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Is it DVT? Wells score and D-dimer may avert costly workup
Use a combination of Wells score and D-dimer test to exclude deep vein thrombosis in low- to intermediate-risk outpatients with suggestive symptoms.1
Strength of recommendation (SOR)
A: Based on one good meta-analysis
Goodacre S, Stevenson M, Wailoo A, Sampson F, Sutton AJ, Thomas S. How should we diagnose suspected deep-vein thrombosis? QJM 2006;99:377–388.
Illustrative case
Your patient is a 47-year-old man who has had pain and swelling in his right leg since yesterday. He has no history of cancer, recent travel, surgery, or blood clots. There has been no known trauma. You observe some tenderness in the calf, and no swelling. A Homan’s sign is negative.
How would you assess for deep venous thrombosis?
Background: What are costs, benefits of different strategies?
Wouldn’t it be nice to be able to rule out deep vein thrombosis (DVT) with a simple history and blood test?
Most patients with suggestive symptoms do not have DVT, but workups for this dangerous condition “range from the accurate but expensive (contrast venography) to the cheap but unreliable (clinical assessment),” noted the researchers who conducted this extensive analysis, seeking a cost-effective strategy to put into practice throughout the United Kingdom’s National Health Service.1 The NHS Health Technology Assessment R&D Program funded the study.
Until now, there has been little clear direction from formal comparisons. Although recent studies2 suggest that combinations of simple diagnostic tests may reduce the need for expensive, definitive tests, none explicitly weigh the costs and benefits of the different strategies; despite a large amount of published data, practice varies considerably.1,3
Clinical Context: Guidelines conflict
While some clinical resources now recommend the Wells criteria and D-dimer as useful tools in the initial workup of suspected DVT,4,5 others still recommend compression ultrasound or impedance plethysmography (IPG) as the initial or confirmatory test in all patients with suspected acute DVT.6 These noninvasive tests do provide reassurance that there is no DVT, but they are costly and less convenient than the Wells score and a D-dimer.
Current guidelines give conflicting recommendations.
- The most recent American Thoracic Society guidelines, from 1999, recommend imaging with ultrasound or impedance plethysmography for all patients with suspected DVT.7
- In contrast, the Institute for Clinical Systems Improvement (ICSI) 2006 guidelines recommend first determining the clinical pretest probability of DVT using the Wells score, and then using a D-dimer test to determine which patients with a low probability test need to proceed to ultrasound. This algorithm recommends ultrasound for all patients with either a moderate or high Wells score.8
Variety of D-dimer tests, range of sensitivities
One meta-analysis of 12 studies compared a highly sensitive ELISA D-dimer assay to the less sensitive SimpliRED D-dimer assay. In studies using the highly sensitive ELISA assay, in patients with negative D-dimer and low or moderate Wells score, the 3-month incidence of DVT was 0.5%. However, using the SimpliRED assay, while the 3-month incidence of DVT was 0.5% with negative D-dimer and low Wells score, it was 3.5% with negative D-dimer and intermediate Wells score.7
Study Summary: Seeking convenience and economy
This systematic review, meta-analysis, and decision analysis sought the most practical, cost-effective strategy to detect DVT. The researchers compared the findings of 18 studies of diagnostic strategies (or algorithms) that combined Wells score (TABLE), D-dimer, ultrasound, or venography, and that followed up patients with negative results for at least 3 months. They developed a decision analysis model to compare the algorithms in a hypothetical cohort of 1000 outpatients with suspected DVT.
Applying the estimated sensitivity and specificity of each algorithm to the hypothetical population, they determined the proportions of patients with and without DVT who would receive treatment and which patients would suffer events relating to DVT or treatment, and then estimated lifetime health outcomes (quality-adjusted life years [QALYs]) and costs of testing and treatment.
Using thresholds for willingness to pay of £10,000, £20,000, and £30,000 per QALY, the study identified 2 optimal diagnostic strategies, both of which incorporated D-dimer testing and Wells score. While one strategy starts with Wells score and the other starts with D-dimer, both recommend that patients with a combination of a negative D-dimer test and an intermediate or low Wells score can be safely discharged without further testing.
One weakness of this study is that the authors made the assumption that ultrasound results are independent of Wells score or D-dimer. While it is unlikely that ultrasound results are related to D-dimer results, there is some evidence that ultrasound is more accurate in patients with higher Wells scores. However, if this true, the authors would have underestimated the cost-effectiveness of the favored strategies. Also, they did not include algorithms that involved plethysmography.
TABLE
Wells score estimates probability of deep vein thrombosis
The elements of the Wells score should be ascertained in the usual evaluation of a patient with suspected DVT.
| 1 POINT EACH FOR: | |
| Active cancer | |
| Paralysis, paresis, recent plaster immobilization of lower limb | |
| Recently bedridden for >3 days or major surgery in past 4 weeks | |
| Localized tenderness along distribution of deep venous system | |
| Entire leg swollen | |
| Calf swelling >3 cm compared to asymptomatic leg | |
| Pitting edema | |
| Collateral superficial veins | |
| –2 POINTS FOR: | |
| Alternative diagnosis as likely or more likely than that of DV T | |
| PROBABILITY: | |
| High | >3 points |
| Intermediate | 1 or 2 points |
| Low | <0 points |
What’s New?: This evidence is definitive
This PURL may be old news to you if you have been watching the evolution of DVT risk scoring and the role of D-dimer. This is one of those approaches for which the evidence grows over time and the adoption spreads slowly. We felt that the cumulative evidence, especially this decision analysis,1 clearly points to the most current Wells score and the D-dimer as the approach of choice for initial evaluation of suspected DVT. This more definitive evidence and the variability of practice both reported in the literature and described by our clinician reviewers led us to decide that this study is a priority update and a practice changer—even if it is a slow practice changer.
Caveats: One strategy doesn’t fit all
The authors stress that their results are most applicable to outpatients with a suspected first DVT.1
- D-dimer levels can be elevated in pregnancy, myocardial infarction, cancer, trauma, and postsurgery. These recommendations do not apply to patients with any of these conditions, patients on anticoagulation therapy, intravenous drug abusers, or patients with recurrent DVT.
- In practices where D-dimer testing is not feasible, ultrasound remains an effective approach to suspected DVT.
Challenges To Implementation: Haven’t memorized the Wells score? No problem
As simple as it seems to add up the Wells score, most of us are not likely to recall the scoring system unless we use it often enough to have memorized it. Lack of immediate access to scoring systems in the context of a hectic schedule is a barrier to adoption.
Fortunately, many handheld and Web-based electronic knowledge resources are available for easy retrieval of the Wells DVT score. Some will even dynamically calculate the score for you.
Ideally, scoring systems such as this need to be integrated into electronic health records for easy access at the point of patient care.
Which Wells score?
There are several other scoring systems for estimating DVT risk, but the Wells DVT score is the best studied. To add to the confusion, Wells and his colleagues have made continuous improvements over time, such that there are several versions of the Wells DVT score.
In a quick Google search, we found six versions in which either the criteria or the interpretation was different, not to mention multiple other systems. The one used in this meta-analysis1 and described in this PURL is the most recent, most accurate and best studied.
PURLs methodology
This study was selected and evaluated using the Family Physician Inquiries Network’s Priority Updates from the Research Literature Surveillance System (PURLs) methodology.
1. Goodacre S, Stevenson M, Wailoo A, Sampson F, Sutton AJ, Thomas S. How should we diagnose suspected deep-vein thrombosis? QJM 2006;99:377-388.
2. Fancher TL, White RH, Kravits RL. Combined use of rapid D-dimer testing and estimation of clinical probability in the diagnosis of deep vein thrombosis: systematic review. BMJ 2004;329:821.-
3. Sampson FC, Goodacre S, Kelly AM, Kerr D. How is deep vein thrombosis diagnosed and managed in UK and Australian emergency departments? Emerg Med J 2005;22:780-782.
4. Deep venous thrombosis (DVT): diagnosis. Pepid-PCP [database online]. Available at www.pepidonline.com.
5. Deep vein thrombosis (DVT). Dynamed [database online]. Updates September 24, 2006. Available at dynamicmedical.com.
6. Landaw S. Approach to the diagnosis and therapy of suspected deep vein thrombosis. UpTodate [database online]. Updated April 25, 2006. Available at uptodate.com. Accessed September 13, 2006.
7. Tapson V, Carroll B, Davidson B, et al. and the American Thoracic Society. ATS guidelines: diagnostic approach to acute venous thromboembolism. Am J Respir Crit Care Med 1999;160:1043-1066.
8. Health care guideline: venous thromboembolism. Institute for clinical Systems Improvement. Revised February 2006. Available at www.icsi.org. Accessed on September 27, 2006.
Use a combination of Wells score and D-dimer test to exclude deep vein thrombosis in low- to intermediate-risk outpatients with suggestive symptoms.1
Strength of recommendation (SOR)
A: Based on one good meta-analysis
Goodacre S, Stevenson M, Wailoo A, Sampson F, Sutton AJ, Thomas S. How should we diagnose suspected deep-vein thrombosis? QJM 2006;99:377–388.
Illustrative case
Your patient is a 47-year-old man who has had pain and swelling in his right leg since yesterday. He has no history of cancer, recent travel, surgery, or blood clots. There has been no known trauma. You observe some tenderness in the calf, and no swelling. A Homan’s sign is negative.
How would you assess for deep venous thrombosis?
Background: What are costs, benefits of different strategies?
Wouldn’t it be nice to be able to rule out deep vein thrombosis (DVT) with a simple history and blood test?
Most patients with suggestive symptoms do not have DVT, but workups for this dangerous condition “range from the accurate but expensive (contrast venography) to the cheap but unreliable (clinical assessment),” noted the researchers who conducted this extensive analysis, seeking a cost-effective strategy to put into practice throughout the United Kingdom’s National Health Service.1 The NHS Health Technology Assessment R&D Program funded the study.
Until now, there has been little clear direction from formal comparisons. Although recent studies2 suggest that combinations of simple diagnostic tests may reduce the need for expensive, definitive tests, none explicitly weigh the costs and benefits of the different strategies; despite a large amount of published data, practice varies considerably.1,3
Clinical Context: Guidelines conflict
While some clinical resources now recommend the Wells criteria and D-dimer as useful tools in the initial workup of suspected DVT,4,5 others still recommend compression ultrasound or impedance plethysmography (IPG) as the initial or confirmatory test in all patients with suspected acute DVT.6 These noninvasive tests do provide reassurance that there is no DVT, but they are costly and less convenient than the Wells score and a D-dimer.
Current guidelines give conflicting recommendations.
- The most recent American Thoracic Society guidelines, from 1999, recommend imaging with ultrasound or impedance plethysmography for all patients with suspected DVT.7
- In contrast, the Institute for Clinical Systems Improvement (ICSI) 2006 guidelines recommend first determining the clinical pretest probability of DVT using the Wells score, and then using a D-dimer test to determine which patients with a low probability test need to proceed to ultrasound. This algorithm recommends ultrasound for all patients with either a moderate or high Wells score.8
Variety of D-dimer tests, range of sensitivities
One meta-analysis of 12 studies compared a highly sensitive ELISA D-dimer assay to the less sensitive SimpliRED D-dimer assay. In studies using the highly sensitive ELISA assay, in patients with negative D-dimer and low or moderate Wells score, the 3-month incidence of DVT was 0.5%. However, using the SimpliRED assay, while the 3-month incidence of DVT was 0.5% with negative D-dimer and low Wells score, it was 3.5% with negative D-dimer and intermediate Wells score.7
Study Summary: Seeking convenience and economy
This systematic review, meta-analysis, and decision analysis sought the most practical, cost-effective strategy to detect DVT. The researchers compared the findings of 18 studies of diagnostic strategies (or algorithms) that combined Wells score (TABLE), D-dimer, ultrasound, or venography, and that followed up patients with negative results for at least 3 months. They developed a decision analysis model to compare the algorithms in a hypothetical cohort of 1000 outpatients with suspected DVT.
Applying the estimated sensitivity and specificity of each algorithm to the hypothetical population, they determined the proportions of patients with and without DVT who would receive treatment and which patients would suffer events relating to DVT or treatment, and then estimated lifetime health outcomes (quality-adjusted life years [QALYs]) and costs of testing and treatment.
Using thresholds for willingness to pay of £10,000, £20,000, and £30,000 per QALY, the study identified 2 optimal diagnostic strategies, both of which incorporated D-dimer testing and Wells score. While one strategy starts with Wells score and the other starts with D-dimer, both recommend that patients with a combination of a negative D-dimer test and an intermediate or low Wells score can be safely discharged without further testing.
One weakness of this study is that the authors made the assumption that ultrasound results are independent of Wells score or D-dimer. While it is unlikely that ultrasound results are related to D-dimer results, there is some evidence that ultrasound is more accurate in patients with higher Wells scores. However, if this true, the authors would have underestimated the cost-effectiveness of the favored strategies. Also, they did not include algorithms that involved plethysmography.
TABLE
Wells score estimates probability of deep vein thrombosis
The elements of the Wells score should be ascertained in the usual evaluation of a patient with suspected DVT.
| 1 POINT EACH FOR: | |
| Active cancer | |
| Paralysis, paresis, recent plaster immobilization of lower limb | |
| Recently bedridden for >3 days or major surgery in past 4 weeks | |
| Localized tenderness along distribution of deep venous system | |
| Entire leg swollen | |
| Calf swelling >3 cm compared to asymptomatic leg | |
| Pitting edema | |
| Collateral superficial veins | |
| –2 POINTS FOR: | |
| Alternative diagnosis as likely or more likely than that of DV T | |
| PROBABILITY: | |
| High | >3 points |
| Intermediate | 1 or 2 points |
| Low | <0 points |
What’s New?: This evidence is definitive
This PURL may be old news to you if you have been watching the evolution of DVT risk scoring and the role of D-dimer. This is one of those approaches for which the evidence grows over time and the adoption spreads slowly. We felt that the cumulative evidence, especially this decision analysis,1 clearly points to the most current Wells score and the D-dimer as the approach of choice for initial evaluation of suspected DVT. This more definitive evidence and the variability of practice both reported in the literature and described by our clinician reviewers led us to decide that this study is a priority update and a practice changer—even if it is a slow practice changer.
Caveats: One strategy doesn’t fit all
The authors stress that their results are most applicable to outpatients with a suspected first DVT.1
- D-dimer levels can be elevated in pregnancy, myocardial infarction, cancer, trauma, and postsurgery. These recommendations do not apply to patients with any of these conditions, patients on anticoagulation therapy, intravenous drug abusers, or patients with recurrent DVT.
- In practices where D-dimer testing is not feasible, ultrasound remains an effective approach to suspected DVT.
Challenges To Implementation: Haven’t memorized the Wells score? No problem
As simple as it seems to add up the Wells score, most of us are not likely to recall the scoring system unless we use it often enough to have memorized it. Lack of immediate access to scoring systems in the context of a hectic schedule is a barrier to adoption.
Fortunately, many handheld and Web-based electronic knowledge resources are available for easy retrieval of the Wells DVT score. Some will even dynamically calculate the score for you.
Ideally, scoring systems such as this need to be integrated into electronic health records for easy access at the point of patient care.
Which Wells score?
There are several other scoring systems for estimating DVT risk, but the Wells DVT score is the best studied. To add to the confusion, Wells and his colleagues have made continuous improvements over time, such that there are several versions of the Wells DVT score.
In a quick Google search, we found six versions in which either the criteria or the interpretation was different, not to mention multiple other systems. The one used in this meta-analysis1 and described in this PURL is the most recent, most accurate and best studied.
PURLs methodology
This study was selected and evaluated using the Family Physician Inquiries Network’s Priority Updates from the Research Literature Surveillance System (PURLs) methodology.
Use a combination of Wells score and D-dimer test to exclude deep vein thrombosis in low- to intermediate-risk outpatients with suggestive symptoms.1
Strength of recommendation (SOR)
A: Based on one good meta-analysis
Goodacre S, Stevenson M, Wailoo A, Sampson F, Sutton AJ, Thomas S. How should we diagnose suspected deep-vein thrombosis? QJM 2006;99:377–388.
Illustrative case
Your patient is a 47-year-old man who has had pain and swelling in his right leg since yesterday. He has no history of cancer, recent travel, surgery, or blood clots. There has been no known trauma. You observe some tenderness in the calf, and no swelling. A Homan’s sign is negative.
How would you assess for deep venous thrombosis?
Background: What are costs, benefits of different strategies?
Wouldn’t it be nice to be able to rule out deep vein thrombosis (DVT) with a simple history and blood test?
Most patients with suggestive symptoms do not have DVT, but workups for this dangerous condition “range from the accurate but expensive (contrast venography) to the cheap but unreliable (clinical assessment),” noted the researchers who conducted this extensive analysis, seeking a cost-effective strategy to put into practice throughout the United Kingdom’s National Health Service.1 The NHS Health Technology Assessment R&D Program funded the study.
Until now, there has been little clear direction from formal comparisons. Although recent studies2 suggest that combinations of simple diagnostic tests may reduce the need for expensive, definitive tests, none explicitly weigh the costs and benefits of the different strategies; despite a large amount of published data, practice varies considerably.1,3
Clinical Context: Guidelines conflict
While some clinical resources now recommend the Wells criteria and D-dimer as useful tools in the initial workup of suspected DVT,4,5 others still recommend compression ultrasound or impedance plethysmography (IPG) as the initial or confirmatory test in all patients with suspected acute DVT.6 These noninvasive tests do provide reassurance that there is no DVT, but they are costly and less convenient than the Wells score and a D-dimer.
Current guidelines give conflicting recommendations.
- The most recent American Thoracic Society guidelines, from 1999, recommend imaging with ultrasound or impedance plethysmography for all patients with suspected DVT.7
- In contrast, the Institute for Clinical Systems Improvement (ICSI) 2006 guidelines recommend first determining the clinical pretest probability of DVT using the Wells score, and then using a D-dimer test to determine which patients with a low probability test need to proceed to ultrasound. This algorithm recommends ultrasound for all patients with either a moderate or high Wells score.8
Variety of D-dimer tests, range of sensitivities
One meta-analysis of 12 studies compared a highly sensitive ELISA D-dimer assay to the less sensitive SimpliRED D-dimer assay. In studies using the highly sensitive ELISA assay, in patients with negative D-dimer and low or moderate Wells score, the 3-month incidence of DVT was 0.5%. However, using the SimpliRED assay, while the 3-month incidence of DVT was 0.5% with negative D-dimer and low Wells score, it was 3.5% with negative D-dimer and intermediate Wells score.7
Study Summary: Seeking convenience and economy
This systematic review, meta-analysis, and decision analysis sought the most practical, cost-effective strategy to detect DVT. The researchers compared the findings of 18 studies of diagnostic strategies (or algorithms) that combined Wells score (TABLE), D-dimer, ultrasound, or venography, and that followed up patients with negative results for at least 3 months. They developed a decision analysis model to compare the algorithms in a hypothetical cohort of 1000 outpatients with suspected DVT.
Applying the estimated sensitivity and specificity of each algorithm to the hypothetical population, they determined the proportions of patients with and without DVT who would receive treatment and which patients would suffer events relating to DVT or treatment, and then estimated lifetime health outcomes (quality-adjusted life years [QALYs]) and costs of testing and treatment.
Using thresholds for willingness to pay of £10,000, £20,000, and £30,000 per QALY, the study identified 2 optimal diagnostic strategies, both of which incorporated D-dimer testing and Wells score. While one strategy starts with Wells score and the other starts with D-dimer, both recommend that patients with a combination of a negative D-dimer test and an intermediate or low Wells score can be safely discharged without further testing.
One weakness of this study is that the authors made the assumption that ultrasound results are independent of Wells score or D-dimer. While it is unlikely that ultrasound results are related to D-dimer results, there is some evidence that ultrasound is more accurate in patients with higher Wells scores. However, if this true, the authors would have underestimated the cost-effectiveness of the favored strategies. Also, they did not include algorithms that involved plethysmography.
TABLE
Wells score estimates probability of deep vein thrombosis
The elements of the Wells score should be ascertained in the usual evaluation of a patient with suspected DVT.
| 1 POINT EACH FOR: | |
| Active cancer | |
| Paralysis, paresis, recent plaster immobilization of lower limb | |
| Recently bedridden for >3 days or major surgery in past 4 weeks | |
| Localized tenderness along distribution of deep venous system | |
| Entire leg swollen | |
| Calf swelling >3 cm compared to asymptomatic leg | |
| Pitting edema | |
| Collateral superficial veins | |
| –2 POINTS FOR: | |
| Alternative diagnosis as likely or more likely than that of DV T | |
| PROBABILITY: | |
| High | >3 points |
| Intermediate | 1 or 2 points |
| Low | <0 points |
What’s New?: This evidence is definitive
This PURL may be old news to you if you have been watching the evolution of DVT risk scoring and the role of D-dimer. This is one of those approaches for which the evidence grows over time and the adoption spreads slowly. We felt that the cumulative evidence, especially this decision analysis,1 clearly points to the most current Wells score and the D-dimer as the approach of choice for initial evaluation of suspected DVT. This more definitive evidence and the variability of practice both reported in the literature and described by our clinician reviewers led us to decide that this study is a priority update and a practice changer—even if it is a slow practice changer.
Caveats: One strategy doesn’t fit all
The authors stress that their results are most applicable to outpatients with a suspected first DVT.1
- D-dimer levels can be elevated in pregnancy, myocardial infarction, cancer, trauma, and postsurgery. These recommendations do not apply to patients with any of these conditions, patients on anticoagulation therapy, intravenous drug abusers, or patients with recurrent DVT.
- In practices where D-dimer testing is not feasible, ultrasound remains an effective approach to suspected DVT.
Challenges To Implementation: Haven’t memorized the Wells score? No problem
As simple as it seems to add up the Wells score, most of us are not likely to recall the scoring system unless we use it often enough to have memorized it. Lack of immediate access to scoring systems in the context of a hectic schedule is a barrier to adoption.
Fortunately, many handheld and Web-based electronic knowledge resources are available for easy retrieval of the Wells DVT score. Some will even dynamically calculate the score for you.
Ideally, scoring systems such as this need to be integrated into electronic health records for easy access at the point of patient care.
Which Wells score?
There are several other scoring systems for estimating DVT risk, but the Wells DVT score is the best studied. To add to the confusion, Wells and his colleagues have made continuous improvements over time, such that there are several versions of the Wells DVT score.
In a quick Google search, we found six versions in which either the criteria or the interpretation was different, not to mention multiple other systems. The one used in this meta-analysis1 and described in this PURL is the most recent, most accurate and best studied.
PURLs methodology
This study was selected and evaluated using the Family Physician Inquiries Network’s Priority Updates from the Research Literature Surveillance System (PURLs) methodology.
1. Goodacre S, Stevenson M, Wailoo A, Sampson F, Sutton AJ, Thomas S. How should we diagnose suspected deep-vein thrombosis? QJM 2006;99:377-388.
2. Fancher TL, White RH, Kravits RL. Combined use of rapid D-dimer testing and estimation of clinical probability in the diagnosis of deep vein thrombosis: systematic review. BMJ 2004;329:821.-
3. Sampson FC, Goodacre S, Kelly AM, Kerr D. How is deep vein thrombosis diagnosed and managed in UK and Australian emergency departments? Emerg Med J 2005;22:780-782.
4. Deep venous thrombosis (DVT): diagnosis. Pepid-PCP [database online]. Available at www.pepidonline.com.
5. Deep vein thrombosis (DVT). Dynamed [database online]. Updates September 24, 2006. Available at dynamicmedical.com.
6. Landaw S. Approach to the diagnosis and therapy of suspected deep vein thrombosis. UpTodate [database online]. Updated April 25, 2006. Available at uptodate.com. Accessed September 13, 2006.
7. Tapson V, Carroll B, Davidson B, et al. and the American Thoracic Society. ATS guidelines: diagnostic approach to acute venous thromboembolism. Am J Respir Crit Care Med 1999;160:1043-1066.
8. Health care guideline: venous thromboembolism. Institute for clinical Systems Improvement. Revised February 2006. Available at www.icsi.org. Accessed on September 27, 2006.
1. Goodacre S, Stevenson M, Wailoo A, Sampson F, Sutton AJ, Thomas S. How should we diagnose suspected deep-vein thrombosis? QJM 2006;99:377-388.
2. Fancher TL, White RH, Kravits RL. Combined use of rapid D-dimer testing and estimation of clinical probability in the diagnosis of deep vein thrombosis: systematic review. BMJ 2004;329:821.-
3. Sampson FC, Goodacre S, Kelly AM, Kerr D. How is deep vein thrombosis diagnosed and managed in UK and Australian emergency departments? Emerg Med J 2005;22:780-782.
4. Deep venous thrombosis (DVT): diagnosis. Pepid-PCP [database online]. Available at www.pepidonline.com.
5. Deep vein thrombosis (DVT). Dynamed [database online]. Updates September 24, 2006. Available at dynamicmedical.com.
6. Landaw S. Approach to the diagnosis and therapy of suspected deep vein thrombosis. UpTodate [database online]. Updated April 25, 2006. Available at uptodate.com. Accessed September 13, 2006.
7. Tapson V, Carroll B, Davidson B, et al. and the American Thoracic Society. ATS guidelines: diagnostic approach to acute venous thromboembolism. Am J Respir Crit Care Med 1999;160:1043-1066.
8. Health care guideline: venous thromboembolism. Institute for clinical Systems Improvement. Revised February 2006. Available at www.icsi.org. Accessed on September 27, 2006.
Copyright © 2007 The Family Physicians Inquiries Network.
All rights reserved.
Double-dose vitamin D lowers cancer risk in women over 55
Increasing the dose of vitamin D3 from the current standard of 400–600 IU per day to 1000 IU per day lowers future risk of cancer in women older than age 55 who do not get adequate vitamin D from sun exposure or diet.1
Strength of recommendation (SOR)
A: Well done randomized controlled trial2
Lappe JM, Travers-Gustafson D, Davies KM et al. Vitamin D Supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr 2007; 85:1586–1591.
Illustrative case
A healthy 60-year-old Chicago woman who takes 1500 mg calcium and a multi vitamin daily tells you she has read that extra vitamins prevent cancer. She is particularly concerned about cancer because of her strong family history. Should you recommend that she take any additional vitamins to reduce her risk of cancer?
Background: Will this trial pass the test of time? We think so
Wouldn’t it be nice if we could recommend something as simple and safe as a daily vitamin to reduce the risk of cancer? Until now, we have had no definitive evidence to support such a recommendation. The Lappe et al trial, however, concluded that improving calcium and vitamin D nutritional status substantially reduces all-cancer risk in postmenopausal women.1 Will this single, relatively small study pass the test of time and be confirmed by future clinical trials? We think so.
- The estimated relative risk reduction was dramatic (0.232) and the 95% confidence interval was 0.09 to 0.60, meaning that the true relative risk reduction has a 95% probability of being in the range of 40% to 91%. The P value of <.005 suggests that the probability of this finding occurring by chance alone is less than 1 in 200.
- Our critical appraisal found no significant flaws in this randomized controlled trial.
- Vitamin D is known to have cancer protective effects at the cellular level.
- Prior population based studies support the association between vitamin D and cancer prevention.
For these reasons—and the fact that 1000 IU vitamin D is very safe for most patients—we find this single RCT convincing as a practice changer. For us, the potential benefit outweighs the potential harm.
United States Preventive services Task Force. A 2003 report on “routine vitamin supplementation to prevent cancer and cardiovascular disease” cited insufficient evidence to recommend the use of supplemental vitamins A, C, E, multivitamins with folic acid, or antioxidants to prevent cancer or cardiovascular disease; vitamin D is not mentioned.3
Institute of medicine. In 2005, the IOM suggested an Adequate Intake (AI) of vitamin D of 400 IU for women from 51 to 70 years of age, and 600 IU for women over 70 years of age, to maintain bone health and normal calcium metabolism in healthy women. The IOM cited epidemiologic studies showing an inverse association between either increased sun exposure or higher vitamin D levels and decreased risk of cancer, and included the caveat that it was premature to recommend taking vitamin D for cancer prevention until well-designed trials prove that vitamin D is protective against cancer.4
Electronic knowledge resources that are evidence-based and frequently updated did not recommend vitamin D for cancer prevention on the dates we searched.5-8
Clinical Context: Food, sun, supplements may not deter deficiency
Few people get enough vitamin D to match the dosage that reduced cancer incidence in this trial. In fact, inadequate vitamin D intake, even to meet current standards, is surprisingly common—even in people who are apparently conscious of their nutritional needs. A Boston hospital found that 32% of healthy students, physicians, and resident physicians were vitamin-D deficient, despite drinking a glass of milk daily, taking a daily multivitamin, and eating salmon at least once a week.9 An estimated 1 billion people worldwide have vitamin D deficiency or insufficiency.9
Many factors affect vitamin D levels (TABLE).9 Foods that contain vitamin D3 include fortified milk (100 IU per cup) and oily fish, including salmon, tuna, sardines, mackerel, and herring (200–300 IU per 3.5-oz serving). Sun exposure for 10 to 15 minutes (without sunscreen) at least twice a week to the face, arms, hands, or back is considered sufficient to provide adequate vitamin D during summer or in warm climates.
Many patients need supplements to reach the levels provided by 1000 IU daily, especially in colder climates. Most over-the-counter supplements containing vitamin D alone contain 400 to 1000 IU vitamin D3. Prescription vitamin D2 capsules contain 50,000 IU.9 Vitamin D is available as vitamin D2 and D3:
- Vitamin D2 is usually labeled vitamin D or calciferol. Vitamin D2 is only 30% as effective as vitamin D3 (doses should be adjusted accordingly).
- Vitamin D3 is labeled vitamin D3 or cholecalciferol.
TABLE
3 ways to get vitamin D: Food, sun, and supplements9
| SOURCE | AMOUNT | |
|---|---|---|
| Food | 1 cup of fortified milk | 100 IU vitamin D3 |
| One serving (3.5 oz) of oily fish (salmon, tuna, sardines, mackerel or herring) | 200 to 300 IU vitamin D | |
| Sun (ultraviolet B radiation) | Expose face, arms, hands, or back for 10 to 15 minutes (without sunscreen) at least twice a week during summer months or in warm climates | 3000 IU vitamin D3 per exposure |
| Supplements | Vitamin D3 | 1000 IU/day |
| Vitamin D2 | 50,000 IU every 2 to 4 weeks |
Study Summary: Cancer was a secondary outcome
This trial was well designed and executed, with impressive findings. The primary outcomes were related to skeletal status and calcium economy. Cancer incidence was one of the secondary outcomes.
This population-based study was randomized, double-blinded, and placebo-controlled, with concealed allocation. The researchers enrolled 1180 women older than 55 years of age, with no known cancer, and with adequate mental and physical health to allow an expected 4 years of participation in the trial. The trial was conducted in rural Nebraska. Eighty-six percent of the participants completed the study. Participants were randomly assigned to 3 groups:
- Placebo (calcium placebo plus vitamin D placebo, n=266)
- calcium-only (1400 mg calcium citrate or 1500 mg calcium carbonate plus vitamin D placebo, n=416)
- Calcium + D (1000 IU [25 mcg] vitamin D plus calcium [as above], n=403)
Every 6 months, adherence was assessed by bottle weight. Mean adherence (taking ≥80% of assigned doses) was 85.7% for vitamin D and 74.4% for calcium. Serum samples were analyzed for 25(OH)D at baseline and then yearly.1
Key results
Fifty women developed non-skin cancer during the study: 13 in the first year, and 37 during the second to fourth years. Excluding cancer diagnosed in the first year (it was assumed that these cancers were present, though undiagnosed, at entry), the relative risk reduction (RRR) for the calcium + D group was 0.232 (confidence interval [CI], 0.09–0.60; P<.005), and the RRR for the calcium-only group was 0.587 (95% CI, 0.29–1.21; P=.147) compared with the placebo group.
Number needed to treat (NNT) to prevent 1 case of cancer for the calcium + D group is 21, with an absolute risk reduction of 0.048, or approximately 5%.
Risk reduction. Using baseline 25(OH)D concentration as the predictor variable and cancer as the outcome variable in logistic regression, Lappe et al predicted a 35% reduced cancer risk for every 25 nmol/L (10 ng/mL) increase in serum 25(OH)D.1
What’s New? First RCT to show reduced cancer incidence
This is the first randomized-controlled clinical trial to show that vitamin D reduces cancer risk. (It is important to note that one prior randomized controlled trial10 found no impact on cancer incidence; however, that trial used a vitamin D3 dose of 400 IU, which is lower than the 1000 IU dose used by Lappe et al.)
Vitamin D curbs carcinogenic potential. The new findings build on prior basic research, which established the pathophysiologic process by which vitamin D may prevent cancer in humans. Vitamin D receptors are found not only in the small intestines, bones, and kidneys, but also in most other tissues, including skin, colon, prostate, breast, and brain. The interaction of 1,25(OH)2D with vitamin D receptors induces terminal differentiation and apoptosis and inhibits cellular growth, angiogenesis, and metastatic potential.10
Other studies suggest vitamin d plays a part. Previous population-based studies also suggested an association between vitamin D and reduced cancer incidence.
Lin et al, as part of the Women’s Health Study, found that higher intake of calcium and vitamin D was associated with a lower risk of breast cancer in premenopausal but not in postmenopausal women. The highest dosage quintile was >548 IU; therefore, many if not most women likely ingested an inadequate dose of vitamin D to reduce risk of cancer.11
The Health Professionals Follow-up Study, which followed a cohort of 47,800 men, from 1986 until 2000, found that low levels of vitamin D were associated with increased incidence of cancer and mortality.12
In the only other randomized controlled trial of vitamin D and cancer (also part of the Women’s Health Initiative), Wactawski-Wende et al found no difference in the risk of colorectal cancer between women taking calcium and vitamin D and women taking placebo, over an average of 7 years of follow-up. However, the vitamin D dose was only 400 IU daily, the dosage recommended for general health and bone health.13
Caveats: Consider toxicity unlikely
Although excess vitamin D intake, leading to a serum level of 25-hydroxyvitamin D (25[OH]D) >150 ng/mL, can cause toxicity, the IOM has set the tolerable upper intake level of vitamin D (a fat-soluble vitamin stored in the liver) at 2000 IU (50 mcg) for adults and children older than 1 year. Moreover, studies have shown that adults can tolerate doses as high as 10,000 IU per day.4
Symptoms of toxicity include nausea, vomiting, poor appetite, constipation, weakness, and weight loss as well as signs and symptoms of hypercalcemia, including mental status changes, renal failure, and arrhythmias.4
Diseases and drugs that affect serum levels. Patients with mild to moderate renal failure or chronic granulomatous diseases, such as sarcoidosis, are at higher risk of developing vitamin D toxicity. Patients with malabsorption syndromes, mild or moderate hepatic failure, or who take certain medications, like anticonvulsants or glucocorticoids, that increase vitamin D metabolism may need higher doses of vitamin D.9
The good sun. Exposure to sunlight never leads to vitamin D toxicity, as UV radiation destroys any excess vitamin D that is produced.10
Challenges To Implementation: A matter of time
The primary challenge is likely to be the competing demands and limited resources inherent in delivering all preventive health services in the primary care setting. By one estimate, implementing all preventive health services recommended by the US Preventive Services Task Force would require 7.4 hours per day, leaving little if any time to address the acute and chronic care needs of each individual patient.14
PURLs methodology
This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed here.
1. Lappe JM, Travers-Gustafson D, Davies KM, et al. Vitamin D supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr 2007;85:1586-15-91.
2. Ebell MH, Siwek J, Weiss BD, et al. Strength of recommendation taxonomy (SORT): A patient-centered approach to grading evidence in the medical literature. J Fam Pract 2004;53:111-120
3. US Preventive Services Task Force Web site. Routine vitamin supplementation to prevent cancer and cardiovascular disease: recommendations and rationale. June 2003. Available at: www.ahrq.gov/clinic/3rduspstf/vitamins/vitaminsrr.htm. Accessed on October 15, 2007.
4. National Institutes of Health, Office of Dietary Supplements. Dietary Supplement Fact Sheet: Vitamin D. 2005. Available at: ods.od.nih.gov/factsheets/vitamind.asp. Accessed on October 15, 2007.
5. Fletcher RH, Fairfield KM. Vitamin supplementation in disease prevention. UpToDate [database online]. Updated January 8, 2007. Available at: www.uptodateonline.com. Accessed on June 25, 2007.
6. Becker KL. Vitamin D intake and supplementation. Dynamed [database online]. Updated June 28, 2007. Available at www.dynamicmedical.com. Accessed on July 5, 2007.
7. Rosen HN. Vitamin D therapy in osteoporosis. UpToDate [database online]. Updated February 21, 2007. Available at www.uptodate.com. Accessed on July 11, 2007.
8. Vitamin D PepidPCP [database online]. Available at www.pepidonline.com. Accessed on August 6, 2007.
9. Holick MF. Vitamin D deficiency. N Engl J Med 2007;357:266-281.
10. Holick M. Vitamin D: its role in cancer prevention and treatment. Progress in Biophysics and Molecular Biology 2006;92:49-59.
11. Lin J, Manson JE, Lee I, et al. Intakes of calcium and vitamin D and breast cancer risk in women. Arch Intern Med 2007;167:1050-1059.
12. Giovannucci E, Liu Y, Rimm EB, et al. Prospective study of predictors of vitamin D status and cancer incidence and mortality in men. J Natl Cancer Inst 2006;98:451-459.
13. Wactawski-Wende J, Kotchen JM, Anderson GL, et al. Calcium plus vitamin D supplementation and the risk of colorectal cancer. N Engl J Med 2006;354:684-696.
14. Yarnall KSH, Pollak KI, Ostbye T, et al. Primary care: is there enough time for prevention? Am J Public Health 2003;93:635-641.
Increasing the dose of vitamin D3 from the current standard of 400–600 IU per day to 1000 IU per day lowers future risk of cancer in women older than age 55 who do not get adequate vitamin D from sun exposure or diet.1
Strength of recommendation (SOR)
A: Well done randomized controlled trial2
Lappe JM, Travers-Gustafson D, Davies KM et al. Vitamin D Supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr 2007; 85:1586–1591.
Illustrative case
A healthy 60-year-old Chicago woman who takes 1500 mg calcium and a multi vitamin daily tells you she has read that extra vitamins prevent cancer. She is particularly concerned about cancer because of her strong family history. Should you recommend that she take any additional vitamins to reduce her risk of cancer?
Background: Will this trial pass the test of time? We think so
Wouldn’t it be nice if we could recommend something as simple and safe as a daily vitamin to reduce the risk of cancer? Until now, we have had no definitive evidence to support such a recommendation. The Lappe et al trial, however, concluded that improving calcium and vitamin D nutritional status substantially reduces all-cancer risk in postmenopausal women.1 Will this single, relatively small study pass the test of time and be confirmed by future clinical trials? We think so.
- The estimated relative risk reduction was dramatic (0.232) and the 95% confidence interval was 0.09 to 0.60, meaning that the true relative risk reduction has a 95% probability of being in the range of 40% to 91%. The P value of <.005 suggests that the probability of this finding occurring by chance alone is less than 1 in 200.
- Our critical appraisal found no significant flaws in this randomized controlled trial.
- Vitamin D is known to have cancer protective effects at the cellular level.
- Prior population based studies support the association between vitamin D and cancer prevention.
For these reasons—and the fact that 1000 IU vitamin D is very safe for most patients—we find this single RCT convincing as a practice changer. For us, the potential benefit outweighs the potential harm.
United States Preventive services Task Force. A 2003 report on “routine vitamin supplementation to prevent cancer and cardiovascular disease” cited insufficient evidence to recommend the use of supplemental vitamins A, C, E, multivitamins with folic acid, or antioxidants to prevent cancer or cardiovascular disease; vitamin D is not mentioned.3
Institute of medicine. In 2005, the IOM suggested an Adequate Intake (AI) of vitamin D of 400 IU for women from 51 to 70 years of age, and 600 IU for women over 70 years of age, to maintain bone health and normal calcium metabolism in healthy women. The IOM cited epidemiologic studies showing an inverse association between either increased sun exposure or higher vitamin D levels and decreased risk of cancer, and included the caveat that it was premature to recommend taking vitamin D for cancer prevention until well-designed trials prove that vitamin D is protective against cancer.4
Electronic knowledge resources that are evidence-based and frequently updated did not recommend vitamin D for cancer prevention on the dates we searched.5-8
Clinical Context: Food, sun, supplements may not deter deficiency
Few people get enough vitamin D to match the dosage that reduced cancer incidence in this trial. In fact, inadequate vitamin D intake, even to meet current standards, is surprisingly common—even in people who are apparently conscious of their nutritional needs. A Boston hospital found that 32% of healthy students, physicians, and resident physicians were vitamin-D deficient, despite drinking a glass of milk daily, taking a daily multivitamin, and eating salmon at least once a week.9 An estimated 1 billion people worldwide have vitamin D deficiency or insufficiency.9
Many factors affect vitamin D levels (TABLE).9 Foods that contain vitamin D3 include fortified milk (100 IU per cup) and oily fish, including salmon, tuna, sardines, mackerel, and herring (200–300 IU per 3.5-oz serving). Sun exposure for 10 to 15 minutes (without sunscreen) at least twice a week to the face, arms, hands, or back is considered sufficient to provide adequate vitamin D during summer or in warm climates.
Many patients need supplements to reach the levels provided by 1000 IU daily, especially in colder climates. Most over-the-counter supplements containing vitamin D alone contain 400 to 1000 IU vitamin D3. Prescription vitamin D2 capsules contain 50,000 IU.9 Vitamin D is available as vitamin D2 and D3:
- Vitamin D2 is usually labeled vitamin D or calciferol. Vitamin D2 is only 30% as effective as vitamin D3 (doses should be adjusted accordingly).
- Vitamin D3 is labeled vitamin D3 or cholecalciferol.
TABLE
3 ways to get vitamin D: Food, sun, and supplements9
| SOURCE | AMOUNT | |
|---|---|---|
| Food | 1 cup of fortified milk | 100 IU vitamin D3 |
| One serving (3.5 oz) of oily fish (salmon, tuna, sardines, mackerel or herring) | 200 to 300 IU vitamin D | |
| Sun (ultraviolet B radiation) | Expose face, arms, hands, or back for 10 to 15 minutes (without sunscreen) at least twice a week during summer months or in warm climates | 3000 IU vitamin D3 per exposure |
| Supplements | Vitamin D3 | 1000 IU/day |
| Vitamin D2 | 50,000 IU every 2 to 4 weeks |
Study Summary: Cancer was a secondary outcome
This trial was well designed and executed, with impressive findings. The primary outcomes were related to skeletal status and calcium economy. Cancer incidence was one of the secondary outcomes.
This population-based study was randomized, double-blinded, and placebo-controlled, with concealed allocation. The researchers enrolled 1180 women older than 55 years of age, with no known cancer, and with adequate mental and physical health to allow an expected 4 years of participation in the trial. The trial was conducted in rural Nebraska. Eighty-six percent of the participants completed the study. Participants were randomly assigned to 3 groups:
- Placebo (calcium placebo plus vitamin D placebo, n=266)
- calcium-only (1400 mg calcium citrate or 1500 mg calcium carbonate plus vitamin D placebo, n=416)
- Calcium + D (1000 IU [25 mcg] vitamin D plus calcium [as above], n=403)
Every 6 months, adherence was assessed by bottle weight. Mean adherence (taking ≥80% of assigned doses) was 85.7% for vitamin D and 74.4% for calcium. Serum samples were analyzed for 25(OH)D at baseline and then yearly.1
Key results
Fifty women developed non-skin cancer during the study: 13 in the first year, and 37 during the second to fourth years. Excluding cancer diagnosed in the first year (it was assumed that these cancers were present, though undiagnosed, at entry), the relative risk reduction (RRR) for the calcium + D group was 0.232 (confidence interval [CI], 0.09–0.60; P<.005), and the RRR for the calcium-only group was 0.587 (95% CI, 0.29–1.21; P=.147) compared with the placebo group.
Number needed to treat (NNT) to prevent 1 case of cancer for the calcium + D group is 21, with an absolute risk reduction of 0.048, or approximately 5%.
Risk reduction. Using baseline 25(OH)D concentration as the predictor variable and cancer as the outcome variable in logistic regression, Lappe et al predicted a 35% reduced cancer risk for every 25 nmol/L (10 ng/mL) increase in serum 25(OH)D.1
What’s New? First RCT to show reduced cancer incidence
This is the first randomized-controlled clinical trial to show that vitamin D reduces cancer risk. (It is important to note that one prior randomized controlled trial10 found no impact on cancer incidence; however, that trial used a vitamin D3 dose of 400 IU, which is lower than the 1000 IU dose used by Lappe et al.)
Vitamin D curbs carcinogenic potential. The new findings build on prior basic research, which established the pathophysiologic process by which vitamin D may prevent cancer in humans. Vitamin D receptors are found not only in the small intestines, bones, and kidneys, but also in most other tissues, including skin, colon, prostate, breast, and brain. The interaction of 1,25(OH)2D with vitamin D receptors induces terminal differentiation and apoptosis and inhibits cellular growth, angiogenesis, and metastatic potential.10
Other studies suggest vitamin d plays a part. Previous population-based studies also suggested an association between vitamin D and reduced cancer incidence.
Lin et al, as part of the Women’s Health Study, found that higher intake of calcium and vitamin D was associated with a lower risk of breast cancer in premenopausal but not in postmenopausal women. The highest dosage quintile was >548 IU; therefore, many if not most women likely ingested an inadequate dose of vitamin D to reduce risk of cancer.11
The Health Professionals Follow-up Study, which followed a cohort of 47,800 men, from 1986 until 2000, found that low levels of vitamin D were associated with increased incidence of cancer and mortality.12
In the only other randomized controlled trial of vitamin D and cancer (also part of the Women’s Health Initiative), Wactawski-Wende et al found no difference in the risk of colorectal cancer between women taking calcium and vitamin D and women taking placebo, over an average of 7 years of follow-up. However, the vitamin D dose was only 400 IU daily, the dosage recommended for general health and bone health.13
Caveats: Consider toxicity unlikely
Although excess vitamin D intake, leading to a serum level of 25-hydroxyvitamin D (25[OH]D) >150 ng/mL, can cause toxicity, the IOM has set the tolerable upper intake level of vitamin D (a fat-soluble vitamin stored in the liver) at 2000 IU (50 mcg) for adults and children older than 1 year. Moreover, studies have shown that adults can tolerate doses as high as 10,000 IU per day.4
Symptoms of toxicity include nausea, vomiting, poor appetite, constipation, weakness, and weight loss as well as signs and symptoms of hypercalcemia, including mental status changes, renal failure, and arrhythmias.4
Diseases and drugs that affect serum levels. Patients with mild to moderate renal failure or chronic granulomatous diseases, such as sarcoidosis, are at higher risk of developing vitamin D toxicity. Patients with malabsorption syndromes, mild or moderate hepatic failure, or who take certain medications, like anticonvulsants or glucocorticoids, that increase vitamin D metabolism may need higher doses of vitamin D.9
The good sun. Exposure to sunlight never leads to vitamin D toxicity, as UV radiation destroys any excess vitamin D that is produced.10
Challenges To Implementation: A matter of time
The primary challenge is likely to be the competing demands and limited resources inherent in delivering all preventive health services in the primary care setting. By one estimate, implementing all preventive health services recommended by the US Preventive Services Task Force would require 7.4 hours per day, leaving little if any time to address the acute and chronic care needs of each individual patient.14
PURLs methodology
This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed here.
Increasing the dose of vitamin D3 from the current standard of 400–600 IU per day to 1000 IU per day lowers future risk of cancer in women older than age 55 who do not get adequate vitamin D from sun exposure or diet.1
Strength of recommendation (SOR)
A: Well done randomized controlled trial2
Lappe JM, Travers-Gustafson D, Davies KM et al. Vitamin D Supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr 2007; 85:1586–1591.
Illustrative case
A healthy 60-year-old Chicago woman who takes 1500 mg calcium and a multi vitamin daily tells you she has read that extra vitamins prevent cancer. She is particularly concerned about cancer because of her strong family history. Should you recommend that she take any additional vitamins to reduce her risk of cancer?
Background: Will this trial pass the test of time? We think so
Wouldn’t it be nice if we could recommend something as simple and safe as a daily vitamin to reduce the risk of cancer? Until now, we have had no definitive evidence to support such a recommendation. The Lappe et al trial, however, concluded that improving calcium and vitamin D nutritional status substantially reduces all-cancer risk in postmenopausal women.1 Will this single, relatively small study pass the test of time and be confirmed by future clinical trials? We think so.
- The estimated relative risk reduction was dramatic (0.232) and the 95% confidence interval was 0.09 to 0.60, meaning that the true relative risk reduction has a 95% probability of being in the range of 40% to 91%. The P value of <.005 suggests that the probability of this finding occurring by chance alone is less than 1 in 200.
- Our critical appraisal found no significant flaws in this randomized controlled trial.
- Vitamin D is known to have cancer protective effects at the cellular level.
- Prior population based studies support the association between vitamin D and cancer prevention.
For these reasons—and the fact that 1000 IU vitamin D is very safe for most patients—we find this single RCT convincing as a practice changer. For us, the potential benefit outweighs the potential harm.
United States Preventive services Task Force. A 2003 report on “routine vitamin supplementation to prevent cancer and cardiovascular disease” cited insufficient evidence to recommend the use of supplemental vitamins A, C, E, multivitamins with folic acid, or antioxidants to prevent cancer or cardiovascular disease; vitamin D is not mentioned.3
Institute of medicine. In 2005, the IOM suggested an Adequate Intake (AI) of vitamin D of 400 IU for women from 51 to 70 years of age, and 600 IU for women over 70 years of age, to maintain bone health and normal calcium metabolism in healthy women. The IOM cited epidemiologic studies showing an inverse association between either increased sun exposure or higher vitamin D levels and decreased risk of cancer, and included the caveat that it was premature to recommend taking vitamin D for cancer prevention until well-designed trials prove that vitamin D is protective against cancer.4
Electronic knowledge resources that are evidence-based and frequently updated did not recommend vitamin D for cancer prevention on the dates we searched.5-8
Clinical Context: Food, sun, supplements may not deter deficiency
Few people get enough vitamin D to match the dosage that reduced cancer incidence in this trial. In fact, inadequate vitamin D intake, even to meet current standards, is surprisingly common—even in people who are apparently conscious of their nutritional needs. A Boston hospital found that 32% of healthy students, physicians, and resident physicians were vitamin-D deficient, despite drinking a glass of milk daily, taking a daily multivitamin, and eating salmon at least once a week.9 An estimated 1 billion people worldwide have vitamin D deficiency or insufficiency.9
Many factors affect vitamin D levels (TABLE).9 Foods that contain vitamin D3 include fortified milk (100 IU per cup) and oily fish, including salmon, tuna, sardines, mackerel, and herring (200–300 IU per 3.5-oz serving). Sun exposure for 10 to 15 minutes (without sunscreen) at least twice a week to the face, arms, hands, or back is considered sufficient to provide adequate vitamin D during summer or in warm climates.
Many patients need supplements to reach the levels provided by 1000 IU daily, especially in colder climates. Most over-the-counter supplements containing vitamin D alone contain 400 to 1000 IU vitamin D3. Prescription vitamin D2 capsules contain 50,000 IU.9 Vitamin D is available as vitamin D2 and D3:
- Vitamin D2 is usually labeled vitamin D or calciferol. Vitamin D2 is only 30% as effective as vitamin D3 (doses should be adjusted accordingly).
- Vitamin D3 is labeled vitamin D3 or cholecalciferol.
TABLE
3 ways to get vitamin D: Food, sun, and supplements9
| SOURCE | AMOUNT | |
|---|---|---|
| Food | 1 cup of fortified milk | 100 IU vitamin D3 |
| One serving (3.5 oz) of oily fish (salmon, tuna, sardines, mackerel or herring) | 200 to 300 IU vitamin D | |
| Sun (ultraviolet B radiation) | Expose face, arms, hands, or back for 10 to 15 minutes (without sunscreen) at least twice a week during summer months or in warm climates | 3000 IU vitamin D3 per exposure |
| Supplements | Vitamin D3 | 1000 IU/day |
| Vitamin D2 | 50,000 IU every 2 to 4 weeks |
Study Summary: Cancer was a secondary outcome
This trial was well designed and executed, with impressive findings. The primary outcomes were related to skeletal status and calcium economy. Cancer incidence was one of the secondary outcomes.
This population-based study was randomized, double-blinded, and placebo-controlled, with concealed allocation. The researchers enrolled 1180 women older than 55 years of age, with no known cancer, and with adequate mental and physical health to allow an expected 4 years of participation in the trial. The trial was conducted in rural Nebraska. Eighty-six percent of the participants completed the study. Participants were randomly assigned to 3 groups:
- Placebo (calcium placebo plus vitamin D placebo, n=266)
- calcium-only (1400 mg calcium citrate or 1500 mg calcium carbonate plus vitamin D placebo, n=416)
- Calcium + D (1000 IU [25 mcg] vitamin D plus calcium [as above], n=403)
Every 6 months, adherence was assessed by bottle weight. Mean adherence (taking ≥80% of assigned doses) was 85.7% for vitamin D and 74.4% for calcium. Serum samples were analyzed for 25(OH)D at baseline and then yearly.1
Key results
Fifty women developed non-skin cancer during the study: 13 in the first year, and 37 during the second to fourth years. Excluding cancer diagnosed in the first year (it was assumed that these cancers were present, though undiagnosed, at entry), the relative risk reduction (RRR) for the calcium + D group was 0.232 (confidence interval [CI], 0.09–0.60; P<.005), and the RRR for the calcium-only group was 0.587 (95% CI, 0.29–1.21; P=.147) compared with the placebo group.
Number needed to treat (NNT) to prevent 1 case of cancer for the calcium + D group is 21, with an absolute risk reduction of 0.048, or approximately 5%.
Risk reduction. Using baseline 25(OH)D concentration as the predictor variable and cancer as the outcome variable in logistic regression, Lappe et al predicted a 35% reduced cancer risk for every 25 nmol/L (10 ng/mL) increase in serum 25(OH)D.1
What’s New? First RCT to show reduced cancer incidence
This is the first randomized-controlled clinical trial to show that vitamin D reduces cancer risk. (It is important to note that one prior randomized controlled trial10 found no impact on cancer incidence; however, that trial used a vitamin D3 dose of 400 IU, which is lower than the 1000 IU dose used by Lappe et al.)
Vitamin D curbs carcinogenic potential. The new findings build on prior basic research, which established the pathophysiologic process by which vitamin D may prevent cancer in humans. Vitamin D receptors are found not only in the small intestines, bones, and kidneys, but also in most other tissues, including skin, colon, prostate, breast, and brain. The interaction of 1,25(OH)2D with vitamin D receptors induces terminal differentiation and apoptosis and inhibits cellular growth, angiogenesis, and metastatic potential.10
Other studies suggest vitamin d plays a part. Previous population-based studies also suggested an association between vitamin D and reduced cancer incidence.
Lin et al, as part of the Women’s Health Study, found that higher intake of calcium and vitamin D was associated with a lower risk of breast cancer in premenopausal but not in postmenopausal women. The highest dosage quintile was >548 IU; therefore, many if not most women likely ingested an inadequate dose of vitamin D to reduce risk of cancer.11
The Health Professionals Follow-up Study, which followed a cohort of 47,800 men, from 1986 until 2000, found that low levels of vitamin D were associated with increased incidence of cancer and mortality.12
In the only other randomized controlled trial of vitamin D and cancer (also part of the Women’s Health Initiative), Wactawski-Wende et al found no difference in the risk of colorectal cancer between women taking calcium and vitamin D and women taking placebo, over an average of 7 years of follow-up. However, the vitamin D dose was only 400 IU daily, the dosage recommended for general health and bone health.13
Caveats: Consider toxicity unlikely
Although excess vitamin D intake, leading to a serum level of 25-hydroxyvitamin D (25[OH]D) >150 ng/mL, can cause toxicity, the IOM has set the tolerable upper intake level of vitamin D (a fat-soluble vitamin stored in the liver) at 2000 IU (50 mcg) for adults and children older than 1 year. Moreover, studies have shown that adults can tolerate doses as high as 10,000 IU per day.4
Symptoms of toxicity include nausea, vomiting, poor appetite, constipation, weakness, and weight loss as well as signs and symptoms of hypercalcemia, including mental status changes, renal failure, and arrhythmias.4
Diseases and drugs that affect serum levels. Patients with mild to moderate renal failure or chronic granulomatous diseases, such as sarcoidosis, are at higher risk of developing vitamin D toxicity. Patients with malabsorption syndromes, mild or moderate hepatic failure, or who take certain medications, like anticonvulsants or glucocorticoids, that increase vitamin D metabolism may need higher doses of vitamin D.9
The good sun. Exposure to sunlight never leads to vitamin D toxicity, as UV radiation destroys any excess vitamin D that is produced.10
Challenges To Implementation: A matter of time
The primary challenge is likely to be the competing demands and limited resources inherent in delivering all preventive health services in the primary care setting. By one estimate, implementing all preventive health services recommended by the US Preventive Services Task Force would require 7.4 hours per day, leaving little if any time to address the acute and chronic care needs of each individual patient.14
PURLs methodology
This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed here.
1. Lappe JM, Travers-Gustafson D, Davies KM, et al. Vitamin D supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr 2007;85:1586-15-91.
2. Ebell MH, Siwek J, Weiss BD, et al. Strength of recommendation taxonomy (SORT): A patient-centered approach to grading evidence in the medical literature. J Fam Pract 2004;53:111-120
3. US Preventive Services Task Force Web site. Routine vitamin supplementation to prevent cancer and cardiovascular disease: recommendations and rationale. June 2003. Available at: www.ahrq.gov/clinic/3rduspstf/vitamins/vitaminsrr.htm. Accessed on October 15, 2007.
4. National Institutes of Health, Office of Dietary Supplements. Dietary Supplement Fact Sheet: Vitamin D. 2005. Available at: ods.od.nih.gov/factsheets/vitamind.asp. Accessed on October 15, 2007.
5. Fletcher RH, Fairfield KM. Vitamin supplementation in disease prevention. UpToDate [database online]. Updated January 8, 2007. Available at: www.uptodateonline.com. Accessed on June 25, 2007.
6. Becker KL. Vitamin D intake and supplementation. Dynamed [database online]. Updated June 28, 2007. Available at www.dynamicmedical.com. Accessed on July 5, 2007.
7. Rosen HN. Vitamin D therapy in osteoporosis. UpToDate [database online]. Updated February 21, 2007. Available at www.uptodate.com. Accessed on July 11, 2007.
8. Vitamin D PepidPCP [database online]. Available at www.pepidonline.com. Accessed on August 6, 2007.
9. Holick MF. Vitamin D deficiency. N Engl J Med 2007;357:266-281.
10. Holick M. Vitamin D: its role in cancer prevention and treatment. Progress in Biophysics and Molecular Biology 2006;92:49-59.
11. Lin J, Manson JE, Lee I, et al. Intakes of calcium and vitamin D and breast cancer risk in women. Arch Intern Med 2007;167:1050-1059.
12. Giovannucci E, Liu Y, Rimm EB, et al. Prospective study of predictors of vitamin D status and cancer incidence and mortality in men. J Natl Cancer Inst 2006;98:451-459.
13. Wactawski-Wende J, Kotchen JM, Anderson GL, et al. Calcium plus vitamin D supplementation and the risk of colorectal cancer. N Engl J Med 2006;354:684-696.
14. Yarnall KSH, Pollak KI, Ostbye T, et al. Primary care: is there enough time for prevention? Am J Public Health 2003;93:635-641.
1. Lappe JM, Travers-Gustafson D, Davies KM, et al. Vitamin D supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr 2007;85:1586-15-91.
2. Ebell MH, Siwek J, Weiss BD, et al. Strength of recommendation taxonomy (SORT): A patient-centered approach to grading evidence in the medical literature. J Fam Pract 2004;53:111-120
3. US Preventive Services Task Force Web site. Routine vitamin supplementation to prevent cancer and cardiovascular disease: recommendations and rationale. June 2003. Available at: www.ahrq.gov/clinic/3rduspstf/vitamins/vitaminsrr.htm. Accessed on October 15, 2007.
4. National Institutes of Health, Office of Dietary Supplements. Dietary Supplement Fact Sheet: Vitamin D. 2005. Available at: ods.od.nih.gov/factsheets/vitamind.asp. Accessed on October 15, 2007.
5. Fletcher RH, Fairfield KM. Vitamin supplementation in disease prevention. UpToDate [database online]. Updated January 8, 2007. Available at: www.uptodateonline.com. Accessed on June 25, 2007.
6. Becker KL. Vitamin D intake and supplementation. Dynamed [database online]. Updated June 28, 2007. Available at www.dynamicmedical.com. Accessed on July 5, 2007.
7. Rosen HN. Vitamin D therapy in osteoporosis. UpToDate [database online]. Updated February 21, 2007. Available at www.uptodate.com. Accessed on July 11, 2007.
8. Vitamin D PepidPCP [database online]. Available at www.pepidonline.com. Accessed on August 6, 2007.
9. Holick MF. Vitamin D deficiency. N Engl J Med 2007;357:266-281.
10. Holick M. Vitamin D: its role in cancer prevention and treatment. Progress in Biophysics and Molecular Biology 2006;92:49-59.
11. Lin J, Manson JE, Lee I, et al. Intakes of calcium and vitamin D and breast cancer risk in women. Arch Intern Med 2007;167:1050-1059.
12. Giovannucci E, Liu Y, Rimm EB, et al. Prospective study of predictors of vitamin D status and cancer incidence and mortality in men. J Natl Cancer Inst 2006;98:451-459.
13. Wactawski-Wende J, Kotchen JM, Anderson GL, et al. Calcium plus vitamin D supplementation and the risk of colorectal cancer. N Engl J Med 2006;354:684-696.
14. Yarnall KSH, Pollak KI, Ostbye T, et al. Primary care: is there enough time for prevention? Am J Public Health 2003;93:635-641.
Copyright © 2007 The Family Physicians Inquiries Network.
All rights reserved.
Stroke prevention: Age alone does not rule out warfarin
Warfarin is as safe as aspirin and more effective for stroke prevention in elders with atrial fibrillation
Strength of recommendation (SOR)
A: Well-designed randomized controlled trial of elderly patients in the primary care setting, consistent with findings from prior RCTs
Mant et al. Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study [BAFTA]): a randomised controlled trial. Lancet 2007;370:493–503.1
Illustrative Case
An 85-year-old woman with hypertension and chronic atrial fibrillation has transferred her care to you. She takes an aspirin a day for cardiovascular prevention. You know that warfarin is better than aspirin for preventing stroke but worry about the increased risk of bleeding with warfarin.
Should you recommend that she stay on aspirin or switch to warfarin?
Background: BAFTA: A realistic study
We have been reluctant to use warfarin in elders with atrial fibrillation for good reason: risk of hemorrhage. Since there are few trials looking at use of warfarin among elders in primary care settings, we are uncertain about the balance of benefits and harms.
The BAFTA study1 is the first trial to compare outcomes of warfarin vs aspirin in elders specifically, in the less-than-ideal conditions of real life.
Guidelines mirror uncertainties
This uncertainty is reflected even in guidelines for anticoagulation in elderly patients with atrial fibrillation.
- The 2004 American College of Chest Physicians Seventh Conference on Antithrombotic and Thrombolytic Therapy recommends treating all patients with atrial fibrillation and high risk of stroke with warfarin. Their definition of high-risk includes any patient with 1 or more of the following risk factors: age >75 years, prior ischemic stroke, transient ischemic attack or systemic embolism, congestive heart failure, impaired left ventricular systolic function, hypertension, or diabetes mellitus.2
- In contrast, the 2006 guidelines for the management of patients with atrial fibrillation from the American College of Cardiology, American Heart Association, and European Society of Cardiology, are more conservative. They recommend that patients with more than 1 risk factor take warfarin, and patients with only 1 risk factor (for example, a patient older than 75 years of age with no other risk factors) take either warfarin or aspirin.3
Clinical context: Reasonable concerns
Fewer than half of the 10% to 12% of people older than 75 with atrial fibrillation are taking warfarin for stroke prevention. In one study, only 35% of patients 85 years and older with no known contraindication to anticoagulation received warfarin.4 Possible reasons for this low rate include:
- cost of monitoring warfarin
- concerns about compliance
- increased risk of hemorrhage
- prior studies focused on younger patients, in closely monitored settings.
These factors lead us to speculate that many physicians believe that the risks of warfarin in elderly patients in primary care settings outweigh any potential benefit.
We think this study demonstrates that we should seriously discuss and consider warfarin therapy for most of our elderly patients with atrial fibrillation.
The key finding from the BAFTA study is that advanced age alone is not a contraindication to the use of warfarin for stroke prevention in elderly patients with atrial fibrillation
Study summary: Primary care setting, elders only
This prospective randomized open-label trial was designed to test the effectiveness and safety of warfarin vs aspirin in the elderly, in a realistic primary care setting. The study compared the frequency of stroke, intracranial hemorrhage, and other significant arterial embolism in patients taking either warfarin or aspirin.
Inclusion criteria. Patients were at least 75 years old (average 81.5 years) with an ECG within the previous 2 years showing atrial fibrillation or atrial flutter. Seventy percent of the patients had been previously diagnosed with atrial fibrillation and 30% were identified because they had an irregular pulse on exam.
Exclusion criteria included rheumatic heart disease, major nontraumatic hemorrhage in the past 5 years, intracranial hemorrhage, endoscopically proven peptic ulcer disease in the past year, esophageal varices, allergy to either study drug, terminal illness, surgery in past 3 months, blood pressure greater than 180/110 mm Hg, or if the primary physician judged that a patient should either be on warfarin or not, based on risk factors.
Patient characteristics. The patients were recruited from 260 general practices in England and Wales. At baseline, 39% to 40% of the patients were already taking warfarin, 12% to 13% had had a prior stroke, 53% to 55% had hypertension, 13% to 14% had diabetes, 19% to 20% had heart failure, and 10% to 12% had a history of myocardial infarction. Patients were followed for an average of 2.7 years.
Aspirin and warfarin regimens. Patients were assigned to either aspirin at a dose of 75 mg/day or warfarin with a target international normalized ratio (INR) of 2.5 and an acceptable range of 2 to 3. Because the study aimed to reflect a realistic primary care setting, the frequency and method of INR testing was left to the discretion of participating physicians.
Patients who had been taking aspirin or warfarin prior to the study discontinued that medicine if they were assigned to the other treatment. Sixty-seven percent of the patients assigned to warfarin continued this treatment throughout the study, and 78% of those who either stopped taking warfarin or never started it were put on either aspirin or clopidogrel. Seventy-six percent of the patients assigned to aspirin took the medicine for the entire study period, while 70% of those who stopped taking aspirin or never started it were either switched to or stayed on warfarin.
INR values. Patients on warfarin had INR values between 2.0 and 3.0 for 67% of the time, below range for 19%, of the time, and above range for 14% of the time. Twenty-two percent of practices had all components of INR monitoring done at the hospital (phlebotomy, INR analysis, and warfarin dosing), 19% of the practices completed all 3 components on site, and the remaining practices had various combinations of onsite and hospital monitoring.
The primary outcomes included disabling stroke (ischemic or hemorrhagic) or clinically significant arterial embolism. There were 24 primary events (1.8% per year) in patients assigned to warfarin compared with 48 primary events (3.8% per year) in those assigned to aspirin, with a relative risk of 0.48 (95% confidence interval [CI], 0.28–0.80 (TABLE). The number needed to treat for 1 year to prevent 1 primary event was 50, when warfarin was compared to aspirin. Warfarin was superior to aspirin in all subgroup analyses, including patients over 85 years old.
Secondary outcomes. There were no significant differences between the warfarin and aspirin groups in the secondary outcomes: hospital admission or death as a result of a non-stroke vascular event (6.1% risk per year with warfarin vs 6.3% risk per year with aspirin), all-cause mortality (8.0% vs 8.4%), and major extracranial hemorrhage (1.4% vs 1.6%). Patients assigned to warfarin, including the subgroup of patients older than 85, did not have an increased risk of a major hemorrhage when compared with those assigned to aspirin (1.9% risk per year with warfarin vs 2.0% risk per year with aspirin; relative risk=0.96; 95% CI, 0.53–1.75).1
TABLE
BAFTA study: Warfarin was as safe as aspirin and more effective in preventing stroke in the elderly
| WARFARIN (488 patients) | ASPIRIN (485 patients) | ||||
|---|---|---|---|---|---|
| PRIMARY EVENTS | Total events | Risk per year | Total events | Risk per year | WARFARIN VA ASPIRIN |
| Stroke | 21 | 1.6% | 44 | 3.4% | RR=0.46 (95% CI, 0.26–0.79) P=.003 |
| Stroke, other intracranial hemorrhage, or systemic embolism | 24 | 1.8% | 48 | 3.8% | RR=0.48 (95% CI, 0.28–0.80) P=.003 |
| RR, relative risk; CI, confidence interval. | |||||
| Source: Mant J, Hobbs FD, Fletcher K et al. Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomised controlled trial. Lancet 2007;370:493-503. | |||||
What’s new?: Age alone does not preclude warfarin
The key finding from the BAFTA study is that advanced age alone is not a contraindication to the use of warfarin for stroke prevention in elderly patients with atrial fibrillation.
This is the first randomized controlled trial of warfarin for atrial fibrillation that included only patients ages 75 and older, conducted in a primary care setting.5
Limitations of earlier studies. The most recent meta-analysis of antithrombotic therapy for stroke prevention in patients with atrial fibrillation included 29 trials with 28,044 patients. This analysis concluded that although both warfarin and aspirin are effective in reducing the risk of stroke in patients with atrial fibrillation (warfarin by 60% and aspirin by 20%), warfarin was more effective than aspirin (relative risk reduction of 39%), with very small (≤0.3% per year) absolute increases in major extracranial hemorrhage.
The average age of patients in those trials, however, was 71. The authors identified the lack of data on older patients (who are at higher risk for serious bleeding events) as a limitation of the meta-analysis. Many of these trials took place in settings with closer monitoring of INR and warfarin dosing than is customary in a primary care setting.5
Caveats: Consider the evidence on benefits and risks
Major bleeding from warfarin is a concern, especially in the elderly. A recent cohort study6 (summarized as a POEM in this journal7) reported high rates of major bleeding (13.1 per hundred person-years or 13.1%) in patients ≥80 years of age during their first year of warfarin therapy. Despite the high risk of bleeding events in this cohort study, there was considerable benefit from warfarin therapy.
None of the patients who remained on warfarin had a thrombotic stroke (personal communication with Dr Hylek by the author). The expected rate of thrombotic stroke is in the range of 5% to 6% per year in this high-risk group.
Furthermore, most of the bleeding events were gastrointestinal and did not lead to catastrophic outcomes.
Do not add warfarin to aspirin in patients >75 years
Dr Hylek also noted that 40% of the patients in their cohort study were taking both warfarin and aspirin, and, although her study did not have sufficient power to detect a difference, prior studies noted increased risk of bleeding with this combination compared to warfarin alone.8,9 For this reason we think the combination of warfarin and aspirin should be avoided in patients over 75.
Target INR <3
Our caveat is the same as the POEM author’s conclusion:7 Patients over 80 should be carefully monitored to keep the INR below 3.0 or for signs of bleeding, especially in the first 90 days of therapy when bleeding is more likely to occur.
A final point that the BAFTA authors make, which is worth repeating here, is that the prior studies showing an increased risk of bleeding complications had INR target rates of 4 to 5, whereas the target in this study was 2 to 3. Two previous studies that also compared aspirin to warfarin with an INR goal of 2 to 3 similarly showed no difference in major bleeding between the 2 groups.10,11
Challenges to Implementation: Meticulous monitoring, patient education
- Managing warfarin therapy requires meticulous care to avoid complications and optimize treatment effect.
- Patients may be reluctant to take warfarin because they may fear bleeding.
- Patients who do agree to take warfarin need education about possible medication interactions, the need for regular INR monitoring, dosage changes, and dietary issues (eg, maintaining a consistent intake of foods containing vitamin K).
Contraindications
Contraindications to the use of warfarin include hypersensitivity to warfarin, severe hepatic disease, alcoholism, recent trauma or surgery, history of falling or significant risk of falls, and active gastrointestinal, respiratory, or genitourinary bleeding.
INR testing systems
Several randomized trials support the use of monitoring systems such as a pharmacist managed anticoagulation service or decision support software, both of which can improve the percentage of patients with therapeutic INR values.12,13
Using point-of-care INR tests in the office provides immediate results which allow for more timely adjustments of warfarin dose.14
PURLs methodology
This study was selected and evaluated using the Family Physician Inquiries Network’s Priority Updates from the Research Literature Surveillance System (PURLs) methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed here.
1. Mant J, Hobbs FD, Fletcher K, et al. Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomised controlled trial. Lancet 2007;370:493-503.
2. Singer DE, Albers GW, Dalen JE, et al. Antithrombotic therapy in atrial fibrillation: The seventh ACCP (American College of Chest Physicians) conference on antithrombotic and thrombolytic therapy. Chest 2004;126:429S-456S.
3. Fuster V, Rydén LE, Cannom DS, et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation—executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation). J Am Coll Cardiol 2006;48:854-906.
4. Go AS, Hylek EM, Borowsky LH, et al. Warfarin use among ambulatory patients with non-valvular atrial fibrillation: The Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) study. Ann Intern Med 1999;131:927.-
5. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: Antithrombotic therapy to prevent stroke in patients who have non-valvular atrial fibrillation. Ann Intern Med 2007;146:857-867.
6. Hylek EM, Evans-Molina C, Shea C, et al. Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation. Circulation 2007;115:2689-2696.
7. POEM: Bleeding risk with warfarin is high among the elderly. J Fam Pract 2007;6:709.-
8. Garcia D, Hylek E. Stroke prevention in elderly patients with atrial fibrillation. Lancet 2007;370:460-461.
9. Perez-Gomez F, Alegria E, Bejon J, et al. Comparative effects of antiplatelet, anticoagulant, or combined therapy in patients with valvular and non-valvular atrial fibrillation: a randomized multicenter study. J Am Coll Cardiol 2004;44:1557-1556.
10. Rash A, Downes T, Portner R, et al. A randomized controlled trial of warfarin versus aspirin for stroke preventions in octogenarians with atrial fibrillation (WASPO). Age Ageing 2007;36:151-156.
11. Gullov AL, Koeford BG, Petersen P, et al. Fixed minidose warfarin and aspirin alone and in combination vs adjusted-dose warfarin for stroke prevention in atrial fibrillation. Arch Intern Med 1998;158:1513-1521.
12. Witt DM, Sadler MA, Shanahan RL, et al. Effect of a centralized clinical pharmacy anticoagulation service on outcomes of anticoagulation therapy. Chest 2005;127:1515-1522.
13. Wurster M, Doran T. Anticoagulation management: a new approach. Disease Management 2006;9:201-209.
14. Dorfman DM, Goonan EM, Boutilier MK, et al. Point-of-care (POC) versus central laboratory instrumentation for monitoring oral anticoagulation. Vasc Med 2005;10:23-27.
Warfarin is as safe as aspirin and more effective for stroke prevention in elders with atrial fibrillation
Strength of recommendation (SOR)
A: Well-designed randomized controlled trial of elderly patients in the primary care setting, consistent with findings from prior RCTs
Mant et al. Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study [BAFTA]): a randomised controlled trial. Lancet 2007;370:493–503.1
Illustrative Case
An 85-year-old woman with hypertension and chronic atrial fibrillation has transferred her care to you. She takes an aspirin a day for cardiovascular prevention. You know that warfarin is better than aspirin for preventing stroke but worry about the increased risk of bleeding with warfarin.
Should you recommend that she stay on aspirin or switch to warfarin?
Background: BAFTA: A realistic study
We have been reluctant to use warfarin in elders with atrial fibrillation for good reason: risk of hemorrhage. Since there are few trials looking at use of warfarin among elders in primary care settings, we are uncertain about the balance of benefits and harms.
The BAFTA study1 is the first trial to compare outcomes of warfarin vs aspirin in elders specifically, in the less-than-ideal conditions of real life.
Guidelines mirror uncertainties
This uncertainty is reflected even in guidelines for anticoagulation in elderly patients with atrial fibrillation.
- The 2004 American College of Chest Physicians Seventh Conference on Antithrombotic and Thrombolytic Therapy recommends treating all patients with atrial fibrillation and high risk of stroke with warfarin. Their definition of high-risk includes any patient with 1 or more of the following risk factors: age >75 years, prior ischemic stroke, transient ischemic attack or systemic embolism, congestive heart failure, impaired left ventricular systolic function, hypertension, or diabetes mellitus.2
- In contrast, the 2006 guidelines for the management of patients with atrial fibrillation from the American College of Cardiology, American Heart Association, and European Society of Cardiology, are more conservative. They recommend that patients with more than 1 risk factor take warfarin, and patients with only 1 risk factor (for example, a patient older than 75 years of age with no other risk factors) take either warfarin or aspirin.3
Clinical context: Reasonable concerns
Fewer than half of the 10% to 12% of people older than 75 with atrial fibrillation are taking warfarin for stroke prevention. In one study, only 35% of patients 85 years and older with no known contraindication to anticoagulation received warfarin.4 Possible reasons for this low rate include:
- cost of monitoring warfarin
- concerns about compliance
- increased risk of hemorrhage
- prior studies focused on younger patients, in closely monitored settings.
These factors lead us to speculate that many physicians believe that the risks of warfarin in elderly patients in primary care settings outweigh any potential benefit.
We think this study demonstrates that we should seriously discuss and consider warfarin therapy for most of our elderly patients with atrial fibrillation.
The key finding from the BAFTA study is that advanced age alone is not a contraindication to the use of warfarin for stroke prevention in elderly patients with atrial fibrillation
Study summary: Primary care setting, elders only
This prospective randomized open-label trial was designed to test the effectiveness and safety of warfarin vs aspirin in the elderly, in a realistic primary care setting. The study compared the frequency of stroke, intracranial hemorrhage, and other significant arterial embolism in patients taking either warfarin or aspirin.
Inclusion criteria. Patients were at least 75 years old (average 81.5 years) with an ECG within the previous 2 years showing atrial fibrillation or atrial flutter. Seventy percent of the patients had been previously diagnosed with atrial fibrillation and 30% were identified because they had an irregular pulse on exam.
Exclusion criteria included rheumatic heart disease, major nontraumatic hemorrhage in the past 5 years, intracranial hemorrhage, endoscopically proven peptic ulcer disease in the past year, esophageal varices, allergy to either study drug, terminal illness, surgery in past 3 months, blood pressure greater than 180/110 mm Hg, or if the primary physician judged that a patient should either be on warfarin or not, based on risk factors.
Patient characteristics. The patients were recruited from 260 general practices in England and Wales. At baseline, 39% to 40% of the patients were already taking warfarin, 12% to 13% had had a prior stroke, 53% to 55% had hypertension, 13% to 14% had diabetes, 19% to 20% had heart failure, and 10% to 12% had a history of myocardial infarction. Patients were followed for an average of 2.7 years.
Aspirin and warfarin regimens. Patients were assigned to either aspirin at a dose of 75 mg/day or warfarin with a target international normalized ratio (INR) of 2.5 and an acceptable range of 2 to 3. Because the study aimed to reflect a realistic primary care setting, the frequency and method of INR testing was left to the discretion of participating physicians.
Patients who had been taking aspirin or warfarin prior to the study discontinued that medicine if they were assigned to the other treatment. Sixty-seven percent of the patients assigned to warfarin continued this treatment throughout the study, and 78% of those who either stopped taking warfarin or never started it were put on either aspirin or clopidogrel. Seventy-six percent of the patients assigned to aspirin took the medicine for the entire study period, while 70% of those who stopped taking aspirin or never started it were either switched to or stayed on warfarin.
INR values. Patients on warfarin had INR values between 2.0 and 3.0 for 67% of the time, below range for 19%, of the time, and above range for 14% of the time. Twenty-two percent of practices had all components of INR monitoring done at the hospital (phlebotomy, INR analysis, and warfarin dosing), 19% of the practices completed all 3 components on site, and the remaining practices had various combinations of onsite and hospital monitoring.
The primary outcomes included disabling stroke (ischemic or hemorrhagic) or clinically significant arterial embolism. There were 24 primary events (1.8% per year) in patients assigned to warfarin compared with 48 primary events (3.8% per year) in those assigned to aspirin, with a relative risk of 0.48 (95% confidence interval [CI], 0.28–0.80 (TABLE). The number needed to treat for 1 year to prevent 1 primary event was 50, when warfarin was compared to aspirin. Warfarin was superior to aspirin in all subgroup analyses, including patients over 85 years old.
Secondary outcomes. There were no significant differences between the warfarin and aspirin groups in the secondary outcomes: hospital admission or death as a result of a non-stroke vascular event (6.1% risk per year with warfarin vs 6.3% risk per year with aspirin), all-cause mortality (8.0% vs 8.4%), and major extracranial hemorrhage (1.4% vs 1.6%). Patients assigned to warfarin, including the subgroup of patients older than 85, did not have an increased risk of a major hemorrhage when compared with those assigned to aspirin (1.9% risk per year with warfarin vs 2.0% risk per year with aspirin; relative risk=0.96; 95% CI, 0.53–1.75).1
TABLE
BAFTA study: Warfarin was as safe as aspirin and more effective in preventing stroke in the elderly
| WARFARIN (488 patients) | ASPIRIN (485 patients) | ||||
|---|---|---|---|---|---|
| PRIMARY EVENTS | Total events | Risk per year | Total events | Risk per year | WARFARIN VA ASPIRIN |
| Stroke | 21 | 1.6% | 44 | 3.4% | RR=0.46 (95% CI, 0.26–0.79) P=.003 |
| Stroke, other intracranial hemorrhage, or systemic embolism | 24 | 1.8% | 48 | 3.8% | RR=0.48 (95% CI, 0.28–0.80) P=.003 |
| RR, relative risk; CI, confidence interval. | |||||
| Source: Mant J, Hobbs FD, Fletcher K et al. Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomised controlled trial. Lancet 2007;370:493-503. | |||||
What’s new?: Age alone does not preclude warfarin
The key finding from the BAFTA study is that advanced age alone is not a contraindication to the use of warfarin for stroke prevention in elderly patients with atrial fibrillation.
This is the first randomized controlled trial of warfarin for atrial fibrillation that included only patients ages 75 and older, conducted in a primary care setting.5
Limitations of earlier studies. The most recent meta-analysis of antithrombotic therapy for stroke prevention in patients with atrial fibrillation included 29 trials with 28,044 patients. This analysis concluded that although both warfarin and aspirin are effective in reducing the risk of stroke in patients with atrial fibrillation (warfarin by 60% and aspirin by 20%), warfarin was more effective than aspirin (relative risk reduction of 39%), with very small (≤0.3% per year) absolute increases in major extracranial hemorrhage.
The average age of patients in those trials, however, was 71. The authors identified the lack of data on older patients (who are at higher risk for serious bleeding events) as a limitation of the meta-analysis. Many of these trials took place in settings with closer monitoring of INR and warfarin dosing than is customary in a primary care setting.5
Caveats: Consider the evidence on benefits and risks
Major bleeding from warfarin is a concern, especially in the elderly. A recent cohort study6 (summarized as a POEM in this journal7) reported high rates of major bleeding (13.1 per hundred person-years or 13.1%) in patients ≥80 years of age during their first year of warfarin therapy. Despite the high risk of bleeding events in this cohort study, there was considerable benefit from warfarin therapy.
None of the patients who remained on warfarin had a thrombotic stroke (personal communication with Dr Hylek by the author). The expected rate of thrombotic stroke is in the range of 5% to 6% per year in this high-risk group.
Furthermore, most of the bleeding events were gastrointestinal and did not lead to catastrophic outcomes.
Do not add warfarin to aspirin in patients >75 years
Dr Hylek also noted that 40% of the patients in their cohort study were taking both warfarin and aspirin, and, although her study did not have sufficient power to detect a difference, prior studies noted increased risk of bleeding with this combination compared to warfarin alone.8,9 For this reason we think the combination of warfarin and aspirin should be avoided in patients over 75.
Target INR <3
Our caveat is the same as the POEM author’s conclusion:7 Patients over 80 should be carefully monitored to keep the INR below 3.0 or for signs of bleeding, especially in the first 90 days of therapy when bleeding is more likely to occur.
A final point that the BAFTA authors make, which is worth repeating here, is that the prior studies showing an increased risk of bleeding complications had INR target rates of 4 to 5, whereas the target in this study was 2 to 3. Two previous studies that also compared aspirin to warfarin with an INR goal of 2 to 3 similarly showed no difference in major bleeding between the 2 groups.10,11
Challenges to Implementation: Meticulous monitoring, patient education
- Managing warfarin therapy requires meticulous care to avoid complications and optimize treatment effect.
- Patients may be reluctant to take warfarin because they may fear bleeding.
- Patients who do agree to take warfarin need education about possible medication interactions, the need for regular INR monitoring, dosage changes, and dietary issues (eg, maintaining a consistent intake of foods containing vitamin K).
Contraindications
Contraindications to the use of warfarin include hypersensitivity to warfarin, severe hepatic disease, alcoholism, recent trauma or surgery, history of falling or significant risk of falls, and active gastrointestinal, respiratory, or genitourinary bleeding.
INR testing systems
Several randomized trials support the use of monitoring systems such as a pharmacist managed anticoagulation service or decision support software, both of which can improve the percentage of patients with therapeutic INR values.12,13
Using point-of-care INR tests in the office provides immediate results which allow for more timely adjustments of warfarin dose.14
PURLs methodology
This study was selected and evaluated using the Family Physician Inquiries Network’s Priority Updates from the Research Literature Surveillance System (PURLs) methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed here.
Warfarin is as safe as aspirin and more effective for stroke prevention in elders with atrial fibrillation
Strength of recommendation (SOR)
A: Well-designed randomized controlled trial of elderly patients in the primary care setting, consistent with findings from prior RCTs
Mant et al. Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study [BAFTA]): a randomised controlled trial. Lancet 2007;370:493–503.1
Illustrative Case
An 85-year-old woman with hypertension and chronic atrial fibrillation has transferred her care to you. She takes an aspirin a day for cardiovascular prevention. You know that warfarin is better than aspirin for preventing stroke but worry about the increased risk of bleeding with warfarin.
Should you recommend that she stay on aspirin or switch to warfarin?
Background: BAFTA: A realistic study
We have been reluctant to use warfarin in elders with atrial fibrillation for good reason: risk of hemorrhage. Since there are few trials looking at use of warfarin among elders in primary care settings, we are uncertain about the balance of benefits and harms.
The BAFTA study1 is the first trial to compare outcomes of warfarin vs aspirin in elders specifically, in the less-than-ideal conditions of real life.
Guidelines mirror uncertainties
This uncertainty is reflected even in guidelines for anticoagulation in elderly patients with atrial fibrillation.
- The 2004 American College of Chest Physicians Seventh Conference on Antithrombotic and Thrombolytic Therapy recommends treating all patients with atrial fibrillation and high risk of stroke with warfarin. Their definition of high-risk includes any patient with 1 or more of the following risk factors: age >75 years, prior ischemic stroke, transient ischemic attack or systemic embolism, congestive heart failure, impaired left ventricular systolic function, hypertension, or diabetes mellitus.2
- In contrast, the 2006 guidelines for the management of patients with atrial fibrillation from the American College of Cardiology, American Heart Association, and European Society of Cardiology, are more conservative. They recommend that patients with more than 1 risk factor take warfarin, and patients with only 1 risk factor (for example, a patient older than 75 years of age with no other risk factors) take either warfarin or aspirin.3
Clinical context: Reasonable concerns
Fewer than half of the 10% to 12% of people older than 75 with atrial fibrillation are taking warfarin for stroke prevention. In one study, only 35% of patients 85 years and older with no known contraindication to anticoagulation received warfarin.4 Possible reasons for this low rate include:
- cost of monitoring warfarin
- concerns about compliance
- increased risk of hemorrhage
- prior studies focused on younger patients, in closely monitored settings.
These factors lead us to speculate that many physicians believe that the risks of warfarin in elderly patients in primary care settings outweigh any potential benefit.
We think this study demonstrates that we should seriously discuss and consider warfarin therapy for most of our elderly patients with atrial fibrillation.
The key finding from the BAFTA study is that advanced age alone is not a contraindication to the use of warfarin for stroke prevention in elderly patients with atrial fibrillation
Study summary: Primary care setting, elders only
This prospective randomized open-label trial was designed to test the effectiveness and safety of warfarin vs aspirin in the elderly, in a realistic primary care setting. The study compared the frequency of stroke, intracranial hemorrhage, and other significant arterial embolism in patients taking either warfarin or aspirin.
Inclusion criteria. Patients were at least 75 years old (average 81.5 years) with an ECG within the previous 2 years showing atrial fibrillation or atrial flutter. Seventy percent of the patients had been previously diagnosed with atrial fibrillation and 30% were identified because they had an irregular pulse on exam.
Exclusion criteria included rheumatic heart disease, major nontraumatic hemorrhage in the past 5 years, intracranial hemorrhage, endoscopically proven peptic ulcer disease in the past year, esophageal varices, allergy to either study drug, terminal illness, surgery in past 3 months, blood pressure greater than 180/110 mm Hg, or if the primary physician judged that a patient should either be on warfarin or not, based on risk factors.
Patient characteristics. The patients were recruited from 260 general practices in England and Wales. At baseline, 39% to 40% of the patients were already taking warfarin, 12% to 13% had had a prior stroke, 53% to 55% had hypertension, 13% to 14% had diabetes, 19% to 20% had heart failure, and 10% to 12% had a history of myocardial infarction. Patients were followed for an average of 2.7 years.
Aspirin and warfarin regimens. Patients were assigned to either aspirin at a dose of 75 mg/day or warfarin with a target international normalized ratio (INR) of 2.5 and an acceptable range of 2 to 3. Because the study aimed to reflect a realistic primary care setting, the frequency and method of INR testing was left to the discretion of participating physicians.
Patients who had been taking aspirin or warfarin prior to the study discontinued that medicine if they were assigned to the other treatment. Sixty-seven percent of the patients assigned to warfarin continued this treatment throughout the study, and 78% of those who either stopped taking warfarin or never started it were put on either aspirin or clopidogrel. Seventy-six percent of the patients assigned to aspirin took the medicine for the entire study period, while 70% of those who stopped taking aspirin or never started it were either switched to or stayed on warfarin.
INR values. Patients on warfarin had INR values between 2.0 and 3.0 for 67% of the time, below range for 19%, of the time, and above range for 14% of the time. Twenty-two percent of practices had all components of INR monitoring done at the hospital (phlebotomy, INR analysis, and warfarin dosing), 19% of the practices completed all 3 components on site, and the remaining practices had various combinations of onsite and hospital monitoring.
The primary outcomes included disabling stroke (ischemic or hemorrhagic) or clinically significant arterial embolism. There were 24 primary events (1.8% per year) in patients assigned to warfarin compared with 48 primary events (3.8% per year) in those assigned to aspirin, with a relative risk of 0.48 (95% confidence interval [CI], 0.28–0.80 (TABLE). The number needed to treat for 1 year to prevent 1 primary event was 50, when warfarin was compared to aspirin. Warfarin was superior to aspirin in all subgroup analyses, including patients over 85 years old.
Secondary outcomes. There were no significant differences between the warfarin and aspirin groups in the secondary outcomes: hospital admission or death as a result of a non-stroke vascular event (6.1% risk per year with warfarin vs 6.3% risk per year with aspirin), all-cause mortality (8.0% vs 8.4%), and major extracranial hemorrhage (1.4% vs 1.6%). Patients assigned to warfarin, including the subgroup of patients older than 85, did not have an increased risk of a major hemorrhage when compared with those assigned to aspirin (1.9% risk per year with warfarin vs 2.0% risk per year with aspirin; relative risk=0.96; 95% CI, 0.53–1.75).1
TABLE
BAFTA study: Warfarin was as safe as aspirin and more effective in preventing stroke in the elderly
| WARFARIN (488 patients) | ASPIRIN (485 patients) | ||||
|---|---|---|---|---|---|
| PRIMARY EVENTS | Total events | Risk per year | Total events | Risk per year | WARFARIN VA ASPIRIN |
| Stroke | 21 | 1.6% | 44 | 3.4% | RR=0.46 (95% CI, 0.26–0.79) P=.003 |
| Stroke, other intracranial hemorrhage, or systemic embolism | 24 | 1.8% | 48 | 3.8% | RR=0.48 (95% CI, 0.28–0.80) P=.003 |
| RR, relative risk; CI, confidence interval. | |||||
| Source: Mant J, Hobbs FD, Fletcher K et al. Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomised controlled trial. Lancet 2007;370:493-503. | |||||
What’s new?: Age alone does not preclude warfarin
The key finding from the BAFTA study is that advanced age alone is not a contraindication to the use of warfarin for stroke prevention in elderly patients with atrial fibrillation.
This is the first randomized controlled trial of warfarin for atrial fibrillation that included only patients ages 75 and older, conducted in a primary care setting.5
Limitations of earlier studies. The most recent meta-analysis of antithrombotic therapy for stroke prevention in patients with atrial fibrillation included 29 trials with 28,044 patients. This analysis concluded that although both warfarin and aspirin are effective in reducing the risk of stroke in patients with atrial fibrillation (warfarin by 60% and aspirin by 20%), warfarin was more effective than aspirin (relative risk reduction of 39%), with very small (≤0.3% per year) absolute increases in major extracranial hemorrhage.
The average age of patients in those trials, however, was 71. The authors identified the lack of data on older patients (who are at higher risk for serious bleeding events) as a limitation of the meta-analysis. Many of these trials took place in settings with closer monitoring of INR and warfarin dosing than is customary in a primary care setting.5
Caveats: Consider the evidence on benefits and risks
Major bleeding from warfarin is a concern, especially in the elderly. A recent cohort study6 (summarized as a POEM in this journal7) reported high rates of major bleeding (13.1 per hundred person-years or 13.1%) in patients ≥80 years of age during their first year of warfarin therapy. Despite the high risk of bleeding events in this cohort study, there was considerable benefit from warfarin therapy.
None of the patients who remained on warfarin had a thrombotic stroke (personal communication with Dr Hylek by the author). The expected rate of thrombotic stroke is in the range of 5% to 6% per year in this high-risk group.
Furthermore, most of the bleeding events were gastrointestinal and did not lead to catastrophic outcomes.
Do not add warfarin to aspirin in patients >75 years
Dr Hylek also noted that 40% of the patients in their cohort study were taking both warfarin and aspirin, and, although her study did not have sufficient power to detect a difference, prior studies noted increased risk of bleeding with this combination compared to warfarin alone.8,9 For this reason we think the combination of warfarin and aspirin should be avoided in patients over 75.
Target INR <3
Our caveat is the same as the POEM author’s conclusion:7 Patients over 80 should be carefully monitored to keep the INR below 3.0 or for signs of bleeding, especially in the first 90 days of therapy when bleeding is more likely to occur.
A final point that the BAFTA authors make, which is worth repeating here, is that the prior studies showing an increased risk of bleeding complications had INR target rates of 4 to 5, whereas the target in this study was 2 to 3. Two previous studies that also compared aspirin to warfarin with an INR goal of 2 to 3 similarly showed no difference in major bleeding between the 2 groups.10,11
Challenges to Implementation: Meticulous monitoring, patient education
- Managing warfarin therapy requires meticulous care to avoid complications and optimize treatment effect.
- Patients may be reluctant to take warfarin because they may fear bleeding.
- Patients who do agree to take warfarin need education about possible medication interactions, the need for regular INR monitoring, dosage changes, and dietary issues (eg, maintaining a consistent intake of foods containing vitamin K).
Contraindications
Contraindications to the use of warfarin include hypersensitivity to warfarin, severe hepatic disease, alcoholism, recent trauma or surgery, history of falling or significant risk of falls, and active gastrointestinal, respiratory, or genitourinary bleeding.
INR testing systems
Several randomized trials support the use of monitoring systems such as a pharmacist managed anticoagulation service or decision support software, both of which can improve the percentage of patients with therapeutic INR values.12,13
Using point-of-care INR tests in the office provides immediate results which allow for more timely adjustments of warfarin dose.14
PURLs methodology
This study was selected and evaluated using the Family Physician Inquiries Network’s Priority Updates from the Research Literature Surveillance System (PURLs) methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed here.
1. Mant J, Hobbs FD, Fletcher K, et al. Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomised controlled trial. Lancet 2007;370:493-503.
2. Singer DE, Albers GW, Dalen JE, et al. Antithrombotic therapy in atrial fibrillation: The seventh ACCP (American College of Chest Physicians) conference on antithrombotic and thrombolytic therapy. Chest 2004;126:429S-456S.
3. Fuster V, Rydén LE, Cannom DS, et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation—executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation). J Am Coll Cardiol 2006;48:854-906.
4. Go AS, Hylek EM, Borowsky LH, et al. Warfarin use among ambulatory patients with non-valvular atrial fibrillation: The Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) study. Ann Intern Med 1999;131:927.-
5. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: Antithrombotic therapy to prevent stroke in patients who have non-valvular atrial fibrillation. Ann Intern Med 2007;146:857-867.
6. Hylek EM, Evans-Molina C, Shea C, et al. Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation. Circulation 2007;115:2689-2696.
7. POEM: Bleeding risk with warfarin is high among the elderly. J Fam Pract 2007;6:709.-
8. Garcia D, Hylek E. Stroke prevention in elderly patients with atrial fibrillation. Lancet 2007;370:460-461.
9. Perez-Gomez F, Alegria E, Bejon J, et al. Comparative effects of antiplatelet, anticoagulant, or combined therapy in patients with valvular and non-valvular atrial fibrillation: a randomized multicenter study. J Am Coll Cardiol 2004;44:1557-1556.
10. Rash A, Downes T, Portner R, et al. A randomized controlled trial of warfarin versus aspirin for stroke preventions in octogenarians with atrial fibrillation (WASPO). Age Ageing 2007;36:151-156.
11. Gullov AL, Koeford BG, Petersen P, et al. Fixed minidose warfarin and aspirin alone and in combination vs adjusted-dose warfarin for stroke prevention in atrial fibrillation. Arch Intern Med 1998;158:1513-1521.
12. Witt DM, Sadler MA, Shanahan RL, et al. Effect of a centralized clinical pharmacy anticoagulation service on outcomes of anticoagulation therapy. Chest 2005;127:1515-1522.
13. Wurster M, Doran T. Anticoagulation management: a new approach. Disease Management 2006;9:201-209.
14. Dorfman DM, Goonan EM, Boutilier MK, et al. Point-of-care (POC) versus central laboratory instrumentation for monitoring oral anticoagulation. Vasc Med 2005;10:23-27.
1. Mant J, Hobbs FD, Fletcher K, et al. Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomised controlled trial. Lancet 2007;370:493-503.
2. Singer DE, Albers GW, Dalen JE, et al. Antithrombotic therapy in atrial fibrillation: The seventh ACCP (American College of Chest Physicians) conference on antithrombotic and thrombolytic therapy. Chest 2004;126:429S-456S.
3. Fuster V, Rydén LE, Cannom DS, et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation—executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation). J Am Coll Cardiol 2006;48:854-906.
4. Go AS, Hylek EM, Borowsky LH, et al. Warfarin use among ambulatory patients with non-valvular atrial fibrillation: The Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) study. Ann Intern Med 1999;131:927.-
5. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: Antithrombotic therapy to prevent stroke in patients who have non-valvular atrial fibrillation. Ann Intern Med 2007;146:857-867.
6. Hylek EM, Evans-Molina C, Shea C, et al. Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation. Circulation 2007;115:2689-2696.
7. POEM: Bleeding risk with warfarin is high among the elderly. J Fam Pract 2007;6:709.-
8. Garcia D, Hylek E. Stroke prevention in elderly patients with atrial fibrillation. Lancet 2007;370:460-461.
9. Perez-Gomez F, Alegria E, Bejon J, et al. Comparative effects of antiplatelet, anticoagulant, or combined therapy in patients with valvular and non-valvular atrial fibrillation: a randomized multicenter study. J Am Coll Cardiol 2004;44:1557-1556.
10. Rash A, Downes T, Portner R, et al. A randomized controlled trial of warfarin versus aspirin for stroke preventions in octogenarians with atrial fibrillation (WASPO). Age Ageing 2007;36:151-156.
11. Gullov AL, Koeford BG, Petersen P, et al. Fixed minidose warfarin and aspirin alone and in combination vs adjusted-dose warfarin for stroke prevention in atrial fibrillation. Arch Intern Med 1998;158:1513-1521.
12. Witt DM, Sadler MA, Shanahan RL, et al. Effect of a centralized clinical pharmacy anticoagulation service on outcomes of anticoagulation therapy. Chest 2005;127:1515-1522.
13. Wurster M, Doran T. Anticoagulation management: a new approach. Disease Management 2006;9:201-209.
14. Dorfman DM, Goonan EM, Boutilier MK, et al. Point-of-care (POC) versus central laboratory instrumentation for monitoring oral anticoagulation. Vasc Med 2005;10:23-27.
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