Stephen G. Pauker

Prevention of VTE in Nonsurgical 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.

On the Elicitation of Preferences for Alternative Therapies

We investigated how variations in the way information is presented to patients influence their choices between alternative therapies. Data were presented summarizing the results of surgery and radiation therapy for lung cancer to 238 ambulatory patients with different chronic medical conditions and to 491 graduate students and 424 physicians. We asked the subjects to imagine that they had lung cancer and to choose between the two therapies on the basis of both cumulative probabilities and life-expectancy data. Different groups of respondents received input data that differed only in whether or not the treatments were identified and whether the outcomes were framed in terms of the probability of living or the probability of dying. In all three populations, the attractiveness of surgery, relative to radiation therapy, was substantially greater when the treatments were identified rather than unidentified, when the information consisted of life expectancy rather than cumulative probability, and when the problem was framed in terms of the probability of living rather than in terms of the probability of dying. We suggest that an awareness of these effects among physicians and patients could help reduce bias and improve the quality of medical decision making.

The Markov Process in Medical Prognosis

The physicians estimate of prognosis under alternative treatment plans is a principal factor in therapeutic decision making. Current methods of reporting prognosis, which include five-year survivals, survival curves, and quality-adjusted life expec tancy, are crude estimates of natural history. In this paper we describe a general- purpose model of medical prognosis based on the Markov process and show how this simple mathematical tool may be used to generate detailed and accurate assessments of life expectancy and health status. (Med Decis Making 3:419-458, 1983)

A convenient approximation of life expectancy (the “DEALE”): II. Use in medical decision-making☆

We show how to use a bedside approximation of life expectancy in quantitative decision-making. This method, the declining exponential approximation of life expectancy (DEALE), enables the physician to collate various survival data with information on morbidity to determine a quality-adjusted expected survival for a potential management plan. The keystone in the DEALE approach is the approximation of survival by a simple exponential function. This approximation makes it possible to translate data from various literature sources (life expectancy tables, five-year survival rates, survival curves, median survival) into a single, unified mortality scale. In this paper, we use the DEALE method to obtain approximations of quality-adjusted life expectancy and illustrate the application of the method in a quantitative analysis of a clinical decision.

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.

Auranofin therapy and quality of life in patients with rheumatoid arthritis. Results of a multicenter trial

In a six-month, randomized, double-blind study at 14 centers, auranofin (3 mg twice daily) was compared with placebo in the treatment of patients with classic or definite rheumatoid arthritis. All patients had unremitting disease for at least the previous six months and at least three months of therapy with nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs, oral steroids, and analgesics were allowed throughout the trial. Efficacy was analyzed in 154 patients who received auranofin and 149 who received placebo. To reflect an expanded view of outcome assessment, the measures used included some 20 nontraditional measures of functional performance, pain, global impression, and utility (worth or value) in addition to five standard clinical measures of rheumatoid synovitis (e.g., number of tender joints). The nontraditional measures were mainly in the form of structured questionnaires administered by trained interviewers. To minimize the statistical problem of multiple comparisons, most of the measures were grouped into four composites--clinical (standard measures), functional, global, and pain--and the treatment effect for each composite was tested at the 0.0125 level of significance. Auranofin was superior to placebo in the clinical (p = 0.003), functional (p = 0.001), and global (p = 0.007) composites and trended similarly in the pain composite (p = 0.021). Individual measures within the composites consistently favored auranofin. Other measures, not part of the composites, also favored auranofin, including a patient utility measure designed for this study, the PUMS (p = 0.002). Results confirm the hypothesis that the favorable effect of auranofin on clinical synovitis is accompanied by improvements across a range of outcomes relevant to the patients quality of life.

Decision Analysis: A Progress Report

Since its introduction into medicine 15 years ago, decision analysis has been applied to difficult clinical problems. Several important advances have made the process more practical and acceptable: computer programs that eliminate the need for burdensome calculations, improved techniques for designing analytic models, the ability to carry out sensitivity analyses over several dimensions simultaneously, and the elaboration of clinically relevant measures of utility. Using these techniques, analysts have addressed many important clinical issues including screening for and prevention of disease, tradeoffs among tests and treatments, and the interpretation of clinical data under conditions of uncertainty. Problems with the approach remain and applications have not been extensive, but decision analysis is evolving as a powerful clinical tool and gradually is gaining acceptance in medical practice.

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.

Cost-effectiveness of Interferon-α2b Treatment for Hepatitis B e Antigen-Positive Chronic Hepatitis B

Chronic hepatitis B virus (HBV) infection affects more than 5% of the world population, an estimated 300 to 350 million people [1-5]. In the United States, more than 1 million persons are persistently infected [3, 6]. The 270 000 to 300 000 cases of acute hepatitis B that occur annually in the United States contribute 5000 to 30 000 new cases of chronic infection [2, 7, 8] because 2% to 10% of infected adults develop chronic hepatitis [9-14]. Despite the availability of a vaccine and a declining incidence among homosexual men and health care workers, the incidence of hepatitis B has remained constant or has even increased in the United States because the incidence in heterosexual persons and intravenous drug users is increasing [12, 15]. Chronic hepatitis B causes significant morbidity and mortality, induces substantial direct and indirect costs [16-18], can lead to cirrhosis, and increases the risk for hepatocellular carcinoma approximately 300-fold compared with the general population [19]. Recombinant interferon-2b was recently approved by the U.S. Food and Drug Administration (FDA) for the treatment of chronic hepatitis B [20], but clinical trials show that only a proportion of treated patients lose viral serologic markers (such as HBV DNA, hepatitis B virus e antigen [HBeAg], or eventually hepatitis B virus surface antigen [HBsAg]) [21-23]. Information on more definitive clinical end points, such as a decline in the incidence and mortality of cirrhosis or hepatocellular carcinoma, must await the results of long-term follow-up during the next 20 to 30 years. Interferon therapy is now available for persons with chronic hepatitis B but is expensive and commonly associated with short-term adverse effects. In our study, we projected the expected clinical and economic outcomes of patients with chronic hepatitis B and estimated the cost-effectiveness of interferon therapy. Methods Decision Analytic Model We determined whether interferon should be given to patients with HBeAg-positive chronic hepatitis B who did not have cirrhosis (as determined by biopsy specimens) by using a decision analytic model to predict the likely clinical and economic outcomes for two cohorts of patients with chronic hepatitis. One cohort received a 16-week course of interferon and the other received standard care (treatment for cirrhosis-related signs and symptoms using diuretics, lactulose, and prophylactic antibiotics). Using a decision analysis software program, Decision Maker 7.0 (Pratt Medical Group, Boston, Massachusetts), we did a Markov computer simulation [24, 25] to estimate prognosis in a hypothetical cohort of patients. The Markov simulation is a modeling technique in which hypothetical patients are followed over time as they move among states of health. We defined each state by serologic viral markers and clinical descriptors (Figure 1). The likelihood and timing of adverse or beneficial events determine prognosis. All patients began the simulation having chronic hepatitis and both HBeAg and HBsAg. After each simulated year, some patients remained in the same state of health, whereas others improved (for example, became HBeAg negative) or developed complications (such as compensated cirrhosis). The likelihood of an improved or worsened state of health was specified by a set of probabilities (Table 1). The simulation continued until no patient remained alive. To estimate the average survival or life expectancy of each cohort, we recorded the number of patients in each state of health at the end of each simulated year; each member of the cohort who remained alive contributed 1 person-year to the total survival of the cohort. Table 1. Baseline Values* Figure 1. States of health in the decision model. Because the quality of life in some states of health may be preferable to that in other states (for example, having asymptomatic chronic hepatitis may be preferable to having decompensated cirrhosis), we calculated the quality-adjusted life expectancy for each cohort by adding less than 1 full person-year for members in these less desirable states. As explained below, we based these adjustments on the judgments of senior clinicians familiar with both liver disease and interferon therapy. For example, we diminished the quality of life for patients with hepatocellular carcinoma by approximately 50%; in other words, in each year in which they were alive and had hepatocellular carcinoma, they contributed only 6 quality-adjusted months to the cohorts quality-adjusted survival. We also diminished the quality of life during the 16-week course of interferon therapy by approximately 13%. Because techniques for quality adjustment remain controversial and are not standardized, we report both life expectancy and quality-adjusted life expectancy for each strategy. We based our economic projections on the costs associated with caring for patients in each state of health each year. In accordance with standard principles of economic analyses [26-28], we discounted both future costs and future life-years by 5% per year to reflect the higher value of spending a dollar now as opposed to a year from now. Although we recognized the importance of other clinical descriptors of disease activity (such as serum enzyme levels [29, 30] and histologic evidence of inflammatory activity [31, 32]) in patients with chronic hepatitis, sufficiently detailed data about prognosis based on combinations of these descriptors along with serologic viral markers and liver function do not currently exist. Consequently, we modeled only the nine states of health shown in Figure 1. The serologic viral marker events we modeled included loss of HBeAg or HBsAg and relapse or reactivation of HBeAg. Clinical events included the progression of chronic hepatitis to compensated and then to decompensated cirrhosis; the development of hepatocellular carcinoma; and death. Data Sources Probabilities and Utilities We did a MEDLINE search and examined the bibliographies of all identified articles. For studies in which data were sparse or missing, we obtained a consensus opinion from an expert panel (see Acknowledgments), using a modified Delphi method. Costs We obtained actual variable hospital costs (the cost to treat one additional patient with the same disease) from the Clinical Cost Manager (Transition Systems I, Boston, Massachusetts) accounting system at New England Medical Center. We approximated physician fees for inpatient and outpatient care by multiplying physician charges by the mean reimbursement-to-charge ratio for internal medicine services (0.51). Laboratory costs were obtained from actual variable costs. Drug costs reflect the wholesale drug price. The expert panel estimated the frequency of hospitalizations, outpatient visits, and laboratory tests, as well as which drugs would probably be used for each health state. Assumptions 1. We considered the prognosis of patients who did not lose HBeAg within 1 year despite receiving interferon therapy to be identical to that of untreated patients. 2. We considered loss of HBsAg to be permanent [33]. Although HBV DNA may persist (as measured by the polymerase chain reaction assay in serum or liver after the loss of HBsAg [34, 35]), we considered patients with chronic hepatitis who lose both HBeAg and HBsAg to be effectively cured, reflecting the natural extension of the asymptomatic healthy carrier who has become HBsAg negative [36]. On the basis of the expert panels recommendations, we assumed that these patients have a risk for developing compensated cirrhosis and hepatocellular carcinoma that is one hundredth that of patients who remain HBsAg positive. 3. We did not consider unusual complications from chronic hepatitis B (such as glomerulonephritis, polyarteritis nodosa, cryoglobulinemia, or vasculitis [37]), some of which may be ameliorated by interferon therapy [38]. 4. We did not include screening for hepatocellular carcinoma in our analysis [39]. Although one study [40] in Asian persons suggested that screening might be advantageous, the benefits may not apply to other groups [41]. An Italian study [42] failed to find any benefit from ultrasonography or -fetoprotein screening tests. 5. We did not consider a second course of interferon therapy in nonresponders or patients who became positive again (reactivation or relapse) for HBeAg (although such patients often respond to a second course of interferon therapy [20]) or in patients with cirrhosis [37, 43-45] because few studies have been done for these settings and no consensus has been reached [43, 46]. 6. We estimated the benefit of interferon from studies with interferon-2b, which appears to be more effective than interferon- [47-49]. Two studies [50] suggest that interferon-2a results in a higher prevalence of anti-interferon antibody than interferon-2b. Other therapies, including combination or sequential therapy with interferon or priming with steroid therapy, have not improved response rates [51, 52]. 7. We considered loss of HBeAg as equivalent to loss of HBV DNA as a marker of viral replication. We did not consider the presence of the precore mutant (HBeAg negative) HBV, which is more likely to be resistant to therapy but is rare in the United States [53-55]. 8. We did not consider liver transplantation because of the frequent recurrence of HBV infection and progressive hepatitis in persons who receive transplanted livers [56-59] and because only a small proportion of patients with decompensated cirrhosis could be served by the currently limited supply of donor organs [60]. 9. We did not consider concomitant infection with hepatitis C virus or hepatitis D (delta) virus. 10. We used age-specific standard life-tables to reflect the underlying background likelihood of dying from causes occurring in the general population [61]. In the base-case analysis, the age at inception was assumed to be 35 years. Sensitivity Analysis Published studies and expert opinion vary in th

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).