2011 ACCF/AHA Focused update of the guideline for the management of patients with peripheral artery disease (updating the 2005 guideline)
2011; Elsevier BV; Volume: 54; Issue: 5 Linguagem: Inglês
10.1016/j.jvs.2011.09.001
ISSN1097-6809
AutoresThom W. Rooke, Alan T. Hirsch, Sanjay Misra, Anton N. Sidawy, Joshua A. Beckman, Laura Findeiss, Jafar Golzarian, Heather L. Gornik, Jonathan L. Halperin, Michael R. Jaff, Gregory L. Moneta, Jeffrey W. Olin, James C. Stanley, Christopher J. White, John V. White, R. Eugene Zierler,
Tópico(s)Vascular Procedures and Complications
ResumoAlice K. Jacobs MD, FACC, FAHA, Chair, Jeffrey L. Anderson, MD, FACC, FAHA, Chair-Elect, Nancy Albert, PhD, CCNS, CCRN, FAHA; Mark A. Creager, MD, FACC, FAHA; Steven M. Ettinger, MD, FACC; Robert A. Guyton, MD, FACC; Jonathan L. Halperin, MD, FACC, FAHA; Judith S. Hochman, MD, FACC, FAHA; Frederick G. Kushner, MD, FACC, FAHA; E. Magnus Ohman, MD, FACC; William Stevenson, MD, FACC, FAHA; Clyde W. Yancy, MD, FACC, FAHA Preamble............e331Introduction.....e351.1Methodology and Evidence Review.......e351.2Organization of the Writing Group.........e361.3Document Review and Approval........e361.4Scope of the Focused Update.......e362Lower Extremity PAD..............e362.5Diagnostic Methods..........e362.5.1Recommendations for Ankle-Brachial Index, Toe-Brachial Index, and Segmental Pressure Examination.............e362.6Treatment........e372.6.1.4Recommendations for Smoking Cessation..........e372.6.1.6Recommendations for Antiplatelet and Antithrombotic Drugs........e382.6.3Recommendations for Critical Limb Ischemia: Endovascular and Open Surgical Treatment for Limb Salvage.......e405Aneurysm of the Abdominal Aorta, Its Branch Vessels, and the Lower Extremities.......e415.2.8.1Recommendations for Management Overview.......e41Referencese.......43Appendix I. Author Relationships With Industry and Other Entities (Relevant).......e45Appendix II. Reviewer Relationships With Industry And Other Entities (Relevant).........e47Appendix III. 2011 Peripheral Artery Disease Focused Update Summary Table.......e49 Keeping pace with the stream of new data and evolving evidence on which guideline recommendations are based is an ongoing challenge to timely development of clinical practice guidelines. In an effort to respond promptly to new evidence, the American College of Cardiology Foundation/American Heart Association (ACCF/AHA) Task Force on Practice Guidelines (Task Force) has created a “focused update” process to revise the existing guideline recommendations that are affected by the evolving data or opinion. New evidence is reviewed in an ongoing fashion to more efficiently respond to important science and treatment trends that could have a major impact on patient outcomes and quality of care. Evidence is reviewed at least twice a year, and updates are initiated on an as-needed basis and completed as quickly as possible while maintaining the rigorous methodology that the ACCF and AHA have developed during their partnership of >20 years. These updated guideline recommendations reflect a consensus of expert opinion after a thorough review primarily of late-breaking clinical trials identified through a broad-based vetting process as being important to the relevant patient population, as well as other new data deemed to have an impact on patient care (see Section 1.1, Methodology and Evidence Review, for details). This focused update is not intended to represent an update based on a complete literature review from the date of the previous guideline publication. Specific criteria/considerations for inclusion of new data include the following:•publication in a peer-reviewed journal;•large, randomized, placebo-controlled trial(s);•nonrandomized data deemed important on the basis of results affecting current safety and efficacy assumptions, including observational studies and meta-analyses;•strength/weakness of research methodology and findings;•likelihood of additional studies influencing current findings;•impact on current and/or likelihood of need to develop new performance measure(s);•request(s) and requirement(s) for review and update from the practice community, key stakeholders, and other sources free of relationships with industry or other potential bias;•number of previous trials showing consistent results; and•need for consistency with a new guideline or guideline updates or revisions. Selected members of the previous writing committee as well as other experts in the subject under consideration are chosen by the ACCF and AHA to examine subject-specific data and to write guidelines in partnership with representatives from other medical organizations and specialty groups. Writing group members review the selected late-breaking clinical trials and other new data that have been vetted through the Task Force; weigh the strength of evidence for or against particular tests, treatments, or procedures; and include estimates of expected outcomes where such data exist. Patient-specific modifiers, comorbidities, and issues of patient preference that may influence the choice of tests or therapies are considered. When available, information from studies on cost is considered, but data on efficacy and outcomes constitute the primary basis for the recommendations contained herein. In analyzing the data and developing recommendations and supporting text, the writing group uses evidence-based methodologies developed by the Task Force.1ACCF/AHA Task Force on Practice GuidelinesMethodologies and Policies from the ACCF/AHA Task Force on Practice Guideline.http://assets.cardiosource.com/Methodology_Manual_for_ACC_AHA_Writing_Committees.pdfGoogle Scholar The Class of Recommendation (COR) is an estimate of the size of the treatment effect considering risks versus benefits in addition to evidence and/or agreement that a given treatment or procedure is or is not useful/effective or in some situations may cause harm. The Level of Evidence (LOE) is an estimate of the certainty or precision of the treatment effect. The writing group reviews and ranks evidence supporting each recommendation with the weight of evidence ranked as LOE A, B, or C according to specific definitions that are included in Table I. Studies are identified as observational, retrospective, prospective, or randomized where appropriate. For certain conditions for which inadequate data are available, recommendations are based on expert consensus and clinical experience and are ranked as LOE C. When recommendations at LOE C are supported by historical clinical data, appropriate references (including clinical reviews) are cited if available. For issues for which sparse data are available, a survey of current practice among the clinicians on the writing group is the basis for LOE C recommendations, and no references are cited. The schema for COR and LOE is summarized in Table I, which also provides suggested phrases for writing recommendations within each COR. A new addition to this methodology is a separation of the Class III recommendations to delineate whether the recommendation is determined to be of “no benefit” or is associated with “harm” to the patient. In addition, in view of the increasing number of comparative effectiveness studies, comparator verbs and suggested phrases for writing recommendations for the comparative effectiveness of one treatment or strategy versus another have been added for COR I and IIa, LOE A or B only.Table IApplying classification of recommendations and Level of evidenceA recommendation with Level of Evidence B or C does not imply that the recommendation is weak. Many important clinical questions addressed in the guidelines do not lend themselves to clinical trials. Although randomized trials are unavailable, there may be a very clear clinical consensus that a particular test or therapy is useful or effective.*Data available from clinical trials or registries about the usefulness/efficacy in different subpopulations, such as sex, age, history of diabetes, history of prior myocardial infarction, history of heart failure, and prior aspirin use.†For comparative effectiveness recommendations (Class I and IIa; Level of Evidence A and B only), studies that support the use of comparator verbs should involve direct comparisons of the treatments or strategies being evaluated. Open table in a new tab A recommendation with Level of Evidence B or C does not imply that the recommendation is weak. Many important clinical questions addressed in the guidelines do not lend themselves to clinical trials. Although randomized trials are unavailable, there may be a very clear clinical consensus that a particular test or therapy is useful or effective. *Data available from clinical trials or registries about the usefulness/efficacy in different subpopulations, such as sex, age, history of diabetes, history of prior myocardial infarction, history of heart failure, and prior aspirin use. †For comparative effectiveness recommendations (Class I and IIa; Level of Evidence A and B only), studies that support the use of comparator verbs should involve direct comparisons of the treatments or strategies being evaluated. In view of the advances in medical therapy across the spectrum of cardiovascular diseases, the Task Force has designated the term guideline-directed medical therapy (GDMT) to represent optimal medical therapy as defined by ACCF/AHA guideline-recommended therapies (primarily Class I). This new term, GDMT, will be used herein and throughout all future guidelines. Because the ACCF/AHA practice guidelines address patient populations (and healthcare providers) residing in North America, drugs that are not currently available in North America are discussed in the text without a specific COR. For studies performed in large numbers of subjects outside North America, each writing group reviews the potential influence of different practice patterns and patient populations on the treatment effect and relevance to the ACCF/AHA target population to determine whether the findings should inform a specific recommendation. The ACCF/AHA practice guidelines are intended to assist healthcare providers in clinical decision making by describing a range of generally acceptable approaches to the diagnosis, management, and prevention of specific diseases or conditions. The guidelines attempt to define practices that meet the needs of most patients in most circumstances. The ultimate judgment regarding care of a particular patient must be made by the healthcare provider and patient in light of all the circumstances presented by that patient. As a result, situations may arise for which deviations from these guidelines may be appropriate. Clinical decision making should involve consideration of the quality and availability of expertise in the area where care is provided. When these guidelines are used as the basis for regulatory or payer decisions, the goal should be improvement in quality of care. The Task Force recognizes that situations arise in which additional data are needed to inform patient care more effectively; these areas will be identified within each respective guideline when appropriate. Prescribed courses of treatment in accordance with these recommendations are effective only if followed. Because lack of patient understanding and adherence may adversely affect outcomes, physicians and other healthcare providers should make every effort to engage the patient's active participation in prescribed medical regimens and lifestyles. In addition, patients should be informed of the risks, benefits, and alternatives to a particular treatment and be involved in shared decision making whenever feasible, particularly for COR IIa and IIb, for which the benefit-to-risk ratio may be lower. The Task Force makes every effort to avoid actual, potential, or perceived conflicts of interest that may arise as a result of industry relationships or personal interests among the members of the writing group. All writing group members and peer reviewers of the guideline are asked to disclose all such current relationships as well as those existing 12 months previously. In December 2009, the ACCF and AHA implemented a new policy for relationships with industry and other entities (RWI) that requires the writing group chair plus a minimum of 50% of the writing group to have no relevant RWI (Appendix I for the ACCF/AHA definition of relevance). These statements are reviewed by the Task Force and all members during each conference call and/or meeting of the writing group and are updated as changes occur. All guideline recommendations require a confidential vote by the writing group and must be approved by a consensus of the voting members. Members are not permitted to write, and must recuse themselves from voting on, any recommendation or section to which their RWI apply. Members who recused themselves from voting are indicated in the list of writing group members, and section recusals are noted in Appendix I. Authors' and peer reviewers' RWI pertinent to this guideline are disclosed in Appendixes I and II, respectively. Additionally, to ensure complete transparency, writing group members' comprehensive disclosure information—including RWI not pertinent to this document—is available as an online supplement. Comprehensive disclosure information for the Task Force is also available online at www.cardiosource.org/ACC/About-ACC/Leadership/Guidelines-and-Documents-Task-Forces.aspx. The work of the writing group was supported exclusively by the ACCF and AHA without commercial support. Writing group members volunteered their time for this activity. In an effort to maintain relevance at the point of care for practicing physicians, the Task Force continues to oversee an ongoing process improvement initiative. As a result, in response to pilot projects, several changes to these guidelines will be apparent, including limited narrative text and a focus on summary and evidence tables. The recommendations in this focused update will be considered current until they are superseded by another focused update or the full-text guideline is revised. Guidelines are official policy of both the ACCF and AHA. Alice K. Jacobs, MD, FACC, FAHA Chair, ACCF/AHA Task Force on Practice Guidelines The results of late-breaking clinical trials presented at the annual scientific meetings of the ACC, AHA, European Society of Cardiology, Society for Vascular Surgery, Society of Interventional Radiology, and Society for Vascular Medicine, as well as selected other data/articles published through December 2010, were reviewed by the 2005 guideline writing committee along with the Task Force and other experts to identify those trials and other key data that may impact guideline recommendations. On the basis of the criteria/considerations noted above, recent trial data and other clinical information were considered important enough to prompt a focused update of the “ACC/AHA 2005 Guidelines for the Management of Patients With Peripheral Arterial Disease (Lower Extremity, Renal, Mesenteric, and Abdominal Aortic).”2Hirsch A.T. Haskal Z.J. Hertzer N.R. et al.ACC/AHA 2005 practice guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): executive summary: a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease).Circulation. 2006; 113: 1474-1547Crossref Scopus (231) Google Scholar Because clinical research and clinical care of vascular disease have a global investigative and international clinical care tradition, efforts were made to harmonize this update with the Trans-Atlantic Inter-Society Consensus document on Management of Peripheral Arterial Disease (TASC) and the Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II) Steering Committee guideline writing efforts.3Norgren L. Hiatt W.R. Dormandy J.A. et al.Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II).Eur J Vasc Endovasc Surg. 2007; 33: S1-S75Abstract Full Text Full Text PDF PubMed Scopus (2278) Google Scholar To provide clinicians with a comprehensive set of data, whenever deemed appropriate or when published, the absolute risk difference and number needed to treat or harm are provided in the guideline, along with confidence intervals (CIs) and data related to the relative treatment effects, such as odds ratio, relative risk, hazard ratio (HR), or incidence rate ratio. Consult the full-text version2Hirsch A.T. Haskal Z.J. Hertzer N.R. et al.ACC/AHA 2005 practice guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): executive summary: a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease).Circulation. 2006; 113: 1474-1547Crossref Scopus (231) Google Scholar or executive summary4Hirsch A.T. Haskal Z.J. Hertzer N.R. et al.ACC/AHA 2005 practice guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease).Circulation. 2006; 113: e463-e654Crossref PubMed Google Scholar of the “ACC/AHA 2005 Guidelines for the Management of Patients With Peripheral Arterial Disease (Lower Extremity, Renal, Mesenteric, and Abdominal Aortic)” for policy on clinical areas not covered by the focused update. Individual recommendations modified in this focused update will be incorporated into future revisions and/or updates of the full-text guideline. For this focused update, all eligible members of the 2005 writing committee were invited to participate; those who agreed (referred to as the 2011 focused update writing group) were required to disclose all RWI relevant to the data under consideration. In addition, new members were invited in order to preserve the required RWI balance. The writing group included representatives from the ACCF, AHA, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society for Vascular Medicine, and Society for Vascular Surgery. This document was reviewed by 2 official reviewers each nominated by the ACCF and the AHA, as well as 2 reviewers each from the Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society for Vascular Medicine, and Society for Vascular Surgery; and 13 individual content reviewers (including members from the following groups: ACCF/AHA Task Force on Clinical Data Standards, ACCF Interventional Scientific Council, 2005 Peripheral Artery Disease Writing Committee, ACCF/AHA Task Force on Performance Measures, ACCF Prevention Committee, and ACCF Peripheral Vascular Disease Committee). All information on reviewers' RWI was distributed to the writing group and is published in this document (Appendix II). This document was approved for publication by the governing bodies of the ACCF and AHA and endorsed by the Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society for Vascular Medicine, and Society for Vascular Surgery. Studies relevant to the management of patients with peripheral artery disease (PAD) (lower extremity, renal, mesenteric, and abdominal aortic) were identified and reviewed as described previously in Section 1.1. On the basis of these data, the writing group determined that updates to the 2005 recommendations were necessary for lower extremity and abdominal aortic disease but that the existing recommendations for renal and mesenteric disease remain valid.4Hirsch A.T. Haskal Z.J. Hertzer N.R. et al.ACC/AHA 2005 practice guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease).Circulation. 2006; 113: e463-e654Crossref PubMed Google Scholar Although the specific recommendations for renal and mesenteric disease did not change, the following observations and clarifications were made:1Medical therapy for renal disease: No new pivotal trials or studies were identified.2Revascularization for renal disease: The writing group acknowledges that some new studies support a more limited role for renal revascularization. For example, the ASTRAL (Angioplasty and Stent for Renal Artery Lesions) investigators5Wheatley K. Ives N. Gray R. et al.Revascularization versus medical therapy for renal-artery stenosis.N Engl J Med. 2009; 361: 1953-1962Crossref PubMed Scopus (880) Google Scholar concluded that there were substantial risks but no clinical benefit from revascularization in patients with atherosclerotic renovascular disease. The writing group concurred that the criteria for patient selection in this randomized controlled trial (RCT) potentially excluded many patients who might have benefitted from intervention. It is anticipated that ongoing studies such as the CORAL (Cardiovascular Outcomes in Renal Atherosclerotic Lesions) trial6Cooper C.J. Murphy T.P. Matsumoto A. et al.Stent revascularization for the prevention of cardiovascular and renal events among patients with renal artery stenosis and systolic hypertension: rationale and design of the CORAL trial.Am Heart J. 2006; 152: 59-66Abstract Full Text Full Text PDF PubMed Scopus (262) Google Scholar will provide additional evidence relevant to these recommendations in the near future.3Methods of revascularization for renal disease: The 2005 recommendations remain current. The 2011 focused update acknowledges the declining use of surgical revascularization and the increasing use of catheter-based revascularization for renal artery stenoses. The writing group determined that new data support the equivalency of surgical and endovascular treatment, with lower morbidity and mortality associated with endovascular treatment but higher patency rates with surgical treatment in those patients who survived for at least 2 years after randomization.5Wheatley K. Ives N. Gray R. et al.Revascularization versus medical therapy for renal-artery stenosis.N Engl J Med. 2009; 361: 1953-1962Crossref PubMed Scopus (880) Google Scholar The writing group also notes that new data suggest that 1) the efficacy of revascularization may be reduced in patients with branch artery stenoses7Alhadad A. Mattiasson I. Ivancev K. et al.Revascularisation of renal artery stenosis caused by fibromuscular dysplasia: effects on blood pressure during 7-year follow-up are influenced by duration of hypertension and branch artery stenosis.J Hum Hypertens. 2005; 19: 761-767Crossref PubMed Scopus (52) Google Scholar and 2) patients undergoing renal artery bypass may do best when surgery is performed in high-volume centers.8Modrall J.G. Rosero E.B. Smith S.T. et al.Operative mortality for renal artery bypass in the United States: results from the National Inpatient Sample.J Vasc Surg. 2008; 48: 317-322Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar Table II contains recommendations for ankle-brachial index (ABI), toe-brachial index, and segmental pressure examination. See Appendix III for supplemental information. ABI, Ankle-brachial index; and PAD, peripheral artery disease. The German Epidemiologic Trial on Ankle Brachial Index Study Group included 6880 patients ≥65 years of age and demonstrated that 21% of the cohort had either asymptomatic or symptomatic PAD.11Diehm C. Allenberg J.R. Pittrow D. et al.Mortality and vascular morbidity in older adults with asymptomatic versus symptomatic peripheral artery disease.Circulation. 2009; 120: 2053-2061Crossref PubMed Scopus (403) Google Scholar On the basis of this large epidemiologic study, the 2011 writing group modified the age for consideration of ABI diagnostic testing to ≥65 years. The writing group considered the potential impact of lowering the PAD detection age to 65 years, acknowledging that the ABI test would be used in an incrementally larger “at-risk” population. This reflects the intent of both the original evidence-based document and this focused update to blunt the profound ongoing underdiagnosis and undertreatment of individuals with PAD until limb ischemic symptoms have become severe. This ABI recommendation is intended for office-based and vascular laboratory diagnostic use and is not intended to serve as a population screening tool. The writing group noted with confidence that no other cardiovascular disease diagnostic test can be applied in an age-defined clinical population with such a high detection rate, low to no risk, and low cost. We encourage expansion of the evidence base by design and completion of ABI screening studies. The definitions of normal and abnormal ABI values have been modified based on publication of the results of the Ankle Brachial Index Collaboration.24Fowkes F.G. Murray G.D. Butcher I. et al.Ankle brachial index combined with Framingham Risk Score to predict cardiovascular events and mortality: a meta-analysis.JAMA. 2008; 300: 197-208Crossref PubMed Scopus (1280) Google Scholar This includes a normal ABI range of 1.00 to 1.40, and abnormal values continue to be defined as those ≤0.90. ABI values of 0.91 to 0.99 are considered “borderline” and values >1.40 indicate noncompressible arteries. The 2005 recommendations stated that segmental pressure measurements are useful in the diagnosis and anatomic localization of lower extremity PAD. The 2011 writing group recognized that vascular diagnostic laboratories could use segmental pressures, Doppler waveform analysis, pulse volume recordings, or ABI with duplex ultrasonography (or some combination of these methods) to document the presence and location of PAD in the lower extremity. Table III contains recommendations for smoking cessation. See Appendix III for supplemental information. PAD, Peripheral artery disease. No prospective RCTs have examined the effects of smoking cessation on cardiovascular events in patients with lower extremity PAD. Observational studies have found that the risk of death, myocardial infarction, and amputation is substantially greater, and lower extremity angioplasty and open surgical revascularization patency rates are lower in individuals with PAD who continue to smoke than in those who stop smoking.34Faulkner K.W. House A.K. Castleden W.M. The effect of cessation of smoking on the accumulative survival rates of patients with symptomatic peripheral vascular disease.Med J Aust. 1983; 1: 217-219PubMed Google Scholar, 35Jonason T. Bergstrom R. Cessation of smoking in patients with intermittent claudication: effects on the risk of peripheral vascular complications, myocardial infarction and mortality.Acta Med Scand. 1987; 221: 253-260Crossref PubMed Scopus (246) Google Scholar, 36Lassila R. Lepantalo M. Cigarette smoking and the outcome after lower limb arterial surgery.Acta Chir Scand. 1988; 154: 635-640PubMed Google Scholar In some studies, exercise time is greater in patients who stop smoking than in current smokers.37Quick C.R. Cotton L.T. The measured effect of stopping smoking on intermittent claudication.Br J Surg. 1982; 69: S24-S26Crossref PubMed Scopus (183) Google Scholar, 38Gardner A.W. The effect of cigarette smoking on exercise capacity in patients with intermittent claudication.Vasc Med. 1996; 1: 181-186PubMed Google Scholar Efforts to achieve smoking cessation are recommended for patients with lower extremity PAD. Physician advice coupled with frequent follow-up achieves 1-year smoking cessation rates of approximately 5% compared with only 0.1% in individuals who try to quit smoking without a physician's intervention.39Law M. Tang J.L. An analysis of the effectiveness of interventions intended to help people stop smoking.Arch Intern Med. 1995; 155: 1933-1941Crossref PubMed Scopus (390) Google Scholar With pharmacological interventions such as nicotine replacement therapy and bupropion, 1-year smoking cessation rates of approximately 16% and 30%, respectively, are achieved in a general population of smokers.33Jorenby D.E. Leischow S.J. Nides M.A. et al.A controlled trial of sustained-release bupropion, a nicotine patch, or both for smoking cessation.N Engl J Med. 1999; 340: 685-691Crossref PubMed Scopus (1326) Google Scholar Varenicline, a nicotinic receptor partial agonist, has demonstrated superior quit rates when compared with nicotine replacement and bupropion in several RCTs.30Gonzales D. Rennard S.I. Nides M. et al.Varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs sustained-release bupropion and placebo for smoking cessation: a randomized controlled trial.JAMA. 2006; 296: 47-55Crossref PubMed Scopus (1174) Google Scholar, 31Jorenby D.E. Hays J.T. Rigotti N.A. et al.Efficacy of varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion for smoking cessation: a randomized controlled trial.JAMA. 2006; 296: 56-63Crossref PubMed Scopus (1188) Google Scholar, 32Nides M. Oncken C. Gonzales D. et al.Smoking cessation with varenicline, a selective alpha4beta2 nicotinic receptor partial agonist: results
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