering outcomes related to stent thrombosis (limb ischemia vs MI). Furthermore, dual antiplatelet ther-apy is associated with an increased risk of major bleeding compared with single antiplatelet ther-apy (see sections 2 and 3 of Vandvik et al 4 in this supplement).

Recommendation

7.1. For patients undergoing peripheral artery PTA with or without stenting, we recommend long-term aspirin (75-100 mg/d) or clopidogrel (75 mg/d) (Grade 1A) . For patients undergoing peripheral artery PTA with stenting, we suggest single rather than dual antiplatelet therapy (Grade 2C) .

Values and preferences: Patients who place a high value on an uncertain reduction in the risk of limb loss and a relatively low value on avoiding a potential increased risk of bleeding are likely to choose to use dual antiplatelet therapy.

8.0 Antithrombotic Therapy Following Peripheral Artery Bypass Graft Surgery

In this section, we review evidence from studies evaluating antithrombotic therapy following periph-eral bypass surgery. For the most part, these data do not suggest that recommendations for antithrom-botic therapy following peripheral artery bypass sur-gery should differ from that in other patients with symptomatic PAD. One exception is the use of dual antiplatelet therapy in patients following prosthetic graft bypass surgery.

Selection of Baseline Risk Estimate

For the comparison of warfarin vs aspirin or clopid-ogrel plus aspirin vs aspirin following PAD surgery, we used as our baseline risk estimate the event rates from patients receiving aspirin in the Dutch Bypass Oral Anticoagulants or Aspirin (BOA) study normalized to 1 year. 67 For the comparison of aspi-rin plus dipyridamole vs placebo, we calculated base-line risk estimates in the placebo group by applying the relative risk for placebo vs aspirin plus dipyri-damole to the aforementioned aspirin baseline risk estimate. 68

8.1 Aspirin and Dipyridamole vs Placebo

We used the data from the Cochrane review of six RCTs with a total of 966 patients 69-74 by Brown et al 68




Tabl

e 6—

[Sec

tion

8.1

-8.3

] Su

mm

ary

of F

indi

ngs:

Asp

irin

Plu

s D

ipyr

idam

ole

vs P

lace

bo

for

Pre

vent

ion

of T

hrom

bos

is A

fter

Per

iphe

ral

Byp

ass

Surg

ery

Out

com

esPa

rtic

ipan

ts (S

tudi

es),

Fol

low

-up

Qua

lity

of th

e E

vide

nce

(GR

AD

E)

Rel

ativ

e E

ffec

t (9

5% C

I)

Ant

icip

ated

Abs

olut

e E

ffec

ts O

ver

1 y

Ris

k W

ithou

t Asp

irin

Ris

k D

iffer

ence

With

Asp

irin

(95%

CI)

Tota

l mor

talit

y75

0 (3

RC

Ts),

12 m

oM

oder

ate

due

to im

prec

isio

n a R

R 0

.86

(0.6

-1.2

2)10

5 pe

r 1,

000 b

14 fe

wer

per

1,0

00 (f

rom

42

few

er to

23

mor

e)M

I no

nfat

al e

vent

s66

7 (3

RC

Ts),

12 m

oM

oder

ate

due

to im

prec

isio

n c R

R 0

.65

(0.4

-1.0

6)28

per

1,0

00 b

9 fe

wer

per

1,0

00 (f

rom

16

few

er to

1

mor

e)St

roke

, d inc

ludi

ng n

onfa

tal i

sche

mic

an

d he

mor

rhag

ic s

trok

es66

7 (3

RC

Ts),

12 m

oM

oder

ate

due

to im

prec

isio

n a R

R 0

.79

(0.4

2-1.

49)

27 p

er 1

,000

b 5

few

er p

er 1

,000

(fro

m 1

5 fe

wer

to

13 m

ore)

Maj

or e

xtra

cran

ial b

leed

e 59

8 (2

RC

Ts),

12 m

oM

oder

ate

due

to im

prec

isio

n f R

R 1

.86

(0.8

5-4.

04)

10 p

er 1

,000

b 8

mor

e pe

r 1,

000

(fro

m 1

few

er to

30

mor

e)A

mpu

tatio

n14

8 (1

RC

Ts),

12 m

oL

ow d

ue to

ris

k of

bia

s g and

im

prec

isio

n c R

R 0

.52

(0.2

7-1.

01)

71 p

er 1

,000

b 34

few

er p

er 1

,000

(fro

m 5

1 fe

wer

to

1 m

ore)

Am

puta

tion

infe

rred

from

loss

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in patients undergoing below-knee prosthetic graft placement, our recommendations for long-term anti-thrombotic therapy following peripheral bypass surgery are the same as those for other patients with symp-tomatic PAD (see section 2).

Recommendation

8.1-8.4. We recommend one of the following antithrombotic regimens to be continued long term in most patients following peripheral artery bypass graft surgery over no antithrom-botic treatment: aspirin 75 to 100 mg daily or clopidogrel 75 mg daily (all Grade 1A) . We rec-ommend single antiplatelet therapy over anti-platelet therapy and warfarin (Grade 1B) . In patients undergoing below-knee bypass graft surgery with prosthetic grafts, we suggest clo-pidogrel 75 mg/d plus aspirin (75-100 mg/d) over aspirin alone for 1 year (Grade 2C) . For all other patients, we suggest single over dual anti-platelet therapy (Grade 2B) .

9.0 Carotid Artery Stenosis

Carotid stenosis may coexist in asymptomatic patients as well as in symptomatic patients with CAD or PAD. Recent prevalence estimates range from 0.2% in men aged , 50 years to 7.5% in men aged � 80 years. 76

9.1 Primary Prevention of Cardiovascular Events

As with patients with asymptomatic PAD, we con-sider the evidence for aspirin therapy for the primary prevention of vascular events and total mortality described in Vandvik et al 4 applicable to patients with asymptomatic carotid stenosis (Table S2). Patients with asymptomatic carotid stenosis may be stratifi ed into low, moderate, or high risk for vascular events as described in section 2 of the cited article. Our recom-mendations for primary prevention in patients with asymptomatic carotid stenosis, therefore, are iden-tical to those for patients with asymptomatic PAD or at risk for CAD. Section 1.2 of Vandvik et al 4 in this supplement provides a more-detailed discussion of the evidence.

9.2 Antithrombotic Therapy for Secondary Prevention in Patients With Symptomatic Carotid Stenosis

The article by Lansberg et al 77 in this supplement provides a full description of the evidence and rec-ommendations for antithrombotic therapy for sec-ondary prevention in patients with symptomatic carotid stenosis. Recommendations are repeated here for readers’ ease of use.

undergoing venous graft bypass (n 5 598), there were no signifi cant differences in the rates of amputation, major bleeding, or death between the two treatment arms. However, in the subgroup of patients under-going prosthetic graft bypass (n 5 253), there was a signifi cant decrease in amputations in patients treated with clopidogrel plus aspirin (24 per 1,000 treated; 95% CI, 35 fewer to three fewer; P 5 .008 using the Wald test for interaction) (Table S15). The sub-study analysis failed to demonstrate or exclude an effect of clopidogrel and aspirin on total mor-tality or major extracranial bleeding. The quality of this evidence is considered low given very serious imprecision.

8.4 Oral Anticoagulants vs Antiplatelet Agents

The BOA study randomized 2,650 patients who had undergone infrainguinal bypass grafting to either high-intensity oral anticoagulation (with phen-procoumon or acenocoumarol [target international normalized ratio, 3-4.5]) or aspirin. 67 Table S16 pro-vides a review of the evidence and quality of this study. This study failed to demonstrate or exclude an effect of oral anticoagulation vs aspirin on all-cause mortality, nonfatal stroke, or limb loss. Although associated with a possible reduction in nonfatal MI, there was a signifi cant increase in extra-cranial major bleeding events in the oral anticoagula-tion group.

Warfarin Plus Aspirin vs Warfarin Alone: Two studies compared warfarin plus aspirin to aspirin alone in patients after lower-limb surgical bypass. 19,20 Both studies were included in the previous eval-uation of the comparison of warfarin plus aspirin vs aspirin alone in patients with symptomatic PAD (see section 3).

In summary, the quality of the evidence for antiplatelet and antithrombotic therapy following PAD surgery for patient-important outcomes, such as amputation, limb loss, and mortality is low to moderate. Aspirin plus dipyridamole was associated with a possible reduction in amputation compared with placebo, but no comparison with aspirin alone has been performed. We did not identify any stud-ies comparing aspirin alone to no aspirin. Aspirin plus clopidogrel was associated with a decrease in amputations over aspirin alone in a subgroup of patients undergoing prosthetic graft placement in one study. 75 Warfarin with or without aspirin is asso-ciated with a signifi cant increase in extracranial bleed-ing compared with aspirin alone. The impact of these therapies on other critical vascular outcomes (nonfa-tal MI or stroke) cannot be adequately assessed based on these studies. With the exception of a weak rec-ommendation for clopid ogrel plus aspirin for 1 year




Recommendations

9.1. For persons with asymptomatic carotid ste-nosis, we suggest aspirin 75 to 100 mg daily over no aspirin therapy (Grade 2B) .

Remarks: Aspirin slightly reduces total mortality regardless of cardiovascular risk profi le if taken over 10 years. In people at moderate to high risk of cardio-vascular events, the reduction in MI is closely balanced with an increase in major bleeds. Whatever their risk status, people who are averse to taking medication over a prolonged time period for very small benefi ts will be disinclined to use aspirin for primary prophylaxis.

9.2-9.3. In patients with symptomatic carotid stenosis (including recent carotid endarterec-tomy), we recommend long-term antiplatelet therapy (clopidogrel [75 mg once daily] or aspirin-extended-release dipyridamole [25 mg/200 mg bid] or aspirin [75-100 mg once daily]) over no antiplatelet therapy (Grade 1A) . We suggest either clopidogrel (75 mg once daily) or aspirin-extended-release dipyridamole (25 mg/200 mg nid) over aspirin (75-100 mg/day) (Grade 2B) .

Acknowledgments Author contributions: As Topic Editor, Dr Alonso-Coello over-saw the development of this article, including the data analysis and subsequent development of the recommendations contained herein. Dr Alonso-Coello: contributed as Topic Editor. Dr Bellmunt: contributed as a frontline clinician . Dr McGorrian: contributed as a panelist. Dr Anand: contributed as a panelist. Dr Guzman: contributed as a panelist. Dr Criqui: contributed as a panelist. Dr Akl: contributed as a panelist. Dr Vandvik: contributed as a panelist. Dr Lansberg: contributed as a panelist. Dr Guyatt: contributed as a panelist. Dr Spencer: contributed as Deputy Editor. Financial/nonfi nancial disclosures: The authors of this guide-line provided detailed confl ict of interest information related to each individual recommendation made in this article. A grid of these disclosures is available online at http://chestjournal.chestpubs.org/content/141/2_suppl/e669S/suppl/DC1. In summary, the authors have reported to CHEST the following confl icts of interest: Dr Bullmunt received funds from Roche for a study unrelated to this guideline and received funds from Ferrer Laboratory for writing a public document related to cilostazol. Dr McGorrian has received conference travel support from Pfi zer Ireland Ltd. Dr Guyatt is co-chair of the GRADE Working Group. Drs Alonso-Coello, Akl, and Vandvik are members of and promi-nent contributors to the GRADE Working Group. Drs Anand, Guzman, Criqui, Lansberg, and Spencer have reported that no potential confl icts of interest exist with any companies/organiza-tions whose products or services may be discussed in this article . Role of sponsors : The sponsors played no role in the develop-ment of these guidelines. Sponsoring organizations cannot recom-mend panelists or topics, nor are they allowed prepublication access to the manuscripts and recommendations. Guideline panel members, including the chair, and members of the Health & Sci-ence Policy Committee are blinded to the funding sources. Fur-ther details on the Confl ict of Interest Policy are available online at http://chestnet.org. Other contributions: We acknowledge Saurabh Kalra for his important contribution to this article, especially in the section on

9.3 Antithrombotic Therapy for Secondary Prevention in Patients Following Carotid Endarterectomy

We believe that the evidence for patients with symptomatic carotid stenosis also applies to patients following carotid endarterectomy (even if previ-ously asymptomatic). Therefore, recommendations for therapy following carotid endartectomy are the same as for patients with symptomatic carotid stenosis.

There are no studies evaluating timing of initiation of antithrombotic therapy before or after endarter-ectomy. For recommendations regarding continua-tion and discontinuation of antithrombotic therapy and timing of reinitiation relative to surgery, see Douketis et al 78 in this supplement.

For completeness, we summarize the limited direct evidence for antiplatelet therapy in patients follow-ing carotid endarterectomy. A Cochrane systematic review identifi ed six RCTs comparing antiplatelet therapy to no antiplatelet therapy in patients with symptomatic or asymptomatic carotid stenosis under-going carotid endarterectomy (with � 3 months of follow-up). 79 Four of the trials tested aspirin (dose range, 50-1,300 mg), 80-83 one trial tested aspirin (990 mg) plus dipyridamole (225 mg), 84 and one trial tested indobufen (400 mg). 85 Five of the six trials used placebo controls. Timing of initiation of anti-platelet therapy ranged from 12 h prior to carotid endarterectomy to up to 3 months after carotid endarterectomy; treatment and follow-up duration ranged from 6 to 54 months. Antiplatelet drugs were associated with a signifi cant reduction in strokes (OR, 0.58; 95% CI, 0.34-0.98); the estimated abso-lute effect was 34 fewer per 1,000 patients treated (2 fewer to 54 fewer). Results failed to demonstrate or exclude an effect of antiplatelet therapy on vas-cular mortality, nonfatal MI, or nonfatal extracranial hemorrhages. Overall quality of the evidence is low because of risk of bias, imprecision, and inconsistency.

Previously presented data in patients with vas-cular disease suggested no benefi t and probable increased harm associated with increasing aspirin doses (section 2 of Vandvik et al 4 ). In addition, the Aspirin and Carotid Endarterectomy trial randomly assigned 2,849 patients scheduled for endarterec-tomy to one of four doses of aspirin (81, 325, 650, and 1,300 mg). 86 Aspirin was started before surgery and continued for 3 months. The combined rate of stroke, MI, and death was lower in the low-dose groups (81 and 325 mg) than in the high-dose groups at 30 days (5.4% vs 7.0%, P 5 .07) and at 3 months (6.2% vs 8.4%, P 5 .03). No RCTs measured patient-important outcomes comparing clopidogrel vs aspirin or clopidogrel plus aspirin vs single antiplatelet ther-apy in patients undergoing carotid endarterectomy.


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12 . Rothwell PM , Fowkes FG , Belch JF , Ogawa H , Warlow CP , Meade TW . Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from ran-domised trials . Lancet . 2011 ; 377 ( 9759 ): 31 - 41 .

13 . Raju NC , Sobieraj-Teague M , Hirsh J , O’Donnell M , Eikelboom J . Effect of aspirin mortality in primary prevention of cardiovascular disease . Am J Med . 2011 ;124(7):621-6329.

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acute limb ischemia. We acknowledge Kristian Thorlund, PhD, for assistance on presentation of continuous outcomes. We thank John Eikelboom, MD, for his contribution of estimates of total mortality for patients on or off aspirin (primary prevention) and Sam Schulman, MD, for assistance with interpretation of bleeding defi nitions. We thank John Wong, MD, for assistance in identify-ing cost-effectiveness implications. Endorsements: This guideline is endorsed by the American Association for Clinical Chemistry, the American College of Clin-ical Pharmacy, the American Society of Health-System Pharma-cists, the American Society of Hematology, and the International Society of Thrombosis and Hematosis. Additional information: The supplement Tables can be found in the Online Data Supplement at http://chestjournal.chestpubs.org/content/141/2_suppl/e669S/suppl/DC1.

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75 . Belch JJ , Dormandy J , Biasi GM , et al . Results of the random-ized, placebo-controlled clopidogrel and acetylsalicylic acid in bypass surgery for peripheral arterial disease (CASPAR) trial. J Vasc Surg . 2010 ;52(4):825-833.

76 . de Weerd M , Greving JP , Hedblad B , et al . Prevalence of asymptomatic carotid artery stenosis in the general popula-

tion: an individual participant data meta-analysis . Stroke . 2010 ; 41 ( 6 ): 1294 - 1297 .

77 . Lansberg MG , O’Donnell MJ , Khatri P , et al . Antithrombotic and thrombolytic therapy for ischemic stroke: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines . Chest . 2012 ; 141 ( 2 ) (suppl): e601S-e636S.

78 . Douketis JD, Spyropoulos AC, Spencer FA, et al. Perioperative management of antithrombotic therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2)(suppl):e326S-e350S.

79 . Engelter S , Lyrer P . Antiplatelet therapy for preventing stroke and other vascular events after carotid endarterec-tomy . Cochrane Database Syst Rev . 2003 ;( 3 ): CD001458 .

80 . Fields WS , Lemak NA , Frankowski RF , Hardy RJ . Con-trolled trial of aspirin in cerebral ischemia. Part II: surgical group . Stroke . 1978 ; 9 ( 4 ): 309 - 319 .

81 . Boysen G , Sørensen PS , Juhler M , et al . Danish very-low-dose aspirin after carotid endarterectomy trial . Stroke . 1988 ; 19 ( 10 ): 1211 - 1215 .

82 . Kretschmer G , Pratschner T , Prager M , et al . Antiplatelet treatment prolongs survival after carotid bifurcation endar-terectomy. Analysis of the clinical series followed by a con-trolled trial . Ann Surg . 1990 ; 211 ( 3 ): 317 - 322 .

83 . Lindblad B , Persson NH , Takolander R , Bergqvist D . Does low-dose acetylsalicylic acid prevent stroke after carotid sur-gery? A double-blind, placebo-controlled randomized trial . Stroke . 1993 ; 24 ( 8 ): 1125 - 1128 .

84 . Harker LA , Bernstein EF , Dilley RB , et al . Failure of aspirin plus dipyridamole to prevent restenosis after carotid endar-terectomy . Ann Intern Med . 1992 ; 116 ( 9 ): 731 - 736 .

85 . Pratesi C , Pulli R , Milanesi G , Lavezzari M , Pamparana F , Bertini D . Indobufen versus placebo in the prevention of restenosis after carotid endarterectomy: a double-blind pilot study . J Int Med Res . 1991 ; 19 ( 3 ): 202 - 209 .

86 . Taylor DW , Barnett HJ , Haynes RB , et al . Low-dose and high-dose acetylsalicylic acid for patients undergoing carotid endarterectomy: a randomised controlled trial. ASA and Carotid Endarterectomy (ACE) Trial Collaborators . Lancet . 1999 ; 353 ( 9171 ): 2179 - 2184 .



Online Data SupplementCHEST

1 © 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians ( www . chestjournal . org / site / misc / reprints . xhtml ). DOI: 10.1378/chest.11-2307

Antithrombotic Therapy in Peripheral Artery Disease

Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

Pablo Alonso-Coello , MD, PhD ; Sergi Bellmunt , MD ; Catherine McGorrian , MBBCh, BAO ; Sonia S. Anand , MD, PhD ; Randolph Guzman , MD, RVT ; Michael H. Criqui , MD, MPH ; Elie A. Akl , MD , MPH, PhD ; Per Olav Vandvik , MD, PhD ; Maarten G. Lansberg , MD, PhD ; Gordon H. Guyatt , MD, FCCP ; and Frederick A. Spencer , MD



2© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2307

Tabl

e S1

—[I

ntro

duct

ion]

Qu

esti

on D

efi n

itio

n an

d E

ligi

bil

ity

Cri

teri

a fo

r A

ntit

hrom

bot

ic T

reat

men

ts i

n PA

D

Sect

ion

Info

rmal

Que

stio

n

PIC

O Q

uest

ion

Popu

latio

nIn

terv

entio

nsC

ompa

rato

rO

utco

mes

2.0

Asy

mpt

omat

ic P

AD

2

.1C

hoic

e of

ant

ithro

mbo

tic

th

erap

yPa

tient

s w

ith a

sym

ptom

atic

PAD

(eg,

AB

PI ,

0.9

)A

spir

inPl

aceb

oTo

tal m

orta

lity

Non

fata

l MI

Non

fata

l str

oke

Maj

or n

onfa

tal

ex

trac

rani

al b

leed

3.0

Sym

ptom

atic

PA

D: p

reve

ntio

n of

car

diov

ascu

lar

even

ts

3

.1C

hoic

e of

ant

ithro

mbo

tic

th

erap

yPa

tient

s w

ith s

ympt

omat

ic P

AD

Asp

irin

Plac

ebo

Tota

l mor

talit

y

3

.2C

lopi

dogr

elA

spir

inN

onfa

tal M

I

3

.3A

spir

in 1

clop

idog

rel

Asp

irin

Non

fata

l str

oke

3

.4A

spir

in 1

OA

Cs

Asp

irin

Maj

or n

onfa

tal

ex

trac

rani

al b

leed

4.0

Sym

ptom

atic

PA

D: m

anag

emen

t of c

laud

icat

ion

4

.1C

hoic

e of

ant

ithro

mbo

tic

th

erap

yPa

tient

s w

ith c

laud

icat

ion

Hep

arin

sPl

aceb

oQ

ualit

y of

life

4

.2C

ilost

azol

Plac

ebo

or p

ento

xify

lline

Max

imum

wal

king

dist

ance

4

.3Pe

ntox

ifylli

nePl

aceb

oM

ajor

non

fata

l

extr

acra

nial

ble

edin

g

4

.4Pr

osta

glan

dins

Plac

ebo

Mor

talit

y

Adv

erse

eve

nts

5.0

Sym

ptom

atic

PA

D: m

anag

emen

t of c

ritic

al li

mb

isch

emia

5

.1C

hoic

e of

ant

ithro

mbo

tic

th

erap

yPa

tient

s w

ith c

ritic

al li

mb

is

chem

ia u

nabl

e to

und

ergo

re

vasc

ular

izat

ion

Pros

tagl

andi

nsPl

aceb

oR

est p

ain

relie

f

Ulc

er h

ealin

g

Am

puta

tions

Mor

talit

y

Adv

erse

eve

nts

(Con

tinu

ed)




Tabl

e S1

—C

onti

nued

Sect

ion

Info

rmal

Que

stio

n

PIC

O Q

uest

ion

Popu

latio

nIn

terv

entio

nsC

ompa

rato

rO

utco

mes

6.0

Acu

te li

mb

isch

emia

6

.1C

hoic

e of

ant

ithro

mbo

tic

th

erap

yPa

tient

s w

ith a

cute

limb

isch

emia

Unf

ract

iona

ted

hepa

rin

No

antic

oagu

latio

nD

eath

6

.2In

traa

rter

ial t

hrom

boly

tic

th

erap

ySu

rger

yA

mpu

tatio

n

6

.3U

roki

nase

or

rt-P

ASt

rept

okin

ase

Non

fata

l str

oke

Maj

or n

onfa

tal

ex

trac

rani

al b

leed

7.0

End

ovas

cula

r su

rger

y

7

.1C

hoic

e of

ant

ithro

mbo

tic

th

erap

y po

st P

TA �

sten

tPa

tient

s un

derg

oing

any

gra

ftA

spir

in p

lus

dipy

rida

mol

ePl

aceb

oVe

ssel

res

teno

sis/

oc

clus

ion

Asp

irin

/dip

yrid

amol

ePh

enpr

ocou

mon

Ticl

opid

ine

Phen

proc

oum

on

Unf

ract

iona

ted

hepa

rin

Subc

utan

eous

nadr

opar

in (L

MW

H)

8.0

Ope

n lo

wer

-lim

b va

scul

ar s

urge

ry

8

.1C

hoic

e of

ant

ithro

mbo

tic

th

erap

yPa

tient

s un

derg

oing

PTA

Asp

irin

or

aspi

rin/

dipy

rida

mol

ePl

aceb

oVa

scul

ar m

orta

lity

8

.2Pa

tient

s un

derg

oing

bel

ow-k

nee

pr

osth

etic

gra

ftA

spir

in o

r as

piri

n/di

pyri

dam

ole

Oth

er a

gent

sN

onfa

tal M

I

8

.3C

lopi

dogr

el p

lus

aspi

rin

Asp

irin

Non

fata

l str

oke

8

.4O

AC

s � as

piri

nA

spir

inM

ajor

non

fata

l

extr

acra

nial

ble

ed

8

.5A

spir

in p

lus

clop

idog

rel

Asp

irin

Am

puta

tion

9.0

Car

otid

ste

nosi

s

9

.1C

hoic

e of

ant

ithro

mbo

tic

th

erap

yPa

tient

s w

ith a

sym

ptom

atic

caro

tid s

teno

sis

Asp

irin

Plac

ebo

Tota

l mor

talit

y

9

.2Pa

tient

s w

ith s

ympt

omat

ic

ca

rotid

ste

nosi

sA

ntip

late

let a

gent

s po

st

en

dart

erec

tom

yPl

aceb

oN

onfa

tal M

I

9

.3Pa

tient

s w

ith c

arot

id s

teno

sis

un

derg

oing

end

arte

rect

omy

Non

fata

l str

oke

Maj

or n

onfa

tal

ex

trac

rani

al b

leed

A

BPI

5 a

nkle

-bra

chia

l pre

ssur

e in

dex;

LM

WH

5 lo

w-m

olec

ular

-wei

ght h

epar

in; M

I 5 m

yoca

rdia

l inf

arct

ion;

OA

C 5

ora

l ant

icoa

gula

nt; P

AD

5 p

erip

hera

l art

eria

l dis

ease

; PIC

O 5

pop

ulat

ion,

inte

rven

tion,

co

mpa

rato

r, ou

tcom

e; P

TA 5

per

cuta

neou

s tr

ansl

umin

al a

ngio

plas

ty; r

t-PA

5 re

com

bina

nt ti

ssue

-typ

e pl

asm

inog

en a

ctiv

ator

.




Tabl

e S2

—[S

ecti

on 1

.1]

Evi

denc

e P

rofi l

e: A

spir

in (

75-1

00 m

g) C

ompa

red

Wit

h N

o A

spir

in i

n th

e P

rim

ary

Pre

vent

ion

of C

ardi

ovas

cula

r D

isea

se

Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

Part

icip

ants

(S

tudi

es),

Fol

low

-up

Ris

k of

Bia

sIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Publ

icat

ion

Bia

sR

elat

ive

Eff

ect

(95%

CI)

Ant

icip

ated

Abs

olut

e E

ffec

ts

Tim

e F

ram

e: 1

0 y

Qua

lity

of

Evi

denc

e W

ithou

t Asp

irin

With

Asp

irin

(9

5% C

I)

Ove

rall

mor

talit

y (c

ritic

al o

utco

me)

, inc

ludi

ng c

ance

r m

orta

lity,

vas

cula

r m

orta

lity,

and

fata

l ble

eds a

100,

076

(9 R

CTs

),

3.8-

10 y

No

seri

ous

ri

sk o

f bia

s b N

o se

riou

s

inco

nsis

tenc

yN

o se

riou

s

indi

rect

ness

Seri

ous

impr

ecis

ion

C

I in

clud

es

no b

enefi

t

Und

etec

ted

RR

0.9

4 (0

.88-

1.00

)60

-y-o

ld m

an c

Mod

erat

e du

e

to im

prec

isio

n 10

0 de

aths

per

1,0

00 d

6 fe

wer

dea

ths

pe

r 10

00 (f

rom

12

few

er

to 0

few

er)

Non

fata

l MI

(cri

tical

out

com

e)

95,0

00 (6

RC

Ts),

3.

8-10

yN

o se

riou

s

risk

of b

ias b

No

seri

ous

in

cons

iste

ncy

No

seri

ous

in

dire

ctne

ssN

o se

riou

s

impr

ecis

ion

Und

etec

ted

RR

0.7

7 (0

.69-

0.86

)L

ow-r

isk

popu

latio

n e H

igh

27 M

I pe

r 1,

000 d

6 fe

wer

MI

pe

r 1,

000

(fro

m 8

few

er

to 4

few

er)

Mod

erat

e-ri

sk p

opul

atio

n e

83 M

I pe

r 1,

000 d

19 fe

wer

MI

pe

r 1,

000

(fro

m 2

6 fe

wer

to

12

few

er)

Hig

h-ri

sk p

opul

atio

n e

136

MI

per

1,00

0 d 31

few

er M

I

per

1,00

0 (f

rom

42

few

er

to 1

9 fe

wer

)

Non

fata

l str

oke

(cri

tical

out

com

e), i

nclu

des

isch

emic

, hem

orrh

agic

, and

unk

now

n ca

use f

95,0

00 (6

RC

Ts),

3.

8-10

yN

o se

riou

s

risk

of b

ias b

No

seri

ous

in

cons

iste

ncy

No

seri

ous

in

dire

ctne

ssN

o se

riou

s

impr

ecis

ion

Und

etec

ted

RR

0.9

5 (0

.85-

1.06

)L

ow-r

isk

popu

latio

n e H

igh

23 s

trok

es p

er 1

,000

d 1

few

er s

trok

e

per

1,00

0 (f

rom

3 fe

wer

to

1 m

ore)

Mod

erat

e-ri

sk p

opul

atio

n e

65 s

trok

es p

er 1

,000

d 3

few

er s

trok

es

pe

r 1,

000

(fro

m 1

0 fe

wer

to

4m

ore)

Hig

h-ri

sk p

opul

atio

n e

108

stro

kes

per

1,00

0 d 5

few

er s

trok

es

pe

r 1,

000

(fro

m 1

6 fe

wer

to

6 m

ore)

(C

onti

nued

)




Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

Part

icip

ants

(S

tudi

es),

Fol

low

-up

Ris

k of

Bia

sIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Publ

icat

ion

Bia

sR

elat

ive

Eff

ect

(95%

CI)

Ant

icip

ated

Abs

olut

e E

ffec

ts

Tim

e F

ram

e: 1

0 y

Qua

lity

of

Evi

denc

e W

ithou

t Asp

irin

With

Asp

irin

(9

5% C

I)

Maj

or e

xtra

cran

ial b

leed

(im

port

ant o

utco

me)

: mai

nly

GI

and

usua

lly d

efi n

ed a

s bl

eed

requ

irin

g tr

ansf

usio

n or

res

ultin

g in

dea

th e

95,0

00 (6

RC

Ts),

3.

8-10

yN

o se

riou

s

risk

of b

ias b

No

seri

ous

in

cons

iste

ncy

No

seri

ous

in

dire

ctne

ssN

o se

riou

s

impr

ecis

ion

Und

etec

ted

RR

1.5

4 (1

.30-

1.82

)L

ow-r

isk

popu

latio

n g H

igh

8 bl

eeds

per

1,0

00 d

4 m

ore

blee

ds

pe

r 1,

000

(fro

m 2

mor

e to

7 m

ore)

Mod

erat

e-ri

sk p

opul

atio

n g

24 b

leed

s pe

r 1,

000 d

16 m

ore

blee

ds

pe

r 1,

000

(fro

m 7

mor

e to

20

mor

e)

Hig

h-ri

sk p

opul

atio

n g

40 b

leed

s pe

r 1,

000 d

22 m

ore

blee

ds

pe

r 1,

000

(fro

m 1

2 m

ore

to 3

3 m

ore)

Bib

liogr

aphy

: Ant

ithro

mbo

tic T

rial

ists

’ (AT

T)

Col

labo

ratio

n; G

aige

nt C

, Bla

ckw

ell L

, Col

lins

R, e

t al

. Asp

irin

in t

he p

rim

ary

and

seco

ndar

y pr

even

tion

of v

ascu

lar

dise

ase:

col

labo

rativ

e m

eta-

anal

ysis

of

indi

vidu

al p

artic

ipan

t dat

a fr

om ra

ndom

ized

tria

ls. L

ance

t . 20

09;3

73(9

678)

:184

9-18

60. R

aju

N, S

obie

raj-T

eagu

e M

, Hir

sh J,

O’D

onne

ll M

, Eik

elbo

om J.

Eff

ect o

f asp

irin

on

mor

talit

y in

pri

mar

y pr

even

tion

of c

ardi

ovas

cula

r di

seas

e. A

m J

Med

, 201

1;12

4(7)

:621

-629

. a RC

T 5

rand

omiz

ed c

ontr

olle

d tr

ial;

RR

5 ri

sk r

atio

. See

Tab

le S

1 fo

r ex

pans

ion

of o

ther

abb

revi

atio

n.

a Thi

s sy

stem

atic

rev

iew

rep

orts

tota

l mor

talit

y an

d in

clud

es th

e m

ost r

ecen

t tri

als

but d

oes

not r

epor

t spe

cifi c

cau

ses

of m

orta

lity.

Oth

er m

eta-

anal

yses

that

use

indi

vidu

al p

atie

nt d

ata

repo

rt r

elat

ive

risk

es

timat

es fo

r va

scul

ar m

orta

lity

(RR

, 0.9

7; 9

5% C

I, 0

.87-

1.09

) can

cer

mor

talit

y (R

R, 0

.66;

95%

CI,

0.5

0-0.

87),

and

fata

l int

racr

ania

l ble

eds

(RR

, 1.7

3; 9

5% C

I, 0

.96-

3.13

). T

he r

isk

of a

fata

l ble

ed (i

nclu

ding

ex

trac

rani

al a

nd in

trac

rani

al) w

as lo

w (0

.3%

with

asp

irin

and

0.2

% w

ith c

ontr

ol).

b Bor

derl

ine

deci

sion

whe

re w

e di

d no

t rat

e do

wn

for r

isk

of b

ias.

Thr

ee o

f the

tria

ls d

id n

ot b

lind

patie

nts,

car

egiv

ers,

or o

utco

me

adju

dica

tor.

Sens

itivi

ty a

naly

ses i

n m

eta-

anal

ysis

by

Raj

u et

al d

id n

ot sh

ow

evid

ence

of r

isk

of b

ias.

c C

ontr

ol g

roup

ris

k es

timat

e fo

r 10

-y m

orta

lity

appl

y to

a 6

0-y-

old

man

and

com

e fr

om p

opul

atio

n-ba

sed

data

from

Sta

tistic

s N

orw

ay. M

orta

lity

incr

ease

s w

ith a

ge (e

g, 5

0-y-

old

man

, 50

deat

hs p

er 1

,000

in

10 y

) and

is lo

wer

in w

omen

than

in m

en (e

g, 3

% in

wom

en a

ged

50 y

vs

5% in

men

age

d 50

y).

d Con

trol

gro

up r

isk

estim

ates

in lo

w-,

mod

erat

e-, a

nd h

igh-

risk

car

diov

ascu

lar

grou

ps a

re b

ased

on

the

Fra

min

gham

sco

re. A

s ex

plai

ned

in th

e ar

ticle

, we

have

use

d da

ta fr

om a

n in

divi

dual

par

ticip

ant d

ata

(IPD

) met

a-an

alys

is to

pro

vide

est

imat

ed r

isks

for

patie

nt-im

port

ant o

utco

mes

not

cov

ered

by

the

Fra

min

gham

ris

k sc

ore.

We

have

als

o ad

just

ed fo

r 20

% o

vere

stim

atio

n as

soci

ated

with

Fra

min

gham

ris

k sc

ore.

e R

isk

grou

ps c

orre

spon

d to

low

ris

k (5

%),

med

ium

ris

k (1

5%),

or h

igh

risk

(25%

) acc

ordi

ng to

the

Fra

min

gham

sco

re (o

r ot

her

risk

tool

) to

estim

ate

10-y

ris

k.

f Of t

he s

trok

es in

the

tria

ls, 8

9 of

682

(13%

) with

out a

spir

in w

ere

hem

orrh

agic

and

116

of 6

55 (1

8%) w

ith a

spir

in w

ere

hem

orrh

agic

. g I

n th

e IP

D m

eta-

anal

ysis

, ris

k fo

r fu

ture

maj

or b

leed

ing

corr

elat

ed w

ith r

isk

for

futu

re c

ardi

ovas

cula

r ev

ents

. The

refo

re, w

e m

ake

the

assu

mpt

ion

that

a p

atie

nt a

t low

, med

ium

, or

high

ris

k of

futu

re c

ar-

diov

ascu

lar

even

ts (d

eter

min

ed b

y F

ram

ingh

am s

core

) will

be

at lo

w, m

ediu

m, o

r hi

gh r

isk

of fu

ture

maj

or b

leed

ing

even

ts, r

espe

ctiv

ely.

Tabl

e S2

—C

onti

nued




Tabl

e S3

—[S

ecti

on 3

.1-3

.4]

Evi

denc

e P

rofi l

e: A

spir

in v

s N

o A

spir

in i

n P

atie

nts

Wit

h Sy

mpt

omat

ic P

AD

Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

Part

icip

ants

(S

tudi

es),

Fol

low

-up

Ris

k of

B

ias

Inco

nsis

tenc

yIn

dire

ctne

ssIm

prec

isio

nPu

blic

atio

n B

ias

Rel

ativ

e E

ffec

t (9

5% C

I)

Ant

icip

ated

Abs

olut

e E

ffec

ts

Tim

e F

ram

e: 5

y

Qua

lity

of

Evi

denc

e R

isk

With

out

Asp

irin

Ris

k D

iffer

ence

W

ith A

spir

in

(95%

CI)

Tota

l mor

talit

y (c

ritic

al o

utco

me)

: sud

den

deat

h, p

ulm

onar

y em

bolis

m, h

emor

rhag

e, u

nkno

wn

caus

e (p

ropo

rtio

n no

t rep

orte

d)

17,0

00 (1

6 R

CTs

),

27 m

oN

o se

riou

s

risk

of b

ias

No

seri

ous

lim

itatio

nsN

o se

riou

s

indi

rect

ness

Impr

ecis

e a

CI

incl

udes

be

nefi t

and

no

eff

ect

Und

etec

ted

RR

0.9

0 (0

.82-

0.99

)13

3 pe

r 1,

000 b

13 fe

wer

per

1,0

00

(f

rom

24

few

er

to 1

few

er)

Mod

erat

e du

e to

impr

ecis

ion a

Non

fata

l MI

(cri

tical

out

com

e)

17,0

00 (1

6 R

CTs

),

27 m

oN

o se

riou

s

risk

of b

ias

No

seri

ous

lim

itatio

nsN

o se

riou

s

indi

rect

ness

No

seri

ous

im

prec

isio

nU

ndet

ecte

dR

R 0

.69

(0.6

0-0.

80)

117

per

1,00

0 c 36

few

er p

er 1

,000

(fro

m 4

6 fe

wer

to

23

few

er)

Hig

h

Non

fata

l str

oke

(cri

tical

out

com

e), i

nclu

ding

isch

emic

, hem

orrh

agic

, and

unk

now

n ca

use c

17,0

00 (1

6 R

CTs

),

27 m

oN

o se

riou

s

risk

of b

ias

No

seri

ous

lim

itatio

nsN

o se

riou

s

indi

rect

ness

No

seri

ous

im

prec

isio

nU

ndet

ecte

dR

R 0

.81

(0.7

1-0.

92)

135

per

1,00

0 c 25

few

er p

er 1

,000

(fro

m 3

9 fe

wer

to

11

few

er)

Hig

h

Maj

or e

xtra

cran

ial b

leed

(im

port

ant o

utco

me)

17,0

00 (1

6 R

CTs

),

27 m

oN

o se

riou

s

risk

of b

ias

No

seri

ous

lim

itatio

nsIn

dire

ctne

ss. B

leed

ing

on

ly r

epor

ted

in

stro

ke/T

IA tr

ials

d

No

seri

ous

im

prec

isio

nU

ndet

ecte

dR

R 2

.69

(1.2

5-5.

76)

15 p

er 1

,000

e 25

mor

e pe

r 1,

000

(f

rom

4 m

ore

to 7

1 m

ore)

Mod

erat

e du

e to

indi

rect

ness

Bib

liogr

aphy

: Ant

ithro

mbo

tic T

rial

ists

’ (AT

T)

Col

labo

ratio

n; B

aige

nt C

, Bla

ckw

ell L

, Col

lins

R, e

t al

. Asp

irin

in t

he p

rim

ary

and

seco

ndar

y pr

even

tion

of v

ascu

lar

dise

ase:

col

labo

rativ

e m

eta-

anal

ysis

of

indi

vidu

al p

artic

ipan

t da

ta f

rom

ran

dom

ized

tri

als.

Lan

cet .

2009

;373

(967

8):1

849-

1860

. CA

PRIE

5 C

lopi

dogr

el v

s A

spir

in i

n Pa

tient

s at

Ris

k fo

r Is

chem

ic E

vent

s; C

HA

RIS

MA

5 C

lopi

dogr

el f

or H

igh

Ath

erot

hrom

botic

Ris

k an

d Is

chem

ic S

tabi

lizat

ion,

Man

agem

ent,

and

Avo

idan

ce; T

IA 5

tran

sien

t isc

hem

ic a

ttac

k. S

ee T

able

S1

and

S2 le

gend

s fo

r ex

pans

ion

of o

ther

abb

revi

atio

ns.

a Rat

ed d

own

for

impr

ecis

ion

beca

use

95%

CI

sugg

ests

pos

sibl

e be

nefi t

and

no

effe

ct o

n to

tal m

orta

lity

b Con

trol

gro

up r

isk

estim

ates

(with

out a

spir

in) c

ome

from

obs

erve

d ye

arly

eve

nt r

ates

in 1

6 R

CTs

rep

orte

d in

the

met

a-an

alys

is, a

djus

ted

to a

5-y

tim

e fr

ame.

The

con

trol

gro

up r

isk

estim

ate

for

tota

l mor

-ta

lity

with

out a

spir

in is

der

ived

from

the

even

t rat

e in

the

aspi

rin

arm

of t

he C

HA

RIS

MA

tria

l, us

ing

the

RR

of 0

.90

to g

et to

the

cont

rol g

roup

ris

k es

timat

e w

ithou

t asp

irin

. c O

f the

str

okes

in th

e m

eta-

anal

ysis

, 0.8

% w

ith a

spir

in w

ere

intr

acra

nial

hem

orrh

ages

, and

0.4

% o

f str

okes

with

out a

spir

in w

ere

intr

acra

nial

hem

orrh

ages

. d R

ated

dow

n fo

r in

dire

ctne

ss b

ecau

se b

leed

ing

was

onl

y re

port

ed in

sub

set o

f tri

als

with

str

oke/

TIA

pop

ulat

ions

. e T

o es

timat

e co

ntro

l gro

up r

isks

for

maj

or b

leed

ing

even

ts, w

e ha

ve u

sed

maj

or b

leed

ing

estim

ates

fro

m t

he a

spir

in a

rm in

the

CA

PRIE

tri

al a

s th

e st

artin

g po

int

(to

ensu

re c

onsi

sten

cy a

cros

s ev

iden

ce

profi

les)

. We

have

then

use

d th

e R

R o

f 2.6

9 to

get

to th

e co

ntro

l gro

up r

isk

estim

ate

with

out a

spir

in.




Tabl

e S4

—[S

ecti

on 3

.1-3

.4]

Evi

denc

e P

rofi l

e: C

lopi

dogr

el v

s A

spir

in f

or t

he S

econ

dary

Pre

vent

ion

of C

ardi

ovas

cula

r E

vent

s in

Pat

ient

s W

ith

Sym

ptom

atic

PA

D

Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

Part

icip

ants

(S

tudi

es),

Fol

low

-up

Ris

k of

B

ias

Inco

nsis

tenc

yIn

dire

ctne

ssIm

prec

isio

nPu

blic

atio

n B

ias

Rel

ativ

e E

ffec

t (9

5% C

I)

Ant

icip

ated

Abs

olut

e E

ffec

ts

Tim

e F

ram

e: 5

y

Qua

lity

of

Evi

denc

e R

isk

With

A

spir

in

Ris

k D

iffer

ence

W

ith C

lopi

dogr

el

(95%

CI)

Tota

l mor

talit

y (c

ritic

al o

utco

me)

: fat

al M

I, fa

tal i

sche

mic

str

oke,

fata

l hem

orrh

agic

str

oke

and

othe

r va

scul

ar d

eath

a

19,1

85 (1

RC

T),

1.

9 y

No

seri

ous

ri

sk o

f bia

sN

o se

riou

s

inco

nsis

tenc

y Su

bgro

up a

naly

sis

sugg

este

d no

ben

efi t

in p

atie

nts

with

ac

ute

MI b

No

seri

ous

in

dire

ctne

ssSe

riou

s im

prec

isio

n

CI

incl

udes

ben

efi t

and

harm

with

cl

opid

ogre

l

Und

etec

ted

RR

0.9

8 (0

.87-

1.10

)12

0 pe

r 1,

000 c

2 fe

wer

per

1,0

00

(f

rom

16

few

er

to 1

2 m

ore)

Mod

erat

e du

e to

impr

ecis

ion

Non

fata

l MI

(cri

tical

out

com

e)

19,1

85 (1

RC

T),

1.

9 y

No

seri

ous

ri

sk o

f bia

sN

o se

riou

s

inco

nsis

tenc

yN

o se

riou

s

indi

rect

ness

Seri

ous

impr

ecis

ion

C

I in

clud

es b

enefi

t an

d no

ben

efi t

with

cl

opid

ogre

l

Und

etec

ted

RR

0.8

5 (0

.72-

1.0)

80 p

er 1

,000

c 12

few

er p

er 1

,000

(fro

m 2

2 fe

wer

to

0 m

ore)

Mod

erat

e du

e to

impr

ecis

ion

Non

fata

l str

oke

(cri

tical

out

com

e): i

sche

mic

and

hem

orrh

agic

str

oke d

19,1

85 (1

RC

T)

1.

9 y

No

seri

ous

ri

sk o

f bia

sN

o se

riou

s

inco

nsis

tenc

yN

o se

riou

s

indi

rect

ness

Seri

ous

impr

ecis

ion

C

I in

clud

es b

enefi

t an

d ha

rm w

ith

clop

idog

rel

Und

etec

ted

RR

0.9

4 (0

.83-

1.06

)11

0 pe

r 1,

000 c

6 fe

wer

per

1,0

00

(f

rom

18

few

er

to 6

mor

e)

Mod

erat

e du

e to

impr

ecis

ion

Maj

or e

xtra

cran

ial b

leed

(im

port

ant o

utco

me)

: any

ble

edin

g di

sord

er, s

ever

e e

19,1

85 (1

RC

T)

1.

9 y

No

seri

ous

ri

sk o

f bia

sN

o se

riou

s

inco

nsis

tenc

yN

o se

riou

s

indi

rect

ness

Seri

ous

impr

ecis

ion

C

I in

clud

es b

enefi

t an

d ha

rm w

ith

clop

idog

rel

Und

etec

ted

RR

0.8

8 (0

.7-1

.12)

40 p

er 1

,000

f 4

few

er p

er 1

,000

(fro

m 1

2 fe

wer

to

4 m

ore)

Mod

erat

e du

e to

impr

ecis

ion

Bib

liogr

aphy

: CA

PRIE

Ste

erin

g C

omm

ittee

. A r

ando

mis

ed, b

linde

d, tr

ial o

f clo

pido

grel

vs

aspi

rin

in p

atie

nts

at r

isk

for

isch

emic

eve

nts

(CA

PRIE

). L

ance

t . 19

96;3

48(9

038)

:132

9-13

39.

a Of t

he d

eath

s in

CA

PRIE

, 27

of 5

71 (4

.7%

) with

asp

irin

wer

e fa

tal b

leed

s an

d 23

of 5

60 (4

.1%

) with

clo

pido

grel

wer

e fa

tal b

leed

s. S

ee T

able

S1,

S2,

and

S3

lege

nds

for

expa

nsio

n of

abb

revi

atio

ns.

b Sub

grou

p an

alys

is o

f com

posi

te e

nd p

oint

rep

orte

d re

lativ

e ri

sk r

educ

tion

of 7

.3%

for

patie

nts

with

str

oke

and

23.8

% fo

r pa

tient

s w

ith P

AD

and

rel

ativ

e ri

sk in

crea

se o

f 3.7

% fo

r pa

tient

s w

ith M

I (t

est f

or

inte

ract

ion

P 5

.043

). B

ased

on

crite

ria

for

cred

ibili

ty, w

e di

d no

t bel

ieve

the

resu

lts fr

om th

e su

bgro

up a

naly

sis

and,

ther

efor

e, d

id n

ot r

ate

dow

n fo

r in

cons

iste

ncy.

c C

ontr

ol g

roup

ris

k es

timat

es fo

r to

tal m

orta

lity

com

es fr

om th

e as

piri

n ar

m o

f the

CH

AR

ISM

A tr

ial.

Est

imat

es fo

r M

I an

d st

roke

com

e fr

om o

bser

ved

even

ts in

a m

eta-

anal

ysis

of 1

6 R

CTs

in s

econ

dary

pr

even

tion

(Bai

gent

, see

Tab

le S

3 le

gend

) adj

uste

d to

5-y

tim

e fr

ame.

d O

f the

str

okes

in C

APR

IE, 2

4 of

486

(4.9

%) w

ith a

spir

in w

ere

hem

orrh

agic

, and

14

of 5

28 (2

.6%

) with

clo

pido

grel

wer

e he

mor

rhag

ic.

e Of t

he m

ajor

ext

racr

ania

l ble

eds

in C

APR

IE, 6

8 of

149

(45.

6%) w

ith a

spir

in w

ere

GI

and

47 o

f 132

(35.

6%) w

ith c

lopi

dogr

el w

ere

GI

( P 5

.05)

. f C

ontr

ol g

roup

ris

k es

timat

es c

ome

from

obs

erve

d m

ajor

ble

edin

g ev

ents

in th

e C

APR

IE tr

ial a

djus

ted

to 5

-y ti

me

fram

e an

d no

t fro

m th

e 16

stu

dies

incl

uded

in th

e m

eta-

anal

ysis

bec

ause

thes

e st

udie

s di

d no

t rep

ort m

ajor

ble

eds

cons

iste

ntly

.




Tabl

e S5

—[S

ecti

on 3

.1-3

.4]

Evi

denc

e P

rofi l

e: A

spir

in P

lus

Clo

pido

grel

vs

Asp

irin

for

Sec

onda

ry P

reve

ntio

n of

Car

diov

ascu

lar

Eve

nts

in P

atie

nts

Wit

h Sy

mpt

omat

ic P

AD

Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

Part

icip

ants

(S

tudi

es),

Fol

low

-up

Ris

k of

Bia

sIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Publ

icat

ion

Bia

sR

elat

ive

Eff

ect

(95%

CI)

Ant

icip

ated

Abs

olut

e E

ffec

ts

Tim

e F

ram

e: 5

y

Qua

lity

of

Evi

denc

e R

isk

With

A

spir

in

Ris

k D

iffer

ence

With

A

spir

in 1

Clo

pido

grel

(9

5% C

I)

Tota

l mor

talit

y (c

ritic

al o

utco

me)

: inc

lude

s de

aths

from

car

diov

ascu

lar

caus

e an

d he

mor

rhag

e a

15,6

03 (1

RC

T),

28 m

oN

o se

riou

s

risk

of b

ias

No

seri

ous

In

cons

iste

ncy b

No

seri

ous

in

dire

ctne

ssSe

riou

s

impr

ecis

ion c

Und

etec

ted

RR

0.9

9 (0

.86-

1.14

)12

0 pe

r 1,

000 d

1 fe

wer

per

1,0

00

(f

rom

16

few

er

to 1

6 m

ore)

Mod

erat

e du

e to

impr

ecis

ion

Non

fata

l MI

(cri

tical

out

com

e)

15,6

03 (1

RC

T),

28 m

oN

o se

riou

s

risk

of b

ias

No

seri

ous

in

cons

iste

ncy

No

seri

ous

in

dire

ctne

ssSe

riou

s

impr

ecis

ion c

Und

etec

ted

RR

0.9

4 (0

.75-

1.18

)80

per

1,0

00 d

4 fe

wer

per

1,0

00

(f

rom

20

few

er

to 1

4 m

ore)

Mod

erat

e du

e to

impr

ecis

ion

Non

fata

l str

oke

(cri

tical

out

com

e): i

nclu

des

isch

emic

, hem

orrh

agic

, and

unk

now

n ca

use e

15,6

03 (1

RC

T),

28 m

oN

o se

riou

s

risk

of b

ias

No

seri

ous

in

cons

iste

ncy

No

seri

ous

in

dire

ctne

ssSe

riou

s

impr

ecis

ion c

Und

etec

ted

RR

0.8

1 (0

.64-

1.02

)11

0 pe

r 1,

000 d

20 fe

wer

per

1,0

00

(f

rom

39

few

er

to 2

mor

e)

Mod

erat

e du

e to

impr

ecis

ion

Maj

or e

xtra

cran

ial b

leed

(cri

tical

out

com

e): s

ever

e bl

eedi

ng a

s de

fi ned

by

the

GU

STO

cri

teri

a bu

t exc

lude

d fa

tal a

nd in

trac

rani

al b

leed

s f

15,6

03 (1

RC

T),

28 m

oN

o se

riou

s

risk

of b

ias

No

sero

us

in

cons

iste

ncy

No

seri

ous

in

dire

ctne

ssSe

riou

s

impr

ecis

ion g

Und

etec

ted

RR

1.2

5 (0

.97-

1.61

)40

per

1,0

00 h

10 m

ore

per

1,00

0

(fro

m 1

few

er

to 2

4 m

ore

Mod

erat

e du

e to

impr

ecis

ion

Bib

liogr

aphy

: Bha

tt D

, Fox

KA

, Hac

ke W

, et a

l. C

lopi

dogr

el a

nd a

spir

in v

s as

piri

n al

one

for

the

prev

entio

n of

ath

erot

hrom

botic

eve

nts.

N E

ngl J

Med

. 200

6;35

4(16

):170

6-17

17. G

UST

O 5

Glo

bal U

se o

f St

rate

gies

to O

pen

Occ

lude

d ar

teri

es. S

ee T

able

S1,

S2,

and

S3

lege

nds

for

expa

nsio

n of

oth

er a

bbre

viat

ions

. a O

f the

dea

ths

in C

HA

RIS

MA

, 17

of 5

71 (3

%) w

ith a

spir

in w

ere

fata

l ble

edin

g ev

ents

and

26

of 5

74 (4

.5%

) with

clo

pido

grel

and

asp

irin

wer

e fa

tal b

leed

ing

even

ts.

b Sub

grou

p an

alys

is fo

und

no s

igni

fi can

t eff

ect o

f clo

pido

grel

on

vasc

ular

mor

talit

y in

pat

ient

s w

ith e

stab

lishe

d ca

rdio

vasc

ular

dis

ease

, in

cont

rast

to in

crea

sed

mor

talit

y in

asy

mpt

omat

ic p

atie

nts.

We

judg

ed

clai

m o

f sub

grou

p ef

fect

to b

e no

t cre

dibl

e (h

igh

num

ber

of s

ubgr

oup

hypo

thes

es te

sted

, unc

lear

whe

ther

an

appr

opri

ate

test

for

inte

ract

ion

used

). c C

I in

clud

es im

port

ant b

enefi

t an

d ha

rm (f

or m

orta

lity)

and

no

bene

fi t (f

or s

trok

e).

d Con

trol

gro

up r

isk

estim

ates

for

tota

l mor

talit

y co

mes

from

the

aspi

rin

arm

of t

he C

HA

RIS

MA

tria

l. E

stim

ates

for

MI

and

stro

ke c

ome

from

obs

erve

d ev

ents

in a

met

a-an

alys

is o

f 16

RC

Ts in

sec

onda

ry

prev

entio

n (B

aige

nt, s

ee T

able

S3

lege

nd) a

djus

ted

to 5

-y ti

me

fram

e.

e Of t

he s

trok

es in

CH

AR

ISM

A, 2

7 of

189

(14%

) with

asp

irin

wer

e in

trac

rani

al h

emor

rhag

es, a

nd 2

6 of

150

(17%

) with

clo

pido

grel

wer

e in

trac

rani

al h

emor

rhag

es.

f We

excl

uded

fata

l ble

edin

g an

d in

trac

rani

al h

emor

rhag

e to

avo

id th

e do

uble

cou

ntin

g of

eve

nts i

n th

e C

HA

RIS

MA

tria

l. Pr

opor

tion

of se

vere

GI

blee

ds in

CH

AR

ISM

A w

as 0

.65%

(not

repo

rted

sepa

rate

ly

for

each

trea

tmen

t arm

). g C

I in

clud

es n

o be

nefi t

and

impo

rtan

t har

m.

h Con

trol

gro

up r

isk

estim

ates

com

e fr

om o

bser

ved

maj

or b

leed

ing

even

ts in

the

CA

PRIE

tria

l, ad

just

ed to

5-y

r tim

e fr

ame,

and

not

from

the

16 s

tudi

es in

clud

ed in

the

met

a-an

alys

is o

r fr

om C

HA

RIS

MA

as

thes

e st

udie

s di

d no

t rep

ort m

ajor

ble

eds

cons

iste

ntly

.




Tabl

e S6

—[S

ecti

on 3

.1-3

.4]

Evi

denc

e P

rofi l

e: M

oder

ate-

Inte

nsit

y W

arfa

rin

(IN

R 2

.0-3

.0)

Plu

s A

spir

in v

s A

spir

in A

lone

for

Sec

onda

ry P

reve

ntio

n of

Car

diov

ascu

lar

Eve

nts

in P

atie

nts

Wit

h Sy

mpt

omat

ic P

AD

Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

Part

icip

ants

(S

tudi

es),

Fol

low

-up

Ris

k of

B

ias

Inco

nsis

tenc

yIn

dire

ctne

ssIm

prec

isio

nPu

blic

atio

n B

ias

Rel

ativ

e E

ffec

t (9

5% C

I)

Est

imat

ion

of A

bsol

ute

Eff

ects

Tim

e F

ram

e: 5

y

Qua

lity

of

Evi

denc

e E

vent

Rat

e W

ith A

spir

in

Ris

k D

iffer

ence

With

W

arfa

rin

1 A

spir

in

(95%

CI)

Tota

l mor

talit

y (c

ritic

al o

utco

me)

3,04

8 (3

RC

Ts),

35

-60

mo

No

seri

ous

ri

sk o

f bia

sSe

riou

s

inco

nsis

tenc

y a ( I

2 5 6

3%)

No

seri

ous

in

dire

ctne

ssIm

prec

ise

CI

in

clud

es b

enefi

t an

d ha

rm

Und

etec

ted

RR

1.1

1 (0

.79-

1.55

)12

0 pe

r 1,

000 b

13 m

ore

per

1,00

0

(fro

m 2

5 fe

wer

to

66 m

ore)

Low

due

to

im

prec

isio

n an

d in

cons

iste

ncy

Non

fata

l MI

(cri

tical

out

com

e)

3,04

8 (3

RC

Ts),

35

-60

mo

No

seri

ous

ri

sk o

f bia

sN

o se

riou

s

inco

nsis

tenc

yN

o se

riou

s

indi

rect

ness

Impr

ecis

e C

I

incl

udes

ben

efi t

and

harm

Und

etec

ted

RR

0.9

5 (0

.64-

0.1.

41)

80 p

er 1

,000

c 4

few

er p

er 1

,000

(fro

m 2

8 fe

wer

to

32 m

ore)

Mod

erat

e du

e to

impr

ecis

ion

Non

fata

l str

oke

(cri

tical

out

com

e): i

sche

mic

and

hem

orrh

agic

d

3,04

8 (3

RC

Ts),

35

-60

mo

No

seri

ous

ri

sk o

f bia

sN

o se

riou

s

inco

nsis

tenc

yN

o se

riou

s

indi

rect

ness

Impr

ecis

e C

I

incl

udes

ben

efi t

and

harm

Und

etec

ted

RR

0.9

2 (0

.64-

1.33

)11

0 pe

r 1,

000 c

8 fe

wer

per

1,0

00

(f

rom

39

few

er to

36

mor

e)

Mod

erat

e du

e to

impr

ecis

ion

Maj

or n

onfa

tal e

xtra

cran

ial b

leed

(cri

tical

out

com

e)

2,99

4 (2

RC

Ts),

35

-60

mo

No

seri

ous

ri

sk o

f bia

sN

o se

riou

s

inco

nsis

tenc

yN

o se

riou

s

indi

rect

ness

No

seri

ous

im

prec

isio

nU

ndet

ecte

dR

R 2

.39

(1.5

0-3.

82)

40 p

er 1

,000

e 55

mor

e pe

r 1,

000

(f

rom

20

mor

e to

11

2 m

ore)

Hig

h

Bur

den

of tr

eatm

ent (

impo

rtan

t out

com

e)

N/A

f W

arfa

rin

. a

spir

inW

arfa

rin:

dai

ly m

edic

atio

n,

di

etar

y an

d ac

tivity

re

stri

ctio

ns, f

requ

ent

bloo

d te

stin

g/m

onito

ring

, in

crea

sed

hosp

ital/c

linic

vi

sits

. d Asp

irin

: dai

ly

med

icat

ion

only

.

Hig

h

Bib

liogr

aphy

: Jo

hnso

n W

C,

Will

iford

WO

; D

epar

tmen

t of

Vet

eran

s A

ffai

rs C

oope

rativ

e St

udy

#362

. B

enefi

ts,

mor

bidi

ty,

and

mor

talit

y as

soci

ated

with

lon

g-te

rm a

dmin

istr

atio

n of

ora

l an

ticoa

gula

nt

ther

apy

to p

atie

nts

with

per

iphe

ral a

rter

ial b

ypas

s pr

oced

ures

: a p

rosp

ectiv

e ra

ndom

ized

stu

dy. J

Vas

c Su

rg . 2

002;

35(3

):41-

421.

Sar

ac T

P, H

uber

TS,

Bac

k M

R, e

t al

. War

fari

n im

prov

es t

he o

utco

me

of

infr

aing

uina

l vei

n by

pass

gra

ftin

g at

hig

h ri

sk fo

r fa

ilure

. J V

asc

Surg

. 199

8;28

(3):4

46-4

57. A

nand

S, Y

usuf

S, X

ie C

, et a

l; W

arfa

rin

Ant

ipla

tele

t Vas

cula

r E

valu

atio

n Tr

ial I

nves

tigat

ors.

Ora

l ant

icoa

gula

nt

and

antip

late

let t

hera

py a

nd p

erip

hera

l art

eria

l dis

ease

. N E

ngl J

Med

. 200

7;35

7(3)

:217

-227

. IN

R 5

inte

rnat

iona

l nor

mal

ized

rat

io; N

/A 5

not

app

licab

le. S

ee T

able

S1,

S2,

and

S3

lege

nds

for

expa

nsio

n of

ot

her

abbr

evia

tions

. a E

xces

s ca

ncer

dea

ths

in o

ne s

tudy

with

war

fari

n an

d as

piri

n.

b Con

trol

gro

up ri

sk e

stim

ates

for t

otal

mor

talit

y co

mes

from

the

aspi

rin

arm

of t

he C

HA

RIS

MA

tria

l. c C

ontr

ol g

roup

ris

k es

timat

es fo

r no

nfat

al M

I an

d no

nfat

al s

trok

es (i

sche

mic

, hem

orrh

agic

, and

unk

now

n ca

use)

com

e fr

om o

bser

ved

even

ts in

the

aspi

rin

arm

of a

met

a-an

alys

is o

f 16

RC

Ts in

sec

onda

ry

prev

entio

n (B

aige

nt e

t al,

see

Tabl

e S3

lege

nd).

d Of t

otal

str

okes

, tw

o of

48

(4%

) with

asp

irin

and

17

of 5

0 (3

4%) w

ith w

arfa

rin

plus

asp

irin

wer

e he

mor

rhag

ic.

e Con

trol

gro

up r

isk

estim

ates

for

maj

or b

leed

s co

me

from

obs

erve

d ra

tes

in th

e as

piri

n-al

one

arm

of t

he C

APR

IE tr

ial.

f As

far

as w

e ar

e aw

are,

no

stud

ies

have

eva

luat

ed d

iffer

ence

s in

bur

den

of tr

eatm

ent b

etw

een

patie

nts

with

PA

D ta

king

war

fari

n vs

asp

irin

. The

re a

re s

tudi

es e

valu

atin

g qu

ality

of l

ife in

pat

ient

s du

ring

w

arfa

rin

trea

tmen

t (w

ith d

ispa

rate

fi nd

ings

), bu

t the

se a

re li

mite

d by

sm

all s

ampl

e si

ze, l

ack

of c

ompa

rato

r, an

d ot

her

desi

gn is

sues

.




Tabl

e S7

—[S

ecti

on 4

.1-4

.4]

Evi

denc

e P

rofi l

e: C

ilos

tazo

l vs

Pla

ceb

o in

Pat

ient

s W

ith

Sym

ptom

atic

PA

D a

nd C

lau

dica

tion

Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

Part

icip

ants

(S

tudi

es),

Fol

low

-up

Ris

k of

Bia

sIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Publ

icat

ion

Bia

sR

elat

ive

Eff

ect

(95%

CI)

Est

imat

ion

of A

bsol

ute

Eff

ects

Qua

lity

of

Evi

denc

e

Eve

nt r

ate

With

N

o C

ilost

azol

a

Ris

k D

iffer

ence

W

ith C

ilost

azol

(9

5% C

I)

Tota

l mor

talit

y (c

ritic

al o

utco

me)

1,43

9 (1

RC

T b )

, 34

mo

Seri

ous

risk

of

bi

as. U

ncle

ar

conc

ealm

ent

of a

lloca

tion

Sing

le s

tudy

only

No

seri

ous

in

dire

ctne

ssSe

riou

s im

prec

isio

n

CIs

are

wid

e an

d on

ly 1

01 e

vent

s

Und

etec

ted

RR

0.9

4 (0

.64-

1.39

)68

per

1,0

00 a

4 le

ss p

er 1

,000

(27

few

er to

26

mor

e)

Low

due

to b

ias

an

d im

prec

isio

n

Qua

lity

of li

fe a

s in

ferr

ed fr

om m

axim

um w

alki

ng d

ista

nce

(impo

rtan

t out

com

e)

1,89

0 (7

RC

Ts),

3-6

mo

Seri

ous

risk

of

bi

as. U

ncle

ar

conc

ealm

ent

of a

lloca

tion

in 4

/7 s

tudi

es

Seri

ous

in

cons

iste

ncy

( I 2 5

69%

)

Seri

ous

in

dire

ctne

ss

Use

of s

urro

gate

en

d po

int

No

seri

ous

im

prec

isio

nU

ndet

ecte

d1.

09 (1

.06-

1.12

)80

0 pe

r 1,

000 c

79 m

ore

per

1,00

0

(55

mor

e to

10

0 m

ore)

Low

due

to b

ias,

inco

nsis

tenc

y,

and

indi

rect

ness

Maj

or e

xtra

cran

ial b

leed

ing

(cri

tical

out

com

e)

2,27

3 (2

RC

Ts),

1-6

mo

No

seri

ous

ri

sk o

f bia

sN

o se

riou

s

inco

nsis

tenc

ySe

riou

s

indi

rect

ness

d Se

riou

s im

prec

isio

n

CIs

are

wid

e an

d bo

rder

on

no e

ffec

t

Und

etec

ted

RR

0.8

9 (0

.46-

1.73

) d 46

per

1,0

00 a

5 fe

wer

per

1,0

00

(f

rom

25

few

er to

33

mor

e)

Low

due

to

in

dire

ctne

ssan

d im

prec

isio

n

Non

fata

l MI

(cri

tical

out

com

e )

……

……

……

……

……

Non

fata

l str

oke

(cri

tical

out

com

e)

……

……

……

……

……

Bib

liogr

aphy

: Rob

less

P, M

ikha

ilidi

s D

P, S

tans

by G

P. C

ilost

azol

for

peri

pher

al a

rter

ial d

isea

se. C

ochr

ane

Dat

abas

e Sy

st R

ev . 2

008;

(1):C

D00

3748

. CA

STL

E 5

Cilo

staz

ol: A

Stu

dy in

Lon

g-Te

rm E

ffec

ts. S

ee

Tabl

e S1

and

S2

lege

nds

for

expa

nsio

n of

oth

er a

bbre

viat

ions

. a C

ontr

ol g

roup

ris

k es

timat

es c

ome

from

obs

erve

d ev

ents

rep

orte

d in

pla

cebo

arm

s of

incl

uded

stu

dies

. b H

iatt

WR

, Mon

ey S

R, B

rass

EP.

Lon

g-te

rm s

afet

y of

cilo

staz

ol in

pat

ient

s w

ith p

erip

hera

l art

ery

dise

ase:

the

CA

STL

E s

tudy

. J V

asc

Surg

. 200

8;47

(2):3

30-3

36.

c Cal

cula

ted

from

poo

led

stan

dard

ized

mea

n di

ffer

ence

s, c

onve

rted

into

ris

k di

ffer

ence

(ass

umed

con

trol

res

pons

e ra

te o

f 80%

). d S

tudi

es w

ere

cond

ucte

d in

pat

ient

s w

ith C

AD

und

ergo

ing

sten

t pla

cem

ent a

nd r

ecei

ving

asp

irin

and

clo

pido

grel

in a

dditi

on to

cilo

staz

ol a

nd p

lace

bo.




Tabl

e S8

—[S

ecti

on 4

.1-4

.4]

Evi

denc

e P

rofi l

e: H

epar

ins

vs P

lace

bo

in P

atie

nts

Wit

h Sy

mpt

omat

ic P

AD

and

Cla

udi

cati

on

Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

Part

icip

ants

(S

tudi

es),

Fol

low

-up

Ris

k of

Bia

sIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Publ

icat

ion

Bia

sR

elat

ive

Eff

ect

(95%

CI)

Est

imat

ion

of A

bsol

ute

Eff

ects

Qua

lity

of

Evi

denc

e E

vent

Rat

e W

ith C

ontr

ol a

Ris

k D

iffer

ence

W

ith H

epar

ins

(95%

CI)

Tota

l mor

talit

y (c

ritic

al o

utco

me)

221

(2 R

CTs

), b,c 6

-18

mo

Seri

ous

risk

of b

ias

No

seri

ous

in

cons

iste

ncy

No

seri

ous

in

dire

ctne

ssSe

riou

s

impr

ecis

ion

Und

etec

ted

N/A

. No

even

ts in

ei

ther

arm

N/A

N/A

Low

due

to

bi

as a

nd s

erio

us

impr

ecis

ion

Dro

pout

and

with

draw

al

rate

29%

Car

diov

ascu

lar

even

ts (T

IA, s

trok

e, u

nsta

ble

angi

na, M

I [c

ritic

al o

utco

me]

)

221

(2 R

CTs

), b,c 6

-18

mo

Seri

ous

risk

of b

ias

No

seri

ous

in

cons

iste

ncy

No

seri

ous

in

dire

ctne

ssSe

riou

s

impr

ecis

ion

CIs

in

clud

e be

nefi t

an

d ha

rm

Und

etec

ted

RR

3.4

7 (0

.74-

16.2

8)18

per

1,0

0044

mor

e pe

r 1,

000

(f

rom

4 fe

wer

to

275

mor

e)

Low

due

to

bi

as a

nd s

erio

us

impr

ecis

ion

Dro

pout

and

with

draw

al r

ate

29%

Maj

or b

leed

ing

even

ts (c

ritic

al o

utco

me)

356

(5 R

CTs

), b-f 6

mo

Seri

ous

risk

of b

ias

No

seri

ous

in

cons

iste

ncy

No

seri

ous

in

dire

ctne

ssSe

riou

s

impr

ecis

ion

Und

etec

ted

N/A

. No

even

ts in

ei

ther

arm

N/A

N/A

Low

due

to

bi

as a

nd s

erio

us

impr

ecis

ion

Allo

catio

n co

ncea

lmen

t

uncl

ear

in 4

/5 s

tudi

es

Qua

lity

of li

fe a

s in

ferr

ed fr

om m

axim

um w

alki

ng d

ista

nce

(impo

rtan

t out

com

e)

201

(1 R

CTs

), b,g 1

8 m

oSe

riou

s ri

sk o

f bia

sSi

ngle

stu

dy

on

lySe

riou

s

indi

rect

ness

Seri

ous

im

prec

isio

n C

Is

incl

ude

bene

fi t

and

harm

Und

etec

ted

1.14

(1.0

7-1.

18 )

800

per

1,00

011

2 m

ore

per

1,00

0

(fro

m 5

8 fe

wer

to

149

mor

e) h

Low

due

to

st

udy

limita

tions

, in

dire

ctne

ss, a

nd

impr

ecis

ion

Dro

pout

and

with

draw

al r

ate

32%

Use

of s

urro

gate

endp

oint

Bib

liogr

aphy

: Cos

mi B

, Con

ti E

, Coc

cher

i S. A

ntic

oagu

lant

s (h

epar

in, l

ow m

olec

ular

wei

ght h

epar

in a

nd o

ral a

ntic

oagu

lant

s) fo

r in

term

itten

t cla

udic

atio

n. C

ochr

ane

Dat

abas

e Sy

st R

ev . 2

001;

(3):C

D00

1999

. Se

e Ta

ble

S1, S

2, a

nd S

6 le

gend

s fo

r ex

pans

ion

of a

bbre

viat

ions

. a C

ontr

ol g

roup

ris

k es

timat

es fo

r m

orta

lity,

car

diov

ascu

lar

even

ts, b

leed

ing

even

ts, a

nd w

alki

ng d

ista

nce

com

e fr

om o

bser

ved

even

ts in

con

trol

arm

s of

RC

Ts.

b Ant

onic

elli

R, S

ardi

na M

, Sco

tti A

, Bon

izzo

ni E

, Pac

iaro

ni E

; Ita

lian

CA

P St

udy

Gro

up. R

ando

miz

ed tr

ial o

f the

eff

ects

of l

ow-d

ose

calc

ium

hep

arin

in p

atie

nts

with

per

iphe

ral a

rter

ial d

isea

se a

nd c

laud

i-ca

tion.

Am

J M

ed . 1

999;

107(

3):2

34-2

39.

c Tes

i M, B

ronc

hi G

F, C

arin

i A, M

orfi n

i M, C

inot

ti S,

Fili

bert

i E. E

ffi ca

cy a

nd s

afet

y of

a n

ew lo

w m

olec

ular

wei

ght h

epar

in in

the

med

ium

term

trea

tmen

t of a

ther

oscl

erot

ic a

rter

iopa

thy

of th

e lo

wer

lim

bs.

J D

rug

Dev

. 198

9;2(

2):7

3-82

. d C

alab

rò A

, Pia

rulli

F, M

ilan

D, R

ossi

A, C

osce

tti G

, Cre

pald

i G. C

linic

al a

sses

smen

t of l

ow m

olec

ular

wei

ght h

epar

in e

ffec

ts in

per

iphe

ral v

ascu

lar

dise

ase.

Ang

iolo

gy . 1

993;

44(3

):188

-195

. e M

anna

rino

E,

Pasq

ualin

i L

, In

noce

nte

S, O

rlan

di U

, Sc

ricc

iolo

V,

Lom

bard

ini

R,

Ciu

ffet

ti G

. E

ffi ca

cy o

f lo

w-m

olec

ular

wei

ght

hepa

rin

in t

he m

anag

emen

t of

int

erm

itten

t cl

audi

catio

n. A

ngio

logy

. 19

91;4

2(1)

:1-7

. f P

alm

ieri

G, A

mbr

osi G

, Agr

ati A

M, F

erra

ro G

, Mar

cozz

i S. A

new

low

mol

ecul

ar w

eigh

t hep

arin

in th

e tr

eatm

ent o

f per

iphe

ral a

rter

ial d

isea

se. I

nt A

ngio

l . 19

88;7

(sup

pl 3

):41-

47.

g In

four

of fi

ve

stud

ies,

dat

a on

wal

king

dis

tanc

e w

as p

rese

nted

in b

ar g

raph

form

onl

y. U

nabl

e to

ass

ess

mea

n di

ffer

ence

bet

wee

n tr

eatm

ent a

rms

in c

hang

e in

wal

king

dis

tanc

e in

thes

e st

udie

s.

h Cal

cula

ted

from

poo

led

stan

dard

ized

mea

n di

ffer

ence

s, c

onve

rted

into

ris

k di

ffer

ence

(ass

umed

con

trol

res

pons

e ra

te o

f 80%

).




Tabl

e S9

—[S

ecti

on 4

.1-4

.4]

Evi

denc

e P

rofi l

e: P

rost

agla

ndin

s vs

Pla

ceb

o in

Pat

ient

s W

ith

Inte

rmit

tent

Cla

udi

cati

on

Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

Part

icip

ants

(S

tudi

es),

Fol

low

-up

Ris

k of

Bia

sIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Publ

icat

ion

Bia

sR

elat

ive

Eff

ect

(95%

CI)

Est

imat

ion

of A

bsol

ute

Eff

ects

Qua

lity

of

Evi

denc

e

Eve

nt R

ate

With

No

Pros

tagl

andi

ns a

Ris

k D

iffer

ence

W

ith P

rost

agla

ndin

s (9

5% C

I)

Mor

talit

y (c

ritic

al o

utco

me )

∗

1,35

4 (3

RC

Ts),

6-

12 m

oSe

riou

s ri

sk o

f bia

sN

o se

riou

s

inco

nsis

tenc

yN

o se

riou

s

indi

rect

ness

Seri

ous

im

prec

isio

nC

Is in

clud

e be

nefi t

and

har

m;

only

5 e

vent

s

Und

etec

ted

RR

0.3

4 (0

.08-

2.39

)10

per

1,0

006

few

er p

er 1

,000

(fro

m 9

few

er to

14

mor

e)

Low

due

to b

ias

an

d im

prec

isio

n U

ncle

ar c

once

alm

ent

of

allo

catio

n in

al

l of t

he s

tudi

es

Qua

lity

of li

fe a

s in

ferr

ed fr

om m

axim

um w

alki

ng d

ista

nce

(impo

rtan

t out

com

e)

1,63

6 (5

RC

Ts),

3-

12 m

oSe

riou

s ri

sk o

f bia

sSe

riou

s

inco

nsis

tenc

y ( I

2 5 4

6%)

Seri

ous

in

dire

ctne

ssN

o se

riou

s

impr

ecis

ion

Und

etec

ted

1.09

(1.0

7-1.

12)

800

per

1,00

0 b 79

mor

e pe

r 1,

000

(5

8 m

ore

to

98 m

ore)

c

Low

due

to b

ias,

inco

nsis

tenc

y,

and

indi

rect

ness

U

ncle

ar c

once

alm

ent

of

allo

catio

n in

al

l of t

he s

tudi

es

Use

of s

urro

gate

end

poin

t

Maj

or e

xtra

cran

ial b

leed

ing

(cri

tical

out

com

e)

……

……

……

……

……

Non

fata

l MI

(cri

tical

out

com

e)

762

(1 R

CT

)

12 m

oSe

riou

s ri

sk o

f bia

sSi

ngle

stu

dy o

nly

No

seri

ous

in

dire

ctne

ssVe

ry s

erio

us

im

prec

isio

nU

ndet

ecte

dR

R 0

.09

(0.0

0-1.

60)

13 p

er 1

,000

11 fe

wer

per

1,0

00

(f

rom

13

few

er to

7

mor

e)

Low

due

to b

ias

an

d im

prec

isio

n U

ncle

ar c

once

alm

ent

of

allo

catio

n in

al

l of t

he s

tudi

es

Non

fata

l str

oke

(cri

tical

out

com

e)

762

(1 R

CT

)

12 m

oSe

riou

s ri

sk o

f bia

sSi

ngle

stu

dy o

nly

No

seri

ous

in

dire

ctne

ssVe

ry s

erio

us

im

prec

isio

nU

ndet

ecte

dR

R 1

.22

(0.3

3-4.

52)

10 p

er 1

,000

2 fe

wer

per

1,0

00

(f

rom

7 fe

wer

to

37

mor

e)

Low

due

to b

ias

an

d im

prec

isio

n U

ncle

ar c

once

alm

ent

of

allo

catio

n in

al

l of t

he s

tudi

es

Bib

liogr

aphy

: Mom

sen

AH

, Jen

sen

MB

, Nor

ager

CB

, Mad

sen

MR

, Ves

ters

gaar

d-A

nder

sen

T, L

indh

olt

JS. D

rug

ther

apy

for

impr

ovin

g w

alki

ng d

ista

nce

in in

term

itten

t cl

audi

catio

n: a

sys

tem

atic

rev

iew

an

d m

eta-

anal

ysis

of r

obus

t ran

dom

ised

con

trol

led

stud

ies.

Eur

J V

asc

End

ovas

c Su

rg . 2

009;

38(4

):463

-474

. See

Tab

le S

1 an

d S2

lege

nds

for

expa

nsio

n of

abb

revi

atio

ns.

a Con

trol

gro

up r

isk

estim

ates

com

e fr

om m

edia

n co

ntro

l rat

e or

rep

rese

ntat

ive

cont

rol g

roup

ris

k of

the

incl

uded

stu

dies

. b A

ssum

ed c

ontr

ol r

espo

nse

rate

of 8

0%.

c Cal

cula

ted

from

poo

led

stan

dard

ized

mea

n di

ffer

ence

s, c

onve

rted

into

ris

k di

ffer

ence

(ass

umed

con

trol

res

pons

e ra

te o

f 80%

)




Tabl

e S1

0 —[S

ecti

on 5

.1]

Evi

denc

e P

rofi l

e: P

rost

anoi

ds v

s P

lace

bo

in P

atie

nts

Wit

h C

riti

cal

Lim

b I

sche

mia

Ine

ligi

ble

for

Rev

ascu

lari

zati

on P

roce

dure

s

Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

Part

icip

ants

(s

tudi

es),

Fol

low

- up

Ris

k of

Bia

sIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Publ

icat

ion

Bia

sR

elat

ive

Eff

ect

(95%

CI)

Est

imat

ion

of A

bsol

ute

Eff

ects

Qua

lity

of

Evi

denc

e

Eve

nt

Rat

e W

ith

Plac

ebo

Ris

k di

ffer

ence

W

ith P

rost

anoi

ds

(95%

CI)

Res

t pai

n re

lief (

any

impr

ovem

ent o

n a

valid

ated

sca

le) (

impo

rtan

t out

com

e)

1,11

6 (9

RC

Ts),

21

.4 w

kSe

riou

s ri

sk o

f

bias

. Allo

catio

n an

d bl

indi

ng

conc

erns

No

seri

ous

in

cons

iste

ncy

No

seri

ous

in

dire

ctne

ssN

o im

prec

isio

nU

ndet

ecte

dR

R 1

.32

(1.1

-1.5

7)24

3 pe

r 1,

000 a

77 m

ore

per

1,00

0

(fro

m 2

4 m

ore

to

138

mor

e)

Mod

erat

e du

e to

risk

of b

ias

Ulc

er h

ealin

g (a

ny d

ecre

ase

in s

ize

of u

lcer

or

pres

ence

of g

ranu

latio

n tis

sue)

(im

port

ant o

utco

me)

1,13

2 (8

RC

Ts),

17

.5 w

kSe

riou

s ri

sk o

f

bias

. Allo

catio

n an

d bl

indi

ng

conc

erns

Seri

ous

in

cons

iste

ncy

( I 2 5

44%

)

No

seri

ous

in

dire

ctne

ssN

o im

prec

isio

nU

ndet

ecte

dR

R 1

.54

(1.2

2-1.

96)

253

per

1,00

0 a 13

6 m

ore

per

1,00

0

(fro

m 5

5 m

ore

to

242

mor

e)

Low

due

to

ri

sk o

f bia

s an

d in

cons

iste

ncy

Am

puta

tions

(maj

or o

r m

inor

am

puta

tions

) (cr

itica

l out

com

e)

1,79

0 (9

RC

Ts),

23

.1 w

kSe

riou

s ri

sk o

f

bias

. Allo

catio

n an

d bl

indi

ng

conc

erns

No

seri

ous

in

cons

iste

ncy

No

seri

ous

in

dire

ctne

ssSe

riou

s im

prec

isio

nU

ndet

ecte

dR

R 0

.89

(0.7

6-1.

04)

313

per

1,00

0 a 34

few

er p

er 1

,000

(fro

m 7

5 fe

wer

to

12 m

ore)

Low

due

to

ri

sk o

f bia

s,

inco

nsis

tenc

y,

and

impr

ecis

ion

CI

incl

udes

bot

h

bene

fi ts

and

harm

s

Mor

talit

y (c

ritic

al o

utco

me)

1,39

1 (5

RC

Ts),

32

wk

Seri

ous

risk

of

bi

as. A

lloca

tion

and

blin

ding

co

ncer

ns

Seri

ous

in

cons

iste

ncy

( I 2 5

40%

)

No

seri

ous

in

dire

ctne

ssSe

riou

s im

prec

isio

nU

ndet

ecte

dR

R 1

.07

(0.6

5-1.

75)

121

per

1,00

0 a 8

mor

e pe

r 1,

000

(f

rom

42

few

er

to 9

0 m

ore)

Low

due

to

ri

sk o

f bia

s,

inco

nsis

tenc

y,

and

impr

ecis

ion

CI

incl

udes

bot

h

bene

fi ts

and

harm

s;

smal

l num

ber

of

even

ts (1

45)

Adv

erse

eve

nts

(impo

rtan

t out

com

e)

716

(8 R

CTs

),

14.4

mo

Seri

ous

risk

of

bi

as. A

lloca

tion

and

blin

ding

co

ncer

ns

No

seri

ous

in

cons

iste

ncy

No

seri

ous

in

dire

ctne

ssN

o im

prec

isio

nU

ndet

ecte

dR

R 2

.35

(1.9

9-2.

78)

77 p

er 1

,000

a 10

3 m

ore

per

1,00

0

(fro

m 7

6 m

ore

to

137

mor

e)

Mod

erat

e du

e to

risk

of b

ias

394

per

1,00

0 a 53

1 m

ore

per

1,00

0

(fro

m 3

90 m

ore

to

701

mor

e)

Bib

liogr

aphy

: Ruf

folo

AJ,

Rom

ano

M, C

iapp

oni A

. Pro

stan

oids

for

criti

cal l

imb

isch

emia

. Coc

hran

e D

atab

ase

of S

yst R

ev . 2

010;

(1):C

D00

6544

. See

Tab

le S

2 le

gend

for

expa

nsio

n of

abb

revi

atio

ns.

a Con

trol

gro

up r

isk

estim

ates

com

e fr

om m

edia

n co

ntro

l rat

e or

rep

rese

ntat

ive

cont

rol g

roup

ris

k of

the

incl

uded

stu

dies

. For

res

t pa

in r

elie

f or

ulc

er h

ealin

g co

ntro

l rat

es r

epre

sent

num

ber

of s

ubje

cts

with

impr

ovem

ent i

n co

ntro

l arm

.




Tabl

e S1

1 —[S

ecti

on 6

.1-6

.3]

Evi

denc

e P

rofi l

e: T

hrom

bol

ysis

vs

Surg

ery

for

the

Tre

atm

ent

of A

cute

Lim

b I

sche

mia

Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

Part

icip

ants

(S

tudi

es),

Fol

low

-up

Ris

k of

Bia

sIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Publ

icat

ion

Bia

sR

elat

ive

Eff

ect

(95%

CI)

Est

imat

ion

of A

bsol

ute

Eff

ects

Qua

lity

of

Evi

denc

e W

ith S

urge

ryR

isk

Diff

eren

ce W

ith

Thr

ombo

lysi

s (9

5% C

I)

Lim

b sa

lvag

e at

1 y

(cri

tical

out

com

e)

654

(2 R

CTs

), a

12 m

oN

o se

riou

s

risk

of b

ias

Seri

ous

in

cons

iste

ncy

( I 2 5

49%

)

No

seri

ous

in

dire

ctne

ssSe

riou

s im

prec

isio

n

CI

incl

udes

har

ms

and

bene

fi ts

Und

etec

ted

RR

1.0

0 (0

.86-

1.17

)75

4 pe

r 1,

000 b

0 fe

wer

per

1,0

00

(f

rom

106

few

er to

12

8 m

ore)

Low

due

to

in

cons

iste

ncy

and

impr

ecis

ion

Am

puta

tion

at 1

y (c

ritic

al o

utco

me)

768

(3 R

CTs

), a

12 m

oN

o se

riou

s

risk

of b

ias

No

seri

ous

in

cons

iste

ncy

No

seri

ous

in

dire

ctne

ssSe

riou

s im

prec

isio

n

CI

incl

udes

har

ms

and

bene

fi ts

Low

num

ber

of e

vent

s

Und

etec

ted

RR

1.1

0 (0

.88-

1.38

)19

0 pe

r 1,

000 b

19 m

ore

per

1,00

0

(fro

m 2

2 fe

wer

to

72 m

ore)

Mod

erat

e du

e to

impr

ecis

ion

Dea

th a

t 1 y

(cri

tical

out

com

e) c

768

(3 R

CTs

), a

12 m

oN

o se

riou

s

risk

of b

ias

Seri

ous

in

cons

iste

ncy

( I 2 5

80%

)

No

seri

ous

in

dire

ctne

ssSe

riou

s im

prec

isio

n

CI

incl

udes

har

ms

and

bene

fi ts

Und

etec

ted

RR

0.7

4 (0

.35-

1.58

)16

9 pe

r 1,

000 b

43 fe

wer

per

1,0

00

(f

rom

109

few

er to

98

mor

e)

Low

due

to

in

cons

iste

ncy

and

impr

ecis

ion

Stro

ke a

t 30

d (c

ritic

al o

utco

me)

d

1,18

0 (5

RC

Ts), a,

e

1-12

mo

No

seri

ous

ri

sk o

f bia

sN

o se

riou

s

inco

nsis

tenc

yN

o se

riou

s

indi

rect

ness

Seri

ous

in

cons

iste

ncy

CI

incl

udes

har

ms

and

bene

fi ts

Low

num

ber

of e

vent

s (8

)

Und

etec

ted

0.01

(0.0

0-0.

02) f

0 pe

r 1,

000 b

10 m

ore

per

1,00

0

(fro

m 0

few

er to

20

mor

e)

Mod

erat

e du

e to

impr

ecis

ion

Ext

racr

ania

l maj

or h

emor

rhag

e at

30

d

1,07

0 (4

RC

Ts), a

1-

12 m

oN

o se

riou

s

risk

of b

ias g

No

seri

ous

in

cons

iste

ncy

No

seri

ous

in

dire

ctne

ss d

Seri

ous

impr

ecis

ion

C

I in

clud

es h

arm

s an

d be

nefi t

s L

ow n

umbe

r of

eve

nts

(60)

Und

etec

ted

RR

2.3

4 (1

.32-

4.14

)12

per

1,0

00 b

16 m

ore

per

1,00

0

(fro

m 3

mor

e to

37

mor

e)

Mod

erat

e du

e to

impr

ecis

ion

Bib

liogr

aphy

: Ber

ridg

e D

C, K

esse

l D

, Rob

erts

on I

. Sur

gery

ver

sus

thro

mbo

lysi

s fo

r ac

ute

limb

isch

aem

ia: i

nitia

l m

anag

emen

t. C

ochr

ane

Dat

abas

e Sy

st R

ev . 2

002;

(3):C

D00

2784

. Our

iel

K, V

eith

FJ,

Sa

saha

ra A

A;

Thr

ombo

lysi

s or

Per

iphe

ral

Art

eria

l Su

rger

y (T

OPA

S) I

nves

tigat

ors.

The

ST

ILE

inv

estig

ator

s. R

esul

ts o

f a

pros

pect

ive

rand

omiz

ed t

rial

eva

luat

ing

surg

ery

vers

us t

hrom

boly

sis

for

isch

aem

ia o

f the

low

er e

xtre

mity

. Ann

Sur

g . 1

994;

220(

3):2

51-2

68. A

com

pari

son

of r

ecom

bina

nt u

roki

nase

with

vas

cula

r su

rger

y as

initi

al tr

eatm

ent f

or a

cute

art

eria

l occ

lusi

on o

f the

legs

. N E

ngl J

Med

. 19

98;3

38(1

6):1

105-

1111

. See

Tab

le S

2 le

gend

for

expa

nsio

n of

abb

revi

atio

ns.

a For

one

stu

dy u

sing

thre

e di

ffer

ent d

oses

of t

he th

rom

boly

tic a

gent

, onl

y th

e op

timal

dos

e is

use

d fo

r co

mpa

riso

n w

ith s

urge

ry.

b Con

trol

gro

up r

isk

estim

ates

from

med

ian

or r

epre

sent

ativ

e co

ntro

l gro

up r

isk

of in

clud

ed s

tudi

es.

c Our

iel e

t al (

1998

) rep

orte

d th

at o

ne in

54

deat

hs in

the

thro

mbo

lysi

s gr

oup

wer

e fr

om in

trac

rani

al h

emor

rhag

e, w

here

as n

one

of 4

6 in

the

surg

ery

grou

p w

ere

from

intr

acra

nial

hem

orrh

age.

d O

f rep

orte

d no

nfat

al s

trok

es, a

ll ha

ppen

ed in

the

thro

mbo

lysi

s gr

oup

and

all w

ere

intr

acra

nial

hem

orrh

ages

(8/8

[100

%])

. e S

TIL

E in

vest

igat

ors

et a

l (19

94 ) i

nclu

ded

patie

nts

with

bot

h ac

ute

and

chro

nic

limb

isch

emia

. f P

oole

d ri

sk d

iffer

ence

pre

sent

ed in

stea

d of

rel

ativ

e ri

sk.

g Con

ceal

men

t of a

lloca

tion

uncl

ear

in o

ne s

tudy

.




Tabl

e S1

2 —[S

ecti

on 6

.1-6

.3]

Evi

denc

e P

rofi l

e: I

ntra

arte

rial

Uro

kina

se v

s In

traa

rter

ial

rt-P

A f

or A

cute

Lim

b I

sche

mia

Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

Part

icip

ants

(S

tudi

es),

Fol

low

-up

Ris

k of

Bia

sIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Publ

icat

ion

Bia

sR

R (9

5% C

I)

Est

imat

ion

of A

bsol

ute

Eff

ects

Qua

lity

of

Evi

denc

e

Eve

nt R

ate

With

In

traa

rter

ial r

t-PA

Ris

k D

iffer

ence

W

ith U

roki

nase

(9

5% C

I)

All-

caus

e m

orta

lity

(cri

tical

out

com

e)

368

(3 R

CTs

), 1-

6 m

oSe

riou

s ri

sk o

f

bias

. Unc

lear

co

ncea

lmen

t of

allo

catio

n

No

seri

ous

in

cons

iste

ncy

No

seri

ous

in

dire

ctne

ssSe

riou

s im

prec

isio

n

CIs

are

wid

e an

d in

clud

e be

nefi t

an

d ha

rm

Und

etec

ted

RR

0.7

9 (0

.26-

2.46

)19

per

1,0

00 a

4 fe

wer

per

1,0

00

(f

rom

14

few

er to

27

mor

e)

Low

due

to

ri

sk o

f bia

s an

d im

prec

isio

n

Am

puta

tion

(cri

tical

out

com

e)

368

(3 R

CTs

), 1-

6 m

oSe

riou

s ri

sk o

f

bias

. Unc

lear

co

ncea

lmen

t of

allo

catio

n

No

seri

ous

in

cons

iste

ncy

No

seri

ous

in

dire

ctne

ssSe

riou

s im

prec

isio

n

CIs

are

wid

e an

d in

clud

e be

nefi t

an

d ha

rm

Und

etec

ted

RR

0.7

8 (0

.23,

2.7

1)89

per

1,0

00 a

20 fe

wer

per

1,0

00

(f

rom

68

few

er to

15

2 m

ore)

Low

due

to

ri

sk o

f bia

s an

d im

prec

isio

n

Maj

or n

onfa

tal e

xtra

cran

ial b

leed

(im

port

ant o

utco

me)

298

(3 R

CTs

), 1-

6 m

oSe

riou

s ri

sk o

f

bias

. Unc

lear

co

ncea

lmen

t of

allo

catio

n

No

seri

ous

in

cons

iste

ncy

No

seri

ous

in

dire

ctne

ssSe

riou

s im

prec

isio

nU

ndet

ecte

dR

R 0

.69

(0.2

3-2.

06)

8 pe

r 1,

000 a

2 fe

wer

per

1,0

00

(f

rom

6 fe

wer

to

8 m

ore)

Low

due

to

ri

sk o

f bia

s an

d im

prec

isio

n C

I in

clud

es h

arm

and

bene

fi t

Bib

liogr

aphy

: Rob

erts

on I

, Kes

sel D

O, B

erri

dge

DC

. Fib

rino

lytic

age

nts

for

peri

pher

al a

rter

ial o

cclu

sion

. Coc

hran

e D

atab

ase

Syst

Rev

. 201

0;(3

):CD

0010

99. S

ee T

able

S1

and

S2 le

gend

s fo

r ex

pans

ion

of a

bbre

viat

ions

. a C

ontr

ol g

roup

ris

k es

timat

e co

mes

from

med

ian

even

t rat

e in

the

rt-P

A a

rm.




Tabl

e S1

3 —[S

ecti

on 8

.1-8

.3]

Evi

denc

e P

rofi l

e: A

spir

in p

lus

Dip

yrid

amol

e vs

Pla

ceb

o fo

r P

reve

ntio

n of

Thr

omb

osis

Aft

er P

erip

hera

l B

ypas

s Su

rger

y

Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

Part

icip

ants

(S

tudi

es),

Fol

low

-up

Ris

k of

Bia

sIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Publ

icat

ion

Bia

sR

elat

ive

Eff

ect

(95%

CI)

Est

imat

ion

of A

bsol

ute

Eff

ects

Ti

me

Peri

od: 1

y

Qua

lity

of

Evi

denc

e E

vent

Rat

e W

ith C

ontr

ol a

Diff

eren

ce W

ith

Asp

irin

1 D

ipyr

idam

ole

(95%

CI)

Am

puta

tion

infe

rred

from

loss

of p

rim

ary

graf

t pat

ency

(cri

tical

out

com

e)

966

(6 R

CTs

), 12

mo

Seri

ous

ri

sk o

f bia

s b N

o se

riou

s

inco

nsis

tenc

ySe

riou

s in

dire

ctne

ss

L

oss

of g

raft

pa

tenc

y is

a

surr

ogat

e

No

seri

ous

im

prec

isio

nU

ndet

ecte

dR

R 0

.68

(0.5

5-0.

83)

71 p

er 1

,000

22 fe

wer

per

1,0

00

(f

rom

32

few

er to

12

few

er)

Low

due

to

ri

sk o

f bia

s an

d

indi

rect

ness

Am

puta

tion

(cri

tical

out

com

e)

148

(1 R

CT

), 12

mo

Seri

ous

ri

sk o

f bia

s b N

o se

riou

s

inco

nsis

tenc

yN

o se

riou

s

indi

rect

ness

Seri

ous

im

prec

isio

n c U

ndet

ecte

dR

R 0

.52

(0.2

7-1.

01)

71 p

er 1

,000

34 fe

wer

per

1,0

00

(f

rom

51

few

er to

1

mor

e)

Low

due

to

ri

sk o

f bia

s an

d im

prec

isio

n

Dea

th (c

ritic

al o

utco

me)

750

(3 R

CTs

), 12

mo

No

risk

of b

ias

No

seri

ous

in

cons

iste

ncy

No

seri

ous

in

dire

ctne

ssSe

riou

s

impr

ecis

ion c

Und

etec

ted

RR

0.8

6 (0

.6-1

.22)

105

per

1,00

014

few

er p

er 1

,000

(fro

m 4

2 fe

wer

to

23 m

ore)

Mod

erat

e du

e to

impr

ecis

ion

MI

(cri

tical

out

com

e)

667

(3 R

CTs

), 12

mo

No

risk

of b

ias

No

seri

ous

in

cons

iste

ncy

No

seri

ous

in

dire

ctne

ssSe

riou

s

impr

ecis

ion c

Und

etec

ted

RR

0.6

5 (0

.4-1

.06)

28 p

er 1

,000

9 fe

wer

per

1,0

00

(f

rom

16

few

er to

1

mor

e)

Mod

erat

e du

e to

impr

ecis

ion

Stro

ke d (

criti

cal o

utco

me)

667

(3 R

CTs

), 12

mo

No

risk

of b

ias

No

seri

ous

in

cons

iste

ncy

No

seri

ous

in

dire

ctne

ssSe

riou

s

impr

ecis

ion c

Und

etec

ted

RR

0.7

9 (0

.42-

1.49

)27

per

1,0

005

few

er p

er 1

,000

(fro

m 1

5 fe

wer

to

13 m

ore)

Mod

erat

e du

e to

impr

ecis

ion

Maj

or e

xtra

cran

ial b

leed

ing e (

criti

cal o

utco

me)

598

(2 R

CTs

), 12

mo

No

risk

of b

ias

No

seri

ous

in

cons

iste

ncy

No

seri

ous

in

dire

ctne

ssSe

riou

s

impr

ecis

ion c

Und

etec

ted

RR

1.8

6 (0

.85-

4.04

)10

per

1,0

008

mor

e pe

r 1,

000

(f

rom

1 fe

wer

to

30 m

ore)

Mod

erat

e du

e to

impr

ecis

ion

Bib

liogr

aphy

: B

row

n J,

Let

haby

A,

Max

wel

l H

, W

awrz

ynia

k A

J, P

rins

MH

. A

ntip

late

let

agen

ts f

or p

reve

ntin

g th

rom

bosi

s af

ter

peri

pher

al a

rter

ial

bypa

ss s

urge

ry.

Coc

hran

e D

atab

ase

Syst

Rev

. 20

08;(4

):CD

0005

35. S

tudy

Gro

up o

n Ph

arm

acol

ogic

al T

reat

men

t A

fter

TPA

. Pla

tele

t in

hibi

tion

with

ASA

/dip

yrid

amol

e af

ter

perc

utan

eous

bal

loon

ang

iopl

asty

in p

atie

nts

with

sym

ptom

atic

low

er li

mb

arte

rial

dis

ease

. A p

rosp

ectiv

e do

uble

-blin

d tr

ial.

Eur

J V

asc

Surg

. 199

4;8(

1):8

3-88

. BO

A 5

Dut

ch B

ypas

s O

ral A

ntic

oagu

lant

s or

Asp

irin

. See

Tab

le S

1 an

d S2

lege

nds

for

expa

nsio

n of

oth

er a

bbre

viat

ions

. a C

ontr

ol g

roup

ris

k es

timat

e de

rive

d fr

om a

pplic

atio

n of

rel

ativ

e ri

sk o

f pla

cebo

vs

aspi

rin/

dipy

rida

mol

e to

asp

irin

eve

nt r

ate

in a

larg

e R

CT

(BO

A) c

ompa

ring

war

fari

n to

asp

irin

follo

win

g pe

riph

eral

art

ery

bypa

ss s

urge

ry (S

tudy

Gro

up o

n Ph

arm

acol

ogic

al T

reat

men

t Aft

er T

PA, 1

994)

. b P

robl

ems

with

allo

catio

n co

ncea

lmen

t and

blin

ding

. c L

ow n

umbe

r of

eve

nts,

CI

incl

udes

impo

rtan

t ben

efi ts

and

har

ms.

d N

one

of th

e st

roke

s w

as d

ue to

intr

acra

nial

ble

edin

g.

e Of t

hese

ble

edin

gs, fi

ve

of 1

9 (2

6%) w

ere

GI.




Tabl

e S1

4 —[S

ecti

on 8

.1-8

.3]

Evi

denc

e P

rofi l

e: A

spir

in a

nd C

lopi

dogr

el v

s A

spir

in A

lone

for

Pat

ient

s W

ith

PAD

Pos

tsu

rgic

al B

elow

Kne

e R

evas

cula

riza

tion

(V

enou

s or

Pro

sthe

tic

Gra

fts)

Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

Part

icip

ants

(S

tudi

es),

Fol

low

- up

Ris

k of

Bia

sIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Publ

icat

ion

Bia

sR

elat

ive

Eff

ect

(95%

CI)

Est

imat

ion

of A

bsol

ute

Eff

ects

Ti

me

Peri

od: 1

y

Qua

lity

of

Evi

denc

e R

isk

With

A

spir

in a

Ris

k D

iffer

ence

With

A

spir

in 1

Clo

pido

grel

(9

5% C

I)

All

caus

e m

orta

lity

(cri

tical

out

com

e)

851

(1 R

CT

),

mea

n �

11

mo a

No

seri

ous

ri

sk o

f bia

s b N

o se

riou

s

inco

nsis

tenc

yN

o se

riou

s

indi

rect

ness

Seri

ous

impr

ecis

ion

C

Is in

clud

e si

gnifi

cant

ha

rm a

nd b

enefi

t (n

o. e

vent

s 5 4

1)

Und

etec

ted

RR

1.4

2 (0

.77-

2.60

)90

per

1,0

0037

mor

e pe

r 1,

000

(f

rom

20

few

er to

14

4 m

ore)

Mod

erat

e du

e to

impr

ecis

ion

MI

(cri

tical

out

com

e): n

ot r

epor

ted

……

……

……

……

……

Stro

ke (c

ritic

al o

utco

me)

: not

rep

orte

d

……

……

……

……

……

Ext

racr

ania

l maj

or b

leed

ing

(cri

tical

out

com

e); s

ever

e G

UST

O c

rite

ria c

851

(1 R

CT

),

mea

n �

11

mo a

No

seri

ous

ri

sk o

f bia

s b N

o se

riou

s

inco

nsis

tenc

yN

o se

riou

s

indi

rect

ness

Seri

ous

impr

ecis

ion

(n

o. e

vent

s 5 1

4U

ndet

ecte

dR

R 1

.73

(0.5

1-5.

88)

19 p

er 1

,000

13 m

ore

per

1,00

0

(fro

m 9

few

er to

92

mor

e)

Mod

erat

e du

e to

impr

ecis

ion

Am

puta

tions

(cri

tical

out

com

e)

851

(1 R

CT

),

mea

n �

11

mo a

No

seri

ous

ri

sk o

f bia

s b N

o se

riou

s

inco

nsis

tenc

yN

o se

riou

s

indi

rect

ness

Seri

ous

impr

ecis

ion

C

Is in

clud

e si

gnifi

cant

ha

rm a

nd b

enefi

t (n

o. e

vent

s 5 7

6)

Und

etec

ted

HR

0.6

9 (0

.45-

1.07

)48

per

1,0

0014

few

er p

er 1

,000

(fro

m 2

6 fe

wer

to

3 m

ore)

Mod

erat

e du

e to

impr

ecis

ion

Bib

liogr

aphy

: Bel

ch J

J, D

orm

andy

J, B

iasi

GM

, et

al. R

esul

ts o

f th

e ra

ndom

ized

, pla

cebo

-con

trol

led

clop

idog

rel a

nd a

cety

lsal

icyl

ic a

cid

in b

ypas

s su

rger

y fo

r pe

riph

eral

art

eria

l dis

ease

(C

ASP

AR

) tr

ial.

J V

asc

Surg

. 201

0;52

(4):8

25-8

33. S

ee T

able

S1,

S2,

S5,

and

S14

lege

nds

for

expa

nsio

n of

abb

revi

atio

ns.

a Con

trol

gro

up r

ates

obt

aine

d fr

om e

vent

rat

es in

asp

irin

arm

of B

OA

stu

dy n

orm

aliz

ed to

1 y

. b E

ight

pat

ient

s lo

st to

follo

w-u

p in

the

inte

rven

tion

grou

p (a

spir

in 1

clop

idog

rel)

and

11 p

atie

nts

in th

e co

mpa

riso

n gr

oup

(asp

irin

gro

up).

c Fat

al b

leed

ing

even

ts w

ere

two

of 4

26 in

the

inte

rven

tion

grou

p (a

spir

in 1

clop

idog

rel g

roup

) and

one

of 4

22 in

the

com

pari

son

grou

p (a

spir

in g

roup

).




Tabl

e S1

5 —[S

ecti

on 8

.1-8

.3]

Evi

denc

e P

rofi l

e: A

spir

in a

nd C

lopi

dogr

el v

s A

spir

in A

lone

for

Pat

ient

s W

ith

PAD

Pos

tsu

rgic

al B

elow

Kne

e R

evas

cula

riza

tion

Wit

h P

rost

heti

c G

raft

s

Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

Part

icip

ants

(s

tudi

es),

Fol

low

-up

Ris

k of

Bia

sIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Publ

icat

ion

Bia

sR

elat

ive

Eff

ect

(95%

CI)

Est

imat

ion

of A

bsol

ute

Eff

ects

Ti

me

Peri

od: 1

y

Qua

lity

of

Evi

denc

e R

isk

With

A

spir

in a

Ris

k D

iffer

ence

With

A

spir

in 1

Clo

pido

grel

(9

5% C

I)

All-

caus

e m

orta

lity

(cri

tical

out

com

e)

253

(1 R

CT

),

mea

n �

11

mo a

No

seri

ous

ri

sk o

f bia

sN

o se

riou

s

inco

nsis

tenc

yN

o se

riou

s

indi

rect

ness

Very

ser

ious

impr

ecis

ion

CIs

incl

ude

sign

ifi ca

nt h

arm

an

d be

nefi t

(n

o. e

vent

s 5 1

0)

Und

etec

ted

RR

1.4

6 (0

.42-

5.07

)90

per

1,0

0041

mor

e pe

r 1,

000

(f

rom

52

few

er to

36

6 m

ore)

Low

due

to

im

prec

isio

n

MI

(cri

tical

out

com

e): n

ot r

epor

ted

Stro

ke (c

ritic

al o

utco

me)

: not

rep

orte

d

Ext

racr

ania

l maj

or b

leed

ing

(cri

tical

out

com

e); s

ever

e G

UST

O c

rite

ria b

253

(1 R

CT

),

mea

n �

11

mo a

No

seri

ous

ri

sk o

f bia

sN

o se

riou

s

inco

nsis

tenc

yN

o se

riou

s

indi

rect

ness

Very

ser

ious

impr

ecis

ion

(no.

eve

nts 5

3)

Und

etec

ted

RR

0.5

0 (0

.05-

5.44

)19

per

1,0

009

few

er p

er 1

,000

(fro

m 1

8 fe

wer

to

84 m

ore)

Low

due

to

im

prec

isio

n

Am

puta

tions

(cri

tical

out

com

e)

253

(1 R

CT

),

mea

n �

11

mo a

No

seri

ous

ri

sk o

f bia

sN

o se

riou

s

inco

nsis

tenc

yN

o se

riou

s

indi

rect

ness

Very

ser

ious

impr

ecis

ion

C

Is in

clud

e si

gnifi

cant

ha

rm a

nd b

enefi

t (n

o. e

vent

s 5 3

6)

Und

etec

ted

HR

0.4

9 (0

.26-

0.93

)48

per

1,0

0024

few

er p

er 1

,000

(fro

m 3

5 fe

wer

to

3 fe

wer

)

Low

due

to

im

prec

isio

n

Bib

liogr

aphy

: Bel

ch J

J, D

orm

andy

J, B

iasi

GM

, et

al. R

esul

ts o

f th

e ra

ndom

ized

, pla

cebo

-con

trol

led

clop

idog

rel a

nd a

cety

lsal

icyl

ic a

cid

in b

ypas

s su

rger

y fo

r pe

riph

eral

art

eria

l dis

ease

(C

ASP

AR

) tr

ial.

J V

asc

Surg

. 201

0;52

(4):8

25-8

33. H

R 5

haz

ard

ratio

. See

Tab

le S

1, S

2, S

5, a

nd S

14 le

gend

s fo

r ex

pans

ion

of o

ther

abb

revi

atio

ns.

a Con

trol

gro

up r

isk

estim

ates

obt

aine

d fr

om e

vent

rat

es in

asp

irin

arm

of B

OA

stu

dy, n

orm

aliz

ed to

1 y

. b U

ncle

ar w

heth

er a

ny o

f sev

ere

blee

ds w

ere

fata

l.




Tabl

e S1

6 —[S

ecti

on 8

.1-8

.3]

Evi

denc

e P

rofi l

e: W

arfa

rin

vs A

spir

in f

or P

atie

nts

Wit

h PA

D P

osts

urg

ical

Rev

ascu

lari

zati

on

Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

Part

icip

ants

(S

tudi

es),

Fol

low

-up

Ris

k of

Bia

sIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Publ

icat

ion

Bia

sR

elat

ive

Eff

ect

(95%

CI)

Est

imat

ion

of A

bsol

ute

Eff

ects

Ti

me

Peri

od: 1

y

Qua

lity

of

Evi

denc

e R

isk

With

A

spir

in a

Ris

k D

iffer

ence

W

ith O

AC

(95%

CI)

All-

caus

e m

orta

lity

(cri

tical

out

com

e)

2 65

0 (1

RC

T) 2

1 m

oN

o se

riou

s

risk

of b

ias b

No

seri

ous

in

cons

iste

ncy

No

seri

ous

in

dire

ctne

ssSe

riou

s im

prec

isio

n

CIs

incl

ude

sign

ifi ca

nt

harm

and

ben

efi t

(no.

eve

nts

, 4

00)

Und

etec

ted

RR

1.0

3 (0

.86-

1.23

)90

per

1,0

002

mor

e pe

r 1,

000

(f

rom

22

few

er to

20

mor

e)

Mod

erat

e du

e to

impr

ecis

ion

MI

(cri

tical

out

com

e), i

nclu

ding

fata

l str

okes

2 65

0 (1

RC

T) 2

1 m

oN

o se

riou

s

risk

of b

ias b

No

seri

ous

in

cons

iste

ncy

No

seri

ous

in

dire

ctne

ssSe

riou

s im

prec

isio

n

CIs

incl

ude

sign

ifi ca

nt

harm

and

ben

efi t

(no.

eve

nts

, 4

00)

Und

etec

ted

RR

0.6

9 (0

.43-

1.1)

18 p

er 1

,000

5 fe

wer

per

1,0

00

(f

rom

10

few

er to

1

mor

e)

Mod

erat

e du

e to

impr

ecis

ion

Stro

ke (c

ritic

al o

utco

me)

, c inc

ludi

ng is

chem

ic, h

emor

rhag

ic, a

nd o

ther

str

oke

type

s; in

clud

es fa

tal s

trok

es

2 65

0 (1

RC

T) 2

1 m

oN

o se

riou

s

risk

of b

ias b

No

seri

ous

in

cons

iste

ncy

No

seri

ous

in

dire

ctne

ssSe

riou

s im

prec

isio

n

CIs

incl

ude

sign

ifi ca

nt

harm

and

ben

efi t

(no.

eve

nts

, 4

00)

Und

etec

ted

RR

0.7

4 (0

.48-

1.14

)21

per

1,0

005

few

er p

er 1

,000

(fro

m 1

1 fe

wer

to

2 m

ore)

Mod

erat

e du

e to

impr

ecis

ion

Ext

racr

ania

l maj

or b

leed

ing

(cri

tical

out

com

e) d ;

nonf

atal

ble

edin

g re

quir

ing

hosp

italiz

atio

n, e

xclu

ding

all

repo

rts

of in

trac

rani

al h

emor

rhag

e or

pos

tsur

gica

l ble

edin

g

2 65

0 (1

RC

T) 2

1 m

oN

o se

riou

s

risk

of b

ias b

No

seri

ous

in

cons

iste

ncy

No

seri

ous

in

dire

ctne

ssSe

riou

s im

prec

isio

n

(no.

eve

nts

, 4

00)

Und

etec

ted

RR

1.9

0 (1

.33-

2.73

)19

per

1,0

0017

mor

e pe

r 1,

000

(f

rom

6 m

ore

to

32 m

ore)

Mod

erat

e du

e to

impr

ecis

ion

Lim

b lo

ss (c

ritic

al o

utco

me)

; all

ampu

tatio

n (ip

sila

tera

l and

con

tral

ater

al)

2 65

0 (1

RC

T) 2

1 m

oN

o se

riou

s

risk

of b

ias b

No

seri

ous

in

cons

iste

ncy

No

seri

ous

in

dire

ctne

ssSe

riou

s im

prec

isio

n

CIs

incl

ude

sign

ifi ca

nt

harm

and

ben

efi t

(no.

eve

nts

, 4

00)

Und

etec

ted

RR

0.9

1 (0

.7-1

.18)

48 p

er 1

,000

4 fe

wer

per

1,0

00

(f

rom

14

few

er to

8

mor

e)

Mod

erat

e du

e to

impr

ecis

ion

Bib

liogr

aphy

: D

utch

Byp

ass

Ora

l A

ntic

oagu

lant

s or

Asp

irin

(B

OA

) St

udy

Gro

up.

Effi

cacy

of

oral

ant

icoa

gula

nts

com

pare

d w

ith a

spir

in a

fter

inf

rain

guin

al b

ypas

s su

rger

y (T

he D

utch

Byp

ass

Ora

l A

ntic

oagu

lant

s or

Asp

irin

Stu

dy):

a ra

ndom

ised

tria

l. L

ance

t . 20

00;3

55(9

201)

:346

-351

. See

Tab

le S

1 an

d S2

lege

nds

for

expa

nsio

n of

abb

revi

atio

ns.

a Con

trol

gro

up r

isk

estim

ates

obt

aine

d fr

om e

vent

rat

es in

asp

irin

arm

of s

tudy

, nor

mal

ized

to 1

y.

b Thi

rtee

n an

d 27

pat

ient

s w

ithdr

ew fr

om th

e w

arfa

rin

and

aspi

rin

arm

s, r

espe

ctiv

ely.

Not

incl

uded

in a

naly

sis.

Six

teen

and

13

patie

nts

wer

e lo

st to

follo

w-u

p, r

espe

ctiv

ely;

incl

uded

in th

e an

alys

is.

c Hem

orrh

agic

str

okes

: 14

of 1

,326

in th

e in

terv

entio

n (O

AC

) gro

up a

nd fo

ur o

f 1,3

24 in

the

com

pari

son

(ant

ipla

tele

t age

nt) g

roup

. d F

atal

ble

edin

g ev

ents

: 16

of 1

,326

in th

e in

terv

entio

n gr

oup

(OA

C g

roup

) and

12

of 1

,324

in th

e co

mpa

riso

n gr

oup

(ant

ipla

tele

t age

nt g

roup

).



DOI 10.1378/chest.11-2307 2012;141; e669S-e690SChest

Maarten G. Lansberg, Gordon H. Guyatt and Frederick A. SpencerRandolph Guzman, Michael H. Criqui, Elie A. Akl, Per Olav Vandvik,

Pablo Alonso-Coello, Sergi Bellmunt, Catherine McGorrian, Sonia S. Anand,Chest Physicians Evidence-Based Clinical Practice Guidelines

Therapy and Prevention of Thrombosis, 9th ed: American College of Antithrombotic Therapy in Peripheral Artery Disease : Antithrombotic

February 26, 2012This information is current as of

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Disease : Antithrombotic Therapy and Prevention of ... · CHEST Supplement CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e669S ANTITHROMBOTIC THERAPY AND PREVENTION OF THROMBOSIS, 9TH