Although venography remains an important screening test for DVT, especially in evaluating the efficacy of new antithrombotic interventions, it has a number of well-recognized limitations, including the following: (1) limited availability in many medical centers; (2) questionable clinical relevance of small or distal thrombi; (3) incomplete or nondiagnostic rates of at least 20 to 40%; (4) moderate interobserver variability in its interpretation; (5) patient discomfort and risks related to the use of a contrast agent; and (6) high financial costs. Furthermore, because venography is not readily repeatable, it can only provide information about thrombosis at a single point in time rather than over a longer a time course during which clinically important VTE may arise.

Venous Doppler ultrasonography (DUS) is now the most universally accepted test for the diagnosis of lower extremity DVT, because it is highly accurate for symptomatic DVT, widely available, and noninvasive, and can be repeated. At the same time, the accuracy of DUS varies among both operators and medical centers. While DUS has reduced sensitivity for detecting DVT in asymptomatic patients, the accuracy of DUS appears to be improving. The lower sensitivity of DUS for detecting small and/or nonocclusive DVTs may even be considered advantageous, since such thrombi appear to be of doubtful clinical significance. The standardization of the DUS technique is critical in reducing the potential for the false-positive test results reported in some trials. As a result of recent improvements in DUS accuracy, an increasing number of clinical trials in thromboprophylaxis are utilizing ultrasound outcomes. We believe that DUS-positive proximal DVT is a clinically relevant finding because of the known association between proximal DVT and PE, and because patients with this finding generally receive anticoagulation therapy in routine practice.

Despite the limitations of each of these screening methods, and thus the possibility of error in the estimates of the absolute rates of DVT, the relative risk reductions (RRRs), derived from studies comparing two prophylaxis regimens are likely to be valid as long as systematic bias has been reduced through the concealed randomization of patients, caregivers, and outcome adjudicators to the study interventions received, and through the complete follow-up of patients.

1.4.2    Appropriate end points in clinical trials of thromboprophylaxis

Physicians differ widely in their views on the appropriate end points for studies of thromboprophylaxis. While some believe that contrast venography should be used as the “best” test to detect all DVTs, others argue that evidence of effectiveness should be based on a proven reduction in all-cause mortality. Both of these antithetical positions clearly have limitations.

Over the years, the majority of prophylaxis trials have used DVT, detected by sensitive screening methods, as the primary efficacy outcome.

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The implementation of evidence-based and thoughtful prophylaxis strategies provides benefit to patients, and should also protect their caregivers and the hospitals providing care from legal liability. We recommend that every hospital develop a formal strategy that addresses the prevention of thromboembolic complications. This should generally be in the form of a written thromboprophylaxis policy, especially for high-risk groups.

1.4 Important issues related to studies of thromboprophylaxis

The appropriate interpretation of published information about thromboprophylaxis requires the consideration of a number of important issues.

1.4.1 Limitations of DVT screening methods

Each of the methods used to screen for DVT in clinical trials has its own limitations. Fibrinogen leg scanning, also called the fibrinogen uptake test (FUT), was used

Table 5—Levels of Thromboembolism Risk in Surgical Patients Without Prophylaxis extensively to detect subclinical DVT in many early prophylaxis trials.

Level of Risk Calf DVT, %





PE, %



Successful Prevention Strategies
Low risk

Minor surgery in patients < 40 yr with no additional risk factors

2 0.4 0.2 < 0.01 No specific prophylaxis; early and “aggressive” mobilization
Moderate risk

Minor surgery in patients with additional risk factors

Surgery in patients aged 40-60 yr with no additional risk factors

10-20 2-4 1-2 0.1-0.4 LDUH (q12h), LMWH (< 3,400 U daily), GCS, or IPC
High risk

Surgery in patients > 60 yr, or age 40-60 with additional risk factors (prior VTE, cancer, molecular hypercoagulability)

20-40 4-8 2-4 0.4-1.0 LDUH (q8h), LMWH (> 3,400 U daily), or IPC
Highest risk

Surgery in patients with multiple risk factors (age > 40 yr, cancer, prior VTE)

Hip or knee arthroplasty, HFS Major trauma; SCI

40-80 10-20 4-10 0.2-5 LMWH (> 3,400 U daily), fondaparinux, oral VKAs (INR, 2-3), or IPC/GCS + LDUH/ LMWH

Modified from Geerts et al.

The test is no longer available because of concerns about the potential for viral transmission with this human blood product. Furthermore, the FUT has been shown to lack both specificity and sensitivity for the detection of DVT, and is poorly correlated with major thromboembolic events. Impedance plethysmography also has been shown to have low accuracy in the screening of asymptomatic high-risk patients, and is no longer utilized.

Contrast venography has long been the diagnostic standard in thromboprophylaxis trials because of its high sensitivity for detecting DVT and the availability of hardcopy images for blinded study adjudication. Many pivotal, practice-changing prophylaxis trials have used venography as the primary outcome measure of efficacy.

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1.3 Risk factor stratification

There are two general approaches to making thromboprophylaxis decisions. One approach considers the risk of VTE in each patient, based on their individual predisposing factors and the risk associated with their current illness or procedure. Prophylaxis is then individually prescribed based on the composite risk estimate. Formal risk assessment models for DVT have been proposed to assist with this process. Because the approach of individual prophylaxis prescribing, based on formal risk-assessment models, has not been adequately validated and is cumbersome without the use of computer technology, it is unlikely to be used routinely by most clinicians. Furthermore, there is little formal understanding of how the various risk factors interact to determine the position of each patient along a continuous spectrum of thromboembolic risk. One simplification of this process for surgical patients involves assigning them to one of four VTE risk levels based on the type of operation (eg, minor or major), age (eg, < 40 years, 40 to 60 years, and > 60 years), and the presence of additional risk factors (eg, cancer or previous VTE) [Table 5]. Despite its limitations, this classification system, which was derived using prospective study data, provides both an estimate of VTE risk and related prophylaxis recommendations.

The second approach involves the implementation of group-specific prophylaxis routinely for all patients who belong to each of the major target groups. We support the latter for several reasons. First, we are unable to confidently identify individual patients who do not require prophylaxis. Second, an individualized approach to prophylaxis has not been subjected to rigorous clinical evaluation. Third, individualizing prophylaxis is logistically complex and is likely associated with suboptimal compliance.

After discussing several important issues related to the interpretation of thromboprophylaxis evidence, the remainder of this article categorizes patients according to the type of hospital service that is providing care for their primary surgical or medical disorder. Within each patient category, the risks of VTE and the effective methods of prophylaxis are discussed, if they are known. For most patient groups, sufficient numbers of randomized clinical trials are available to allow strong recommendations (ie, Grade 1A or Grade 1B) to be made with regard to the benefits and risks of specific thromboprophylaxis options.

VTE is an important health-care problem, resulting in significant mortality, morbidity, and resource expenditure. Despite the continuing need for additional data, we believe that there is sufficient evidence to recommend routine thromboprophylaxis for many hospitalized patient groups.

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FD&C Act and Drug Approval

Manufacturers of drugs that lack required approval, including those that are not marketed in accordance with an OTC drug monograph, have not provided the US Food and Drug Administration (FDA) with evidence demonstrating that their products are safe and effective. Many health-care providers may be unaware that unapproved drugs exist because drug product labels do not document FDA approval.

Under the Federal Food, Drug, and Cosmetic (FD&C) Act, all “new drugs” are required to obtain approval under section 505 prior to marketing. Most drugs are considered new drugs under the FD&C Act, but a drug may be excluded from being deemed a new drug (and, therefore, not required to obtain approval under section 505) if it is “generally recognized, among experts qualified by scientific training and experience to evaluate the safety and effectiveness of drugs, as safe and effective [GRAS/E] for use under the conditions prescribed, recommended, or suggested in the labeling thereof.” The GRAS/E standard is outlined in Table 2. The FDA believes that it is not likely that any currently marketed prescription drug is GRAS/E6 because the standard is very high. Even though there may be excellent clinical studies of various prescription drug products reported in the literature, it is highly unlikely that these reports have the same quality and quantity of scientific data as that in an NDA.

FD&C Act and Drug Approval

The Federal Food and Drugs Act of 1906 brought drug regulation under federal law. That act prohibited the sale of adulterated or misbranded drugs but did not require that drugs be approved by the FDA. The act has since been amended a number of times, often in response to tragedies. The 1938 amendment to the FD&C Act required that the FDA review and approve new drugs for safety but not effectiveness before they could be sold legally in interstate commerce. The FD&C Act made it the sponsor’s burden to show the FDA that the drug was safe through the submission of an NDA. Between 1938 and 1962, the FDA considered drugs that were identical, related, or similar (IRS) to an approved drug to be “covered” by that approval, and allowed those IRS drugs to be marketed without independent approval.

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Many health-care providers may be unaware that unapproved drugs exist because the product labels of these drugs do not disclose that they lack FDA approval. The FDA recently took action against unapproved prescription oral cough, cold, and allergy drug products because of concerns about the potential risks of these products, particularly some extended-release formulations that have not been reviewed for quality. There is a potential for medication errors because product names and labeling have not been reviewed for potential confusion, with some products inappropriately labeled for use in children aged < 2 years. FDA-approved prescription drugs or drugs appropriately marketed as over the counter remain available for treatment of cough, cold, and allergy symptoms. Such products are of known efficacy, safety, identity, quality, and purity. Removing unapproved drugs from the marketplace and encouraging manufacturers of unapproved products to seek FDA review and approval is a top priority for the FDA. Since the initiation of the Unapproved Drugs Initiative in 2006, the FDA has removed ~ 1,500 unapproved products from the market and has worked with firms to bring other unapproved drugs into the approval process. The FDA remains committed to its mission of ensuring that safe and effective drugs are available to American consumers.    CHEST 2011; 140(2):295-300

Abbreviations: ACCP = American College of Chest Physicians; ANDA = abbreviated new drug application; DESI = Drug Efficacy Study Implementation; FDA = US Food and Drug Administration; FD&C = Federal Food, Drug, and Cosmetic; GRAS/E = generally recognized as safe and effective; IRS = identical, related, or similar; NAS/NRC = National Academy of Sciences/National Research Council; NDA = new drug application; NDC = National Drug Code; OTC = over the counter

The new drug approval and over-the-counter (OTC) drug monograph processes play an essential role in ensuring that all drugs are both safe and effective for their intended uses. Drugs that have approved new drug applications (NDAs), abbreviated new drug applications (ANDAs), or active ingredients and labeling that are in accordance with an OTC drug monograph may be marketed legally in the United States (Table 1).

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