When is rational to order a diagnostic test, or prescribe treatment: the threshold model as an explanation of practice variation.

BACKGROUND: The threshold model represents an important advance in the field of medical decision-making. It is a linchpin between evidence (which exists on the continuum of credibility) and decision-making (which is a categorical exercise - we decide to act or not act). The threshold concept is closely related to the question of rational decision-making. When should the physician act, that is order a diagnostic test, or prescribe treatment? The threshold model embodies the decision theoretic rationality that says the most rational decision is to prescribe treatment when the expected treatment benefit outweighs its expected harms. However, the well-documented large variation in the way physicians order diagnostic tests or decide to administer treatments is consistent with a notion that physicians' individual action thresholds vary. METHODS: We present a narrative review summarizing the existing literature on physicians' use of a threshold strategy for decision-making. RESULTS: We found that the observed variation in decision action thresholds is partially due to the way people integrate benefits and harms. That is, explanation of variation in clinical practice can be reduced to a consideration of thresholds. Limited evidence suggests that non-expected utility threshold (non-EUT) models, such as regret-based and dual-processing models, may explain current medical practice better. However, inclusion of costs and recognition of risk attitudes towards uncertain treatment effects and comorbidities may improve the explanatory and predictive value of the EUT-based threshold models. CONCLUSIONS: The decision when to act is closely related to the question of rational choice. We conclude that the medical community has not yet fully defined criteria for rational clinical decision-making. The traditional notion of rationality rooted in EUT may need to be supplemented by reflective rationality, which strives to integrate all aspects of medical practice - medical, humanistic and socio-economic - within a coherent reasoning system.

Using nonrandomized studies to inform complex clinical decisions: the thorny issue of cranial radiation therapy for T-cell acute lymphoblastic leukemia.

BACKGROUND: There are no randomized controlled trials to inform the decision of which cranial radiation therapy (CRT) strategy to apply to pediatric patients with T-cell acute lymphoblastic leukemia (ALL). PROCEDURE: We performed a decision analysis using a Markov model in which we compared the life expectancy and quality-adjusted life expectancy when administering one of three CRT strategies to a cohort of patients with T-cell ALL: (1) omission of CRT for all patients; (2) CRT only for those with evidence of leukemic involvement in the central nervous system at diagnosis (therapeutic strategy); or (3) CRT for all (prophylactic strategy). RESULTS: When considering plausible event-free survival rates and late mortality after cure for groups of pediatric patients with T-cell ALL, the strategies of omitting CRT, administering therapeutic CRT, and administering prophylactic CRT result in similar short-term (7-year) survival. When considering the increased contribution of deaths from late effects, the strategy of prophylactic CRT is associated with lower life expectancy when compared to the other two strategies. The Monte Carlo probabilistic sensitivity analysis demonstrated that the strategy of prophylactic CRT was the preferred strategy only 5% of the time. CONCLUSIONS: Similar short-term survival may be expected when comparing the strategies of total omission of CRT, therapeutic CRT, and prophylactic CRT for patients with T-cell ALL. Long-term survival is likely inferior for the strategy of prophylactic CRT. The synthesis of nonrandomized trials and the application of decision analysis can help inform complex decision making in pediatric oncology.

Improving the efficiency and relevance of evidence-based recommendations in the era of whole-genome sequencing: an EGAPP methods update.

To provide an update on recent revisions to Evaluation of Genomic Applications in Practice and Prevention (EGAPP) methods designed to improve efficiency, and an assessment of the implications of whole genome sequencing for evidence-based recommendation development. Improvements to the EGAPP approach include automated searches for horizon scanning, a quantitative ranking process for topic prioritization, and the development of a staged evidence review and evaluation process. The staged process entails (i) triaging tests with minimal evidence of clinical validity, (ii) using and updating existing reviews, (iii) evaluating clinical validity prior to analytic validity or clinical utility, (iv) using decision modeling to assess potential clinical utility when direct evidence is not available. EGAPP experience to date suggests the following approaches will be critical for the development of evidence based recommendations in the whole genome sequencing era: (i) use of triage approaches and frameworks to improve efficiency, (ii) development of evidence thresholds that consider the value of further research, (iii) incorporation of patient preferences, and (iv) engagement of diverse stakeholders. The rapid advances in genomics present a significant challenge to traditional evidence based medicine, but also an opportunity for innovative approaches to recommendation development.

Dual processing model of medical decision-making.

BACKGROUND: Dual processing theory of human cognition postulates that reasoning and decision-making can be described as a function of both an intuitive, experiential, affective system (system I) and/or an analytical, deliberative (system II) processing system. To date no formal descriptive model of medical decision-making based on dual processing theory has been developed. Here we postulate such a model and apply it to a common clinical situation: whether treatment should be administered to the patient who may or may not have a disease. METHODS: We developed a mathematical model in which we linked a recently proposed descriptive psychological model of cognition with the threshold model of medical decision-making and show how this approach can be used to better understand decision-making at the bedside and explain the widespread variation in treatments observed in clinical practice. RESULTS: We show that physician's beliefs about whether to treat at higher (lower) probability levels compared to the prescriptive therapeutic thresholds obtained via system II processing is moderated by system I and the ratio of benefit and harms as evaluated by both system I and II. Under some conditions, the system I decision maker's threshold may dramatically drop below the expected utility threshold derived by system II. This can explain the overtreatment often seen in the contemporary practice. The opposite can also occur as in the situations where empirical evidence is considered unreliable, or when cognitive processes of decision-makers are biased through recent experience: the threshold will increase relative to the normative threshold value derived via system II using expected utility threshold. This inclination for the higher diagnostic certainty may, in turn, explain undertreatment that is also documented in the current medical practice. CONCLUSIONS: We have developed the first dual processing model of medical decision-making that has potential to enrich the current medical decision-making field, which is still to the large extent dominated by expected utility theory. The model also provides a platform for reconciling two groups of competing dual processing theories (parallel competitive with default-interventionalist theories).

Valvular and structural heart disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).

This chapter about antithrombotic therapy for valvular heart disease is part of the American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Grade 1 recommendations are strong and indicate that the benefits do, or do not, outweigh risks, burden, and costs. Grade 2 suggests that individual patient values might lead to different choices (for a full understanding of the grading see Guyatt et al, CHEST 2008; 133[suppl]:123S-131S). Among the key recommendations in this chapter are the following: for patients with rheumatic mitral valve disease complicated singly or in combination by the presence of atrial fibrillation (AF), previous systemic embolism, or left atrial thrombus, we recommend vitamin K antagonist (VKA) therapy (Grade 1A). For patients with rheumatic mitral valve disease and normal sinus rhythm, without left atrial enlargement, we do not suggest antithrombotic therapy unless a separate indication exists (Grade 2C). For patients with mitral valve prolapse (MVP), not complicated by AF, who have not had systemic embolism, unexplained transient ischemic attacks, or ischemic stroke, we recommend against antithrombotic therapy (Grade 1C). In patients with mitral annular calcification complicated by systemic embolism or ischemic stroke, we recommend antiplatelet agent (APA) therapy (Grade 1B). For patients with isolated calcific aortic valve disease, we suggest against antithrombotic therapy (Grade 2C). But, for those with aortic valve disease who have experienced ischemic stroke, we suggest APA therapy (Grade 2C). For patients with stroke associated with aortic atherosclerotic lesions, we recommend low-dose aspirin (ASA) therapy (Grade 1C). For patients with cryptogenic ischemic stroke and a patent foramen ovale (PFO), we recommend APA therapy (Grade 1A). For patients with mechanical heart valves, we recommend VKA therapy (Grade 1A). For patients with mechanical heart valves and history of vascular disease or who have additional risk factors for thromboembolism, we recommend the addition of low-dose aspirin ASA to VKA therapy (Grade 1B). We suggest ASA not be added to long-term VKA therapy in patients with mechanical heart valves who are at particularly high risk of bleeding (Grade 2C). For patients with bioprosthetic heart valves, we recommend ASA (Grade 1B). For patients with bioprosthetic heart valves and additional risk factors for thromboembolism, we recommend VKA therapy (Grade 1C). For patients with infective endocarditis, we recommend against antithrombotic therapy, unless a separate indication exists (Grade 1B).

Grades of recommendation for antithrombotic agents: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).

This chapter describes the system used by the American College of Chest Physicians to grade recommendations for antithrombotic and thrombolytic therapy as part of the Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Clinicians need to know if a recommendation is strong or weak, and the methodologic quality of the evidence underlying that recommendation. We determine the strength of a recommendation by considering the balance between the desirable effects of an intervention and the undesirable effects (incremental harms, burdens, and for select recommendations, costs). If the desirable effects outweigh the undesirable effects, we recommend that clinicians offer an intervention to typical patients. The uncertainty associated with the balance between the desirable and undesirable effects will determine the strength of recommendations. If we are confident that benefits do or do not outweigh harms, burden, and costs, we make a strong recommendation in our formulation, Grade 1. If we are less certain of the magnitude of the benefits and risks, burden, and costs, and thus their relative impact, we make a weaker Grade 2 recommendation. For grading methodologic quality, randomized controlled trials (RCTs) begin as high-quality evidence (designated by "A"), but quality can decrease to moderate ("B"), or low ("C") as a result of poor design and conduct of RCTs, imprecision, inconsistency of results, indirectness, or a high likelihood for reporting bias. Observational studies begin as low quality of evidence (C) but can increase in quality on the basis of very large treatment effects. Strong (Grade 1) recommendations can be applied uniformly to most patients. Weak (Grade 2) suggestions require more judicious application, particularly considering patient values and preferences and, when resource limitations play an important role, issues of cost.

Does error and adverse event reporting by physicians and nurses differ?

BACKGROUND: Some hospitals have instituted voluntary electronic error reporting systems (e-ERSs) to gather data on medical errors, adverse events, near misses, or environmental issues in a peer review-protected environment. An e-ERS allows for real-time review, oversight, and intervention and provides insight into hospital processes in need of modification to reduce the likelihood of adverse hospital events. In a descriptive study of a standardized, Web-based reporting system, the reporting practices of physicians and nurses were compared. METHODS: Twenty-nine acute care hospitals and one long-term care organization implemented an e-ERS between August 2000 and December 2005. The reporting system consisted of a secure, Web-based portal available on all hospital computers. Events were classified by the level of impact on the patient using a standard classification scheme. All reports that occurred from August 2000 through January 2006 were analyzed in aggregate analyses. Hospitals and patients were de-identified to study investigators. RESULTS: Some 266,224 events were reported over 7.3 million inpatient days--1 event per 27.5 days. Physicians were the reporters of 1.1% of total events, nurses 45.3%, and other hospital employees 53.6%. Physicians were more likely to be the reporter for events that caused permanent harm, near death, or death of a patient (p < .01). Nurses were more likely to be the reporter for events that caused no or temporary harm (p < .01). DISCUSSION: Physicians reported a narrower spectrum of events than nurses; they were more likely to report as the impact of events on patients increased but less likely to report fatal events. Nurses' reporting remained stable across impact levels. Differences exist between whether nurses and physicians report events; physicians must be encouraged to increase their reporting of adverse events.

Voluntary electronic reporting of medical errors and adverse events. An analysis of 92,547 reports from 26 acute care hospitals.

OBJECTIVE: To describe the rate and types of events reported in acute care hospitals using an electronic error reporting system (e-ERS). DESIGN: Descriptive study of reported events using the same e-ERS between January 1, 2001 and September 30, 2003. SETTING: Twenty-six acute care nonfederal hospitals throughout the U.S. that voluntarily implemented a web-based e-ERS for at least 3 months. PARTICIPANTS: Hospital employees and staff. INTERVENTION: A secure, standardized, commercially available web-based reporting system. RESULTS: Median duration of e-ERS use was 21 months (range 3 to 33 months). A total of 92,547 reports were obtained during 2,547,154 patient-days. Reporting rates varied widely across hospitals (9 to 95 reports per 1,000 inpatient-days; median=35). Registered nurses provided nearly half of the reports; physicians contributed less than 2%. Thirty-four percent of reports were classified as nonmedication-related clinical events, 33% as medication/infusion related, 13% were falls, 13% as administrative, and 6% other. Among 80% of reports that identified level of impact, 53% were events that reached a patient ("patient events"), 13% were near misses that did not reach the patient, and 14% were hospital environment problems. Among 49,341 patient events, 67% caused no harm, 32% temporary harm, 0.8% life threatening or permanent harm, and 0.4% contributed to patient deaths. CONCLUSIONS: An e-ERS provides an accessible venue for reporting medical errors, adverse events, and near misses. The wide variation in reporting rates among hospitals, and very low reporting rates by physicians, requires investigation.

Empirical anti-Candida therapy among selected patients in the intensive care unit: a cost-effectiveness analysis.

BACKGROUND: Mortality from invasive candidiasis is high. Low culture sensitivity and treatment delay contribute to increased mortality, but nonselective early therapy may result in excess costs and drug resistance. OBJECTIVE: To determine the cost-effectiveness of anti-Candida strategies for high-risk patients in the intensive care unit (ICU). DESIGN: Cost-effectiveness decision model. DATA SOURCES: Published data to 10 May 2005, identified from MEDLINE and Cochrane Library searches, ICU databases, expert estimates, and actual hospital costs. TARGET POPULATION: Patients in the ICU with suspected infection who have not responded to antibacterial therapy. TIME HORIZON: Lifetime. PERSPECTIVE: Societal. INTERVENTIONS: Fluconazole, caspofungin, amphotericin B, or lipid formulation of amphotericin B given as either empirical or culture-based therapy and no anti-Candida therapy. OUTCOME MEASURES: Incremental life expectancy and incremental cost per discounted life-year (DLY) saved. RESULTS OF BASE-CASE ANALYSIS: Ten percent of the target population will have invasive candidiasis. Empirical caspofungin therapy is the most effective strategy but is expensive (295,115 dollars per DLY saved). Empirical fluconazole therapy is the most reasonable strategy (12,593 dollars per DLY saved) and decreases mortality from 44.0% to 30.4% in patients with invasive candidiasis and from 22.4% to 21.0% in the overall target cohort. RESULTS OF SENSITIVITY ANALYSIS: Empirical fluconazole therapy is reasonable for likelihoods of invasive candidiasis greater than 2.5% or fluconazole resistance less than 24.0%. For higher resistance levels, empirical caspofungin therapy is preferred. For low prevalences of invasive candidiasis, culture-based fluconazole is reasonable. For prevalences exceeding 60%, empirical caspofungin therapy is reasonable. For caspofungin to be reasonable at a prevalence of 10%, its cost must be reduced by 58%. LIMITATIONS: Less severe illness and limited use of broad-spectrum antimicrobial agents, typical of smaller hospitals, could result in a lower risk for invasive candidiasis. CONCLUSIONS: In patients in the ICU with suspected infection who have not responded to antibiotic treatment, empirical fluconazole should reduce mortality at an acceptable cost. The use of empirical strategies in low-risk patients is not justified.

A meta-analysis of randomized controlled trials comparing coronary artery bypass graft with percutaneous transluminal coronary angioplasty: one- to eight-year outcomes.

OBJECTIVES: We performed a meta-analysis of randomized trials comparing coronary artery bypass graft surgery (CABG) with percutaneous transluminal coronary angioplasty (PTCA) for the treatment of coronary artery disease, incorporating new trials and examining long-term outcomes. BACKGROUND: Previous meta-analyses of trials comparing CABG with PTCA have reported short- and intermediate-term outcomes, but since then longer term follow-up and newer trials have been published. METHODS: We performed a meta-analysis of 13 randomized trials on 7,964 patients comparing PTCA with CABG. RESULTS: We found a 1.9% absolute survival advantage favoring CABG over PTCA for all trials at five years (p < 0.02), but no significant advantage at one, three, or eight years. In subgroup analysis of multivessel disease, CABG provided significant survival advantage at both five and eight years. Patients randomized to PTCA had more repeat revascularizations at all time points (risk difference [RD] 24% to 38%, p < 0.001); with stents, this RD was reduced to 15% at one and three years. Stents also resulted in a significant decrease in nonfatal myocardial infarction at three years when compared with CABG. For diabetic patients, CABG provided a significant survival advantage over PTCA at 4 years but not at 6.5 years. CONCLUSIONS: Our results suggest that, when compared with PTCA, CABG is associated with a lower five-year mortality, less angina, and fewer revascularization procedures. For patients with multivessel disease, CABG provided a survival advantage at five to eight years, and for diabetics, a survival advantage at four years. The addition of stents reduced the need for repeat revascularization by about half.

Cost-effectiveness of prophylactic low molecular weight heparin in pregnant women with a prior history of venous thromboembolism.

PURPOSE: Women with a history of prior venous thromboembolism have an increased risk for recurrence during pregnancy. Although thromboprophylaxis reduces this risk, recent evidence suggests that, in many cases, prophylaxis can be safely withheld because the estimated recurrence risk is very low. The balance of risks and benefits in women with different recurrence risks has not been examined. METHODS: We developed a Markov state transition decision analytic model to compare prophylactic low molecular weight heparin to expectant management for pregnant women with a single prior venous thromboembolism. A lifetime time horizon and societal perspective were assumed. Input data were obtained by literature review. Outcomes were expressed as U.S. dollars per quality-adjusted life-year (QALY). RESULTS: For "low-risk" women with a prior venous thromboembolism associated with a transient risk factor and no known thrombophilic condition (recurrence risk 0.5%), expectant management was both more effective and less costly than prophylaxis. For "high-risk" women with prior idiopathic venous thromboembolism or known thrombophilic condition (recurrence risk 5.9%), prophylaxis was associated with a reasonable cost-effectiveness ratio (USD 38,700 per QALY) given a risk of bleeding complications <1.0% (base case 0.5%). CONCLUSION: For low-risk women with prior venous thromboembolism, expectant management during pregnancy leads to better outcomes than administration of prophylactic low molecular weight heparin. For high-risk women, antepartum thromboprophylaxis is a cost-effective use of resources.

The discrepancy between observational studies and randomized trials of menopausal hormone therapy: did expectations shape experience?

Differences between observational and randomized studies of the effects of menopausal hormone therapy (HT) on coronary heart disease (CHD) have been attributed to the fact that women who choose to use HT tend to be healthier than those who do not. Although this bias should affect all clinical outcomes with modifiable risk factors, estimates for stroke and pulmonary embolism were unaffected. The authors sought possible explanations for this isolated discrepancy in CHD findings. Unlike the randomized Women's Health Initiative (WHI) trial, the observational Nurses' Health Study (NHS) did not try to detect silent myocardial infarctions. Many women present with atypical ischemic symptoms. Hormone therapy users who believe that HT reduces CHD risks might not interpret ischemic symptoms as related to CHD, might not seek medical attention, and might present differently to their physicians, all of which could lead to more unrecognized myocardial infarctions among HT users in the NHS. In addition, persons completing death certificates and NHS physicians interpreting death certificates were not blinded to the use of HT. If persons assigning cause of death knew the patient had used HT and believed that HT prevented CHD, they might have been more likely to assign a condition other than CHD as the cause of death. If HT users were 20% less likely to have their infarctions recognized and their deaths attributed to CHD, a true increase in CHD due to HT use would appear to be a reduction in CHD. Combining these reporting biases with socioeconomic differences between users and nonusers could explain discrepancies. Beliefs held by patients, clinicians, and investigators might have affected the ascertainment of CHD outcomes in observational studies.

Antithrombotic therapy in valvular heart disease--native and prosthetic: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.

This chapter about antithrombotic therapy in native and prosthetic valvular heart disease is part of the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy: Evidence Based Guidelines. Grade 1 recommendations are strong and indicate that the benefits do, or do not, outweigh risks, burden, and costs. Grade 2 suggests that individual patients' values may lead to different choices (for a full understanding of the grading see Guyatt et al, CHEST 2004; 126:179S-187S). Among the key recommendations in this chapter are the following: For patients with rheumatic mitral valve disease and atrial fibrillation (AF), or a history of previous systemic embolism, we recommend long-term oral anticoagulant (OAC) therapy (target international normalized ratio [INR], 2.5; range, 2.0 to 3.0) [Grade 1C+]. For patients with rheumatic mitral valve disease with AF or a history of systemic embolism who suffer systemic embolism while receiving OACs at a therapeutic INR, we recommend adding aspirin, 75 to 100 mg/d (Grade 1C). For those patients unable to take aspirin, we recommend adding dipyridamole, 400 mg/d, or clopidogrel (Grade 1C). In people with mitral valve prolapse (MVP) without history of systemic embolism, unexplained transient ischemic attacks (TIAs), or AF, we recommended against any antithrombotic therapy (Grade 1C). In patients with MVP and documented but unexplained TIAs, we recommend long-term aspirin therapy, 50 to 162 mg/d (Grade 1A). For all patients with mechanical prosthetic heart valves, we recommend vitamin K antagonists (Grade 1C+). For patients with a St. Jude Medical (St. Paul, MN) bileaflet valve in the aortic position, we recommend a target INR of 2.5 (range, 2.0 to 3.0) [Grade 1A]. For patients with tilting disk valves and bileaflet mechanical valves in the mitral position, we recommend a target INR of 3.0 (range, 2.5 to 3.5) [Grade 1C+]. For patients with caged ball or caged disk valves, we suggest a target INR of 3.0 (range, 2.5 to 3.5) in combination with aspirin, 75 to 100 mg/d (Grade 2A). For patients with bioprosthetic valves, we recommend vitamin K antagonists with a target INR of 2.5 (range, 2.0 to 3.0) for the first 3 months after valve insertion in the mitral position (Grade 1C+) and in the aortic position (Grade 2C). For patients with bioprosthetic valves who are in sinus rhythm and do not have AF, we recommend long-term (> 3 months) therapy with aspirin, 75 to 100 mg/d (Grade 1C+).

Prevention of VTE in orthopedic surgery patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.

BACKGROUND: VTE is a serious, but decreasing complication following major orthopedic surgery. This guideline focuses on optimal prophylaxis to reduce postoperative pulmonary embolism and DVT. METHODS: The methods of this guideline follow those described in Methodology for the Development 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: In patients undergoing major orthopedic surgery, we recommend the use of one of the following rather than no antithrombotic prophylaxis: low-molecular-weight heparin; fondaparinux; dabigatran, apixaban, rivaroxaban (total hip arthroplasty or total knee arthroplasty but not hip fracture surgery); low-dose unfractionated heparin; adjusted-dose vitamin K antagonist; aspirin (all Grade 1B); or an intermittent pneumatic compression device (IPCD) (Grade 1C) for a minimum of 10 to 14 days. We suggest the use of low-molecular-weight heparin in preference to the other agents we have recommended as alternatives (Grade 2C/2B), and in patients receiving pharmacologic prophylaxis, we suggest adding an IPCD during the hospital stay (Grade 2C). We suggest extending thromboprophylaxis for up to 35 days (Grade 2B). In patients at increased bleeding risk, we suggest an IPCD or no prophylaxis (Grade 2C). In patients who decline injections, we recommend using apixaban or dabigatran (all Grade 1B). We suggest against using inferior vena cava filter placement for primary prevention in patients with contraindications to both pharmacologic and mechanical thromboprophylaxis (Grade 2C). We recommend against Doppler (or duplex) ultrasonography screening before hospital discharge (Grade 1B). For patients with isolated lower-extremity injuries requiring leg immobilization, we suggest no thromboprophylaxis (Grade 2B). For patients undergoing knee arthroscopy without a history of VTE, we suggest no thromboprophylaxis (Grade 2B). CONCLUSIONS: Optimal strategies for thromboprophylaxis after major orthopedic surgery include pharmacologic and mechanical approaches.

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

BACKGROUND: Objective testing for DVT is crucial because clinical assessment alone is unreliable and the consequences of misdiagnosis are serious. This guideline focuses on the identification of optimal strategies for the diagnosis of DVT in ambulatory adults. METHODS: The methods of this guideline follow those described in Methodology for the Development 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. RESULTS: We suggest that clinical assessment of pretest probability of DVT, rather than performing the same tests in all patients, should guide the diagnostic process for a first lower extremity DVT (Grade 2B). In patients with a low pretest probability of first lower extremity DVT, we recommend initial testing with D-dimer or ultrasound (US) of the proximal veins over no diagnostic testing (Grade 1B), venography (Grade 1B), or whole-leg US (Grade 2B). In patients with moderate pretest probability, we recommend initial testing with a highly sensitive D-dimer, proximal compression US, or whole-leg US rather than no testing (Grade 1B) or venography (Grade 1B). In patients with a high pretest probability, we recommend proximal compression or whole-leg US over no testing (Grade 1B) or venography (Grade 1B). CONCLUSIONS: Favored strategies for diagnosis of first DVT combine use of pretest probability assessment, D-dimer, and US. There is lower-quality evidence available to guide diagnosis of recurrent DVT, upper extremity DVT, and DVT during pregnancy.