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Sertraline effective for children and adolescents with major depression
Sertraline (Zoloft) is effective and generally well tolerated for the short-term treatment of major depressive disorder in both children and adolescents.
Although the studies were not powered to detect a difference in efficacy and safety between age groups, decreased efficacy and increased side effects were seen in children ages 6 to 11 years. Because treatment with sertraline was only studied for 10 weeks, the efficacy and safety of long-term treatment remain unknown.
Sertraline (Zoloft) is effective and generally well tolerated for the short-term treatment of major depressive disorder in both children and adolescents.
Although the studies were not powered to detect a difference in efficacy and safety between age groups, decreased efficacy and increased side effects were seen in children ages 6 to 11 years. Because treatment with sertraline was only studied for 10 weeks, the efficacy and safety of long-term treatment remain unknown.
Sertraline (Zoloft) is effective and generally well tolerated for the short-term treatment of major depressive disorder in both children and adolescents.
Although the studies were not powered to detect a difference in efficacy and safety between age groups, decreased efficacy and increased side effects were seen in children ages 6 to 11 years. Because treatment with sertraline was only studied for 10 weeks, the efficacy and safety of long-term treatment remain unknown.
Estrogen plus progestin may increase incidence of dementia
Estrogen plus progestin does not decrease— and may actually increase—the incidence of dementia, mild cognitive impairment, and cognitive dysfunction in elderly postmenopausal women. The effect of unopposed estrogen on these outcomes is still unknown. With these new findings and the recently reported results of the Women’s Health Initiative, for most women the benefits of estrogen plus progestin do not outweigh the risks.
Estrogen plus progestin does not decrease— and may actually increase—the incidence of dementia, mild cognitive impairment, and cognitive dysfunction in elderly postmenopausal women. The effect of unopposed estrogen on these outcomes is still unknown. With these new findings and the recently reported results of the Women’s Health Initiative, for most women the benefits of estrogen plus progestin do not outweigh the risks.
Estrogen plus progestin does not decrease— and may actually increase—the incidence of dementia, mild cognitive impairment, and cognitive dysfunction in elderly postmenopausal women. The effect of unopposed estrogen on these outcomes is still unknown. With these new findings and the recently reported results of the Women’s Health Initiative, for most women the benefits of estrogen plus progestin do not outweigh the risks.
How beneficial are thiazolidinediones for diabetes mellitus?
The thiazolidinediones pioglitazone (Actos) and rosiglitazone (Avandia) are effective at lowering fasting plasma glucose (FPG) and glycosylated hemoglobin (Hb A1c) in patients with type 2 diabetes when used either as monotherapy or in combination with sulfonylureas, metformin, or insulin. The glucose-lowering effects appear comparable with those of sulfonylureas and metformin alone. Currently, there are no randomized trials directly comparing patient-oriented outcomes of the thiazolidinediones with those of sulfonylureas and metformin. Grade of recommendation: B (on the basis of extrapolations from randomized trials and low quality randomized trials).
Evidence summary
Proper nutrition and exercise remain the cornerstones of diabetes therapy; medication management, however, is often necessary.1 Both pioglitazone and rosiglitazone have similar glucose-lowering effects. See the tables in the online version of this Clinical Inquiry at www.fpin.org for a summary of monotherapy and combination clinical trials.
Pioglitazone has consistently been shown to decrease triglycerides and increase high-density lipoprotein and rosiglitazone increases total cholesterol, HDL, and low-density lipoprotein. The clinical significance of these effects has not been established. Both medications are generally well tolerated but have the potential to cause edema and mildly decrease hemoglobin and hematocrit.2-9
To date, there have been reports of pulmonary edema and hepatotoxicity associated with the use of rosiglitazone. In all cases, rosiglitazone was found to be a possible, not a definite, cause.10-12
Recommendations from others
The American Diabetes Association and the American Association of Clinical Endocrinologists do not recommend one class of antidiabetic medication over another.1,13 Both of the thiazolidinediones are indicated for monotherapy and in combination with a sulfonylurea and metformin. However, only pioglitazone is indicated in combination with insulin. They are highly metabolized by the liver and should not be used in patients with liver enzymes greater than 2.5 times the upper limit of normal. Routine liver monitoring is recommended at baseline, every 2 months for the first year, and then periodically thereafter.1 Patients with New York Heart Association class III or IV heart failure should not use thiazolidinediones. In addition, thiazolidinediones cost considerably more than sulfonylureas and metformin.14 Therefore, thiazolidinediones are not generally considered for first-line therapy.15 These agents may be most beneficial in patients with insulin resistance and patients with renal dysfunction.1
TABLE
Effects of rosiglitazone and pioglitazone, by dosage
| Drug and dosage | Control | Adjunct medication | Change in Hb A1c vs comparison (%) | Change in FPG vs comparison (mg/dL) |
|---|---|---|---|---|
| Rosiglitazone | ||||
| 4 mg bid2 | placebo | none | -1.5* | -73* |
| 2 mg bid3 | glyburide | none | +0.4 | +5 |
| 4 mg bid | +0.2† | -11 | ||
| 8 mg bid4 | placebo | metformin | -1.3* | -54.3* |
| 2 mg bid5 | placebo | sulfonylurea | -1.1* | -43.6* |
| 4 mg bid6 | placebo | insulin | -1.3‡ | -55.8‡ |
| Pioglitazone | ||||
| 45 mg qd7 | placebo | none | -1.6* | -65.3* |
| 30 mg qd8 | placebo | sulfonylurea | -1.3* | -57.9* |
| 30 mg qd9 | placebo | metformin | -0.83* | -37.7* |
| Hb A1cdenotes glycosylated hemoglobin; FPG, fasting plasma glucose; bid, twice a day; qd, every day. | ||||
| *P < .05 versus control. | ||||
| †P= not significant. | ||||
| ‡P= < .006 versus placebo plus insulin. | ||||
| Find further details online at www.fpin.org. | ||||
Read a clinical commentary by Steven Zweig, MD, at www.fpin.org
1. The American Association of Clinical Endocrinologists. Endocrin Pract 2000;
2. Lebovitz HE, Dole JF, Patwardhan R, et al. J Clin Endocrinol Metab 2001;86:280-8.
3. Charbonnel B, Lonnqvist F, Jones N, et al. Diabetes 1999;48 (suppl 1):A114.-
4. Fonseca V, Rosenstock J, Patwardhan R, et al. JAMA 2000;283:1695-702.
5. Wolffenbuttel BH, Gomist R, Squatrito S, et al. Diabet Med 2000;17:40-7.
6. Raskin P, Rendell M, Riddle MC, et al. Diabetes Care 2001;24:1226-32.
7. Aronoff S, Rosenblatt S, Braithwaite S, et al. Diabetes Care 2000;23:1605-11.
8. Kipnes MS, Krosnick A, Rendell MS, et al. Am J Med 2001;111:10-7.
9. Einhorn D, Rendell M, Rosenzweig J, et al. Clin Ther 2000;22:1395-409.
10. Thomas ML, Lloyd SJ. Ann Pharmacother 2001;35:123-4.
11. Al-Salman J, Arjomand H, Kemp DG, et al. Ann Intern Med 2000;132:121-4.
12. Forman LM, Simmons DA, Diamond RH. Ann Intern Med 2000;132:118-20.
13. The American Diabetes Association. Diabetes 2001;(suppl 1):S1-S133.
14. Holmboe ES. Clinical applications. JAMA 2002;287:373-6.
15. Inzucchi SE. Scientific review. JAMA 2002;287:360-72.
The thiazolidinediones pioglitazone (Actos) and rosiglitazone (Avandia) are effective at lowering fasting plasma glucose (FPG) and glycosylated hemoglobin (Hb A1c) in patients with type 2 diabetes when used either as monotherapy or in combination with sulfonylureas, metformin, or insulin. The glucose-lowering effects appear comparable with those of sulfonylureas and metformin alone. Currently, there are no randomized trials directly comparing patient-oriented outcomes of the thiazolidinediones with those of sulfonylureas and metformin. Grade of recommendation: B (on the basis of extrapolations from randomized trials and low quality randomized trials).
Evidence summary
Proper nutrition and exercise remain the cornerstones of diabetes therapy; medication management, however, is often necessary.1 Both pioglitazone and rosiglitazone have similar glucose-lowering effects. See the tables in the online version of this Clinical Inquiry at www.fpin.org for a summary of monotherapy and combination clinical trials.
Pioglitazone has consistently been shown to decrease triglycerides and increase high-density lipoprotein and rosiglitazone increases total cholesterol, HDL, and low-density lipoprotein. The clinical significance of these effects has not been established. Both medications are generally well tolerated but have the potential to cause edema and mildly decrease hemoglobin and hematocrit.2-9
To date, there have been reports of pulmonary edema and hepatotoxicity associated with the use of rosiglitazone. In all cases, rosiglitazone was found to be a possible, not a definite, cause.10-12
Recommendations from others
The American Diabetes Association and the American Association of Clinical Endocrinologists do not recommend one class of antidiabetic medication over another.1,13 Both of the thiazolidinediones are indicated for monotherapy and in combination with a sulfonylurea and metformin. However, only pioglitazone is indicated in combination with insulin. They are highly metabolized by the liver and should not be used in patients with liver enzymes greater than 2.5 times the upper limit of normal. Routine liver monitoring is recommended at baseline, every 2 months for the first year, and then periodically thereafter.1 Patients with New York Heart Association class III or IV heart failure should not use thiazolidinediones. In addition, thiazolidinediones cost considerably more than sulfonylureas and metformin.14 Therefore, thiazolidinediones are not generally considered for first-line therapy.15 These agents may be most beneficial in patients with insulin resistance and patients with renal dysfunction.1
TABLE
Effects of rosiglitazone and pioglitazone, by dosage
| Drug and dosage | Control | Adjunct medication | Change in Hb A1c vs comparison (%) | Change in FPG vs comparison (mg/dL) |
|---|---|---|---|---|
| Rosiglitazone | ||||
| 4 mg bid2 | placebo | none | -1.5* | -73* |
| 2 mg bid3 | glyburide | none | +0.4 | +5 |
| 4 mg bid | +0.2† | -11 | ||
| 8 mg bid4 | placebo | metformin | -1.3* | -54.3* |
| 2 mg bid5 | placebo | sulfonylurea | -1.1* | -43.6* |
| 4 mg bid6 | placebo | insulin | -1.3‡ | -55.8‡ |
| Pioglitazone | ||||
| 45 mg qd7 | placebo | none | -1.6* | -65.3* |
| 30 mg qd8 | placebo | sulfonylurea | -1.3* | -57.9* |
| 30 mg qd9 | placebo | metformin | -0.83* | -37.7* |
| Hb A1cdenotes glycosylated hemoglobin; FPG, fasting plasma glucose; bid, twice a day; qd, every day. | ||||
| *P < .05 versus control. | ||||
| †P= not significant. | ||||
| ‡P= < .006 versus placebo plus insulin. | ||||
| Find further details online at www.fpin.org. | ||||
Read a clinical commentary by Steven Zweig, MD, at www.fpin.org
The thiazolidinediones pioglitazone (Actos) and rosiglitazone (Avandia) are effective at lowering fasting plasma glucose (FPG) and glycosylated hemoglobin (Hb A1c) in patients with type 2 diabetes when used either as monotherapy or in combination with sulfonylureas, metformin, or insulin. The glucose-lowering effects appear comparable with those of sulfonylureas and metformin alone. Currently, there are no randomized trials directly comparing patient-oriented outcomes of the thiazolidinediones with those of sulfonylureas and metformin. Grade of recommendation: B (on the basis of extrapolations from randomized trials and low quality randomized trials).
Evidence summary
Proper nutrition and exercise remain the cornerstones of diabetes therapy; medication management, however, is often necessary.1 Both pioglitazone and rosiglitazone have similar glucose-lowering effects. See the tables in the online version of this Clinical Inquiry at www.fpin.org for a summary of monotherapy and combination clinical trials.
Pioglitazone has consistently been shown to decrease triglycerides and increase high-density lipoprotein and rosiglitazone increases total cholesterol, HDL, and low-density lipoprotein. The clinical significance of these effects has not been established. Both medications are generally well tolerated but have the potential to cause edema and mildly decrease hemoglobin and hematocrit.2-9
To date, there have been reports of pulmonary edema and hepatotoxicity associated with the use of rosiglitazone. In all cases, rosiglitazone was found to be a possible, not a definite, cause.10-12
Recommendations from others
The American Diabetes Association and the American Association of Clinical Endocrinologists do not recommend one class of antidiabetic medication over another.1,13 Both of the thiazolidinediones are indicated for monotherapy and in combination with a sulfonylurea and metformin. However, only pioglitazone is indicated in combination with insulin. They are highly metabolized by the liver and should not be used in patients with liver enzymes greater than 2.5 times the upper limit of normal. Routine liver monitoring is recommended at baseline, every 2 months for the first year, and then periodically thereafter.1 Patients with New York Heart Association class III or IV heart failure should not use thiazolidinediones. In addition, thiazolidinediones cost considerably more than sulfonylureas and metformin.14 Therefore, thiazolidinediones are not generally considered for first-line therapy.15 These agents may be most beneficial in patients with insulin resistance and patients with renal dysfunction.1
TABLE
Effects of rosiglitazone and pioglitazone, by dosage
| Drug and dosage | Control | Adjunct medication | Change in Hb A1c vs comparison (%) | Change in FPG vs comparison (mg/dL) |
|---|---|---|---|---|
| Rosiglitazone | ||||
| 4 mg bid2 | placebo | none | -1.5* | -73* |
| 2 mg bid3 | glyburide | none | +0.4 | +5 |
| 4 mg bid | +0.2† | -11 | ||
| 8 mg bid4 | placebo | metformin | -1.3* | -54.3* |
| 2 mg bid5 | placebo | sulfonylurea | -1.1* | -43.6* |
| 4 mg bid6 | placebo | insulin | -1.3‡ | -55.8‡ |
| Pioglitazone | ||||
| 45 mg qd7 | placebo | none | -1.6* | -65.3* |
| 30 mg qd8 | placebo | sulfonylurea | -1.3* | -57.9* |
| 30 mg qd9 | placebo | metformin | -0.83* | -37.7* |
| Hb A1cdenotes glycosylated hemoglobin; FPG, fasting plasma glucose; bid, twice a day; qd, every day. | ||||
| *P < .05 versus control. | ||||
| †P= not significant. | ||||
| ‡P= < .006 versus placebo plus insulin. | ||||
| Find further details online at www.fpin.org. | ||||
Read a clinical commentary by Steven Zweig, MD, at www.fpin.org
1. The American Association of Clinical Endocrinologists. Endocrin Pract 2000;
2. Lebovitz HE, Dole JF, Patwardhan R, et al. J Clin Endocrinol Metab 2001;86:280-8.
3. Charbonnel B, Lonnqvist F, Jones N, et al. Diabetes 1999;48 (suppl 1):A114.-
4. Fonseca V, Rosenstock J, Patwardhan R, et al. JAMA 2000;283:1695-702.
5. Wolffenbuttel BH, Gomist R, Squatrito S, et al. Diabet Med 2000;17:40-7.
6. Raskin P, Rendell M, Riddle MC, et al. Diabetes Care 2001;24:1226-32.
7. Aronoff S, Rosenblatt S, Braithwaite S, et al. Diabetes Care 2000;23:1605-11.
8. Kipnes MS, Krosnick A, Rendell MS, et al. Am J Med 2001;111:10-7.
9. Einhorn D, Rendell M, Rosenzweig J, et al. Clin Ther 2000;22:1395-409.
10. Thomas ML, Lloyd SJ. Ann Pharmacother 2001;35:123-4.
11. Al-Salman J, Arjomand H, Kemp DG, et al. Ann Intern Med 2000;132:121-4.
12. Forman LM, Simmons DA, Diamond RH. Ann Intern Med 2000;132:118-20.
13. The American Diabetes Association. Diabetes 2001;(suppl 1):S1-S133.
14. Holmboe ES. Clinical applications. JAMA 2002;287:373-6.
15. Inzucchi SE. Scientific review. JAMA 2002;287:360-72.
1. The American Association of Clinical Endocrinologists. Endocrin Pract 2000;
2. Lebovitz HE, Dole JF, Patwardhan R, et al. J Clin Endocrinol Metab 2001;86:280-8.
3. Charbonnel B, Lonnqvist F, Jones N, et al. Diabetes 1999;48 (suppl 1):A114.-
4. Fonseca V, Rosenstock J, Patwardhan R, et al. JAMA 2000;283:1695-702.
5. Wolffenbuttel BH, Gomist R, Squatrito S, et al. Diabet Med 2000;17:40-7.
6. Raskin P, Rendell M, Riddle MC, et al. Diabetes Care 2001;24:1226-32.
7. Aronoff S, Rosenblatt S, Braithwaite S, et al. Diabetes Care 2000;23:1605-11.
8. Kipnes MS, Krosnick A, Rendell MS, et al. Am J Med 2001;111:10-7.
9. Einhorn D, Rendell M, Rosenzweig J, et al. Clin Ther 2000;22:1395-409.
10. Thomas ML, Lloyd SJ. Ann Pharmacother 2001;35:123-4.
11. Al-Salman J, Arjomand H, Kemp DG, et al. Ann Intern Med 2000;132:121-4.
12. Forman LM, Simmons DA, Diamond RH. Ann Intern Med 2000;132:118-20.
13. The American Diabetes Association. Diabetes 2001;(suppl 1):S1-S133.
14. Holmboe ES. Clinical applications. JAMA 2002;287:373-6.
15. Inzucchi SE. Scientific review. JAMA 2002;287:360-72.
Evidence-based answers from the Family Physicians Inquiries Network
Can a simple warfarin initiation scheme predict the maintenance dose in patients with nonrheumatic atrial fibrillation?
ABSTRACT
BACKGROUND: Initiating warfarin in patients with atrial fibrillation at a typical loading dose of 10 mg daily for 2 days may be associated with excess anticoagulation, especially in older patients. In addition, daily monitoring associated with this regimen may be inconvenient for outpatients. Initiating warfarin at 5 mg daily may produce more consistent anticoagulation and eliminate the need for daily monitoring. The investigators tested whether administering 5 mg warfarin daily for 4 days and checking the anticoagulation status via the international normalized ratio (INR) on the fifth day could predict an early warfarin maintenance dose.
POPULATION STUDIED: This study included 61 outpatients with nonrheumatic atrial fibrillation, not receiving heparin, between the ages of 42 to 88 years (mean age = 71 years). Patients were excluded from the study if they were being treated with a drug known to interact with warfarin or had a coagulation disorder, contraindication to warfarin therapy, previous course of anticoagulation treatment, or baseline INR > 1.2, or if they refused to participate.
STUDY DESIGN AND VALIDITY: This was a prospective cohort study in which patients were given 5 mg warfarin daily for 4 days (day 1 to day 4). The INR was measured on day 5 and the patient’s physician freely chose a new dose. The INR was checked at least once a week for the next 2 weeks. Patients were followed for 3 months. The warfarin dose was considered stable when the INR was between 2 and 3 on 3 consecutive occasions at least 1 week apart. The stable weekly warfarin dose was plotted against the INR obtained on the fifth day of initiation to establish a scheme for predicting an early warfarin maintenance dose. To test the validity of this scheme, 23 additional patients with nonrheumatic atrial fibrillation were given the predicted warfarin maintenance dose based on their INR on day 5 and were followed for 3 months. Although the characteristics of this additional group of patients were not stated, these subjects were enrolled according to the same criteria.
OUTCOMES MEASURED: The outcome of this study was to determine whether the INR on day 5 of warfarin treatment could predict an early warfarin maintenance dose. Major and minor bleeding episodes and thromboembolic complications were also measured.
RESULTS: Of 91 patients eligible to participate in the study, 61 were included in the analysis. Thirty patients could not be evaluated either because they failed to reach a therapeutic INR within 3 months or because they did not complete the follow-up period. The relationship between the weekly maintenance dose and the INR on day 5 followed a hyperbolic curve, demonstrating a direct relationship between the INR on day 5 and the weekly warfarin dose. During the evaluation phase that was conducted in 23 additional patients, the mean difference between the predicted and actual doses of warfarin was 1.6 mg/week (95% CI, .0007-3.195 mg) with a maximum difference of 9 mg/week. One minor bleeding episode was reported among the 61 initial patients and 23 additional patients. The dosing regimen, based on the INR after 4 days of 5 mg warfarin, is shown in the Table.
TABLE
WARFARIN DOSING REGIMEN USED IN STUDY
| INR on Day 5 | Approximate Daily Warfarin Dose (mg)* |
| 1.3 | 6 |
| 1.4 | 5 to 6 |
| 1.5 | 5 |
| 1.6 | 4 to 5 |
| 1.7 | 4 to 4.5 |
| 1.8 | 4 |
| 1.9 | 3.5 to 4 |
| 2.0 | 3.5 |
| *Doses are rounded and calculated from a cumulative weekly dose. | |
Starting outpatients with 5 mg per day of warfarin and basing a maintenance dose on the INR obtained on the fifth day is an effective way to initiate therapy. The difference between the actual and predicted maintenance doses was small, indicating that this simple scheme is a good model for predicting the warfarin maintenance dose. Although only 23 patients were tested using this warfarin dosage scheme, clinicians may consult it when choosing a warfarin maintenance dose rather than using the trial-and-error method that is often pursued in daily practice.
ABSTRACT
BACKGROUND: Initiating warfarin in patients with atrial fibrillation at a typical loading dose of 10 mg daily for 2 days may be associated with excess anticoagulation, especially in older patients. In addition, daily monitoring associated with this regimen may be inconvenient for outpatients. Initiating warfarin at 5 mg daily may produce more consistent anticoagulation and eliminate the need for daily monitoring. The investigators tested whether administering 5 mg warfarin daily for 4 days and checking the anticoagulation status via the international normalized ratio (INR) on the fifth day could predict an early warfarin maintenance dose.
POPULATION STUDIED: This study included 61 outpatients with nonrheumatic atrial fibrillation, not receiving heparin, between the ages of 42 to 88 years (mean age = 71 years). Patients were excluded from the study if they were being treated with a drug known to interact with warfarin or had a coagulation disorder, contraindication to warfarin therapy, previous course of anticoagulation treatment, or baseline INR > 1.2, or if they refused to participate.
STUDY DESIGN AND VALIDITY: This was a prospective cohort study in which patients were given 5 mg warfarin daily for 4 days (day 1 to day 4). The INR was measured on day 5 and the patient’s physician freely chose a new dose. The INR was checked at least once a week for the next 2 weeks. Patients were followed for 3 months. The warfarin dose was considered stable when the INR was between 2 and 3 on 3 consecutive occasions at least 1 week apart. The stable weekly warfarin dose was plotted against the INR obtained on the fifth day of initiation to establish a scheme for predicting an early warfarin maintenance dose. To test the validity of this scheme, 23 additional patients with nonrheumatic atrial fibrillation were given the predicted warfarin maintenance dose based on their INR on day 5 and were followed for 3 months. Although the characteristics of this additional group of patients were not stated, these subjects were enrolled according to the same criteria.
OUTCOMES MEASURED: The outcome of this study was to determine whether the INR on day 5 of warfarin treatment could predict an early warfarin maintenance dose. Major and minor bleeding episodes and thromboembolic complications were also measured.
RESULTS: Of 91 patients eligible to participate in the study, 61 were included in the analysis. Thirty patients could not be evaluated either because they failed to reach a therapeutic INR within 3 months or because they did not complete the follow-up period. The relationship between the weekly maintenance dose and the INR on day 5 followed a hyperbolic curve, demonstrating a direct relationship between the INR on day 5 and the weekly warfarin dose. During the evaluation phase that was conducted in 23 additional patients, the mean difference between the predicted and actual doses of warfarin was 1.6 mg/week (95% CI, .0007-3.195 mg) with a maximum difference of 9 mg/week. One minor bleeding episode was reported among the 61 initial patients and 23 additional patients. The dosing regimen, based on the INR after 4 days of 5 mg warfarin, is shown in the Table.
TABLE
WARFARIN DOSING REGIMEN USED IN STUDY
| INR on Day 5 | Approximate Daily Warfarin Dose (mg)* |
| 1.3 | 6 |
| 1.4 | 5 to 6 |
| 1.5 | 5 |
| 1.6 | 4 to 5 |
| 1.7 | 4 to 4.5 |
| 1.8 | 4 |
| 1.9 | 3.5 to 4 |
| 2.0 | 3.5 |
| *Doses are rounded and calculated from a cumulative weekly dose. | |
Starting outpatients with 5 mg per day of warfarin and basing a maintenance dose on the INR obtained on the fifth day is an effective way to initiate therapy. The difference between the actual and predicted maintenance doses was small, indicating that this simple scheme is a good model for predicting the warfarin maintenance dose. Although only 23 patients were tested using this warfarin dosage scheme, clinicians may consult it when choosing a warfarin maintenance dose rather than using the trial-and-error method that is often pursued in daily practice.
ABSTRACT
BACKGROUND: Initiating warfarin in patients with atrial fibrillation at a typical loading dose of 10 mg daily for 2 days may be associated with excess anticoagulation, especially in older patients. In addition, daily monitoring associated with this regimen may be inconvenient for outpatients. Initiating warfarin at 5 mg daily may produce more consistent anticoagulation and eliminate the need for daily monitoring. The investigators tested whether administering 5 mg warfarin daily for 4 days and checking the anticoagulation status via the international normalized ratio (INR) on the fifth day could predict an early warfarin maintenance dose.
POPULATION STUDIED: This study included 61 outpatients with nonrheumatic atrial fibrillation, not receiving heparin, between the ages of 42 to 88 years (mean age = 71 years). Patients were excluded from the study if they were being treated with a drug known to interact with warfarin or had a coagulation disorder, contraindication to warfarin therapy, previous course of anticoagulation treatment, or baseline INR > 1.2, or if they refused to participate.
STUDY DESIGN AND VALIDITY: This was a prospective cohort study in which patients were given 5 mg warfarin daily for 4 days (day 1 to day 4). The INR was measured on day 5 and the patient’s physician freely chose a new dose. The INR was checked at least once a week for the next 2 weeks. Patients were followed for 3 months. The warfarin dose was considered stable when the INR was between 2 and 3 on 3 consecutive occasions at least 1 week apart. The stable weekly warfarin dose was plotted against the INR obtained on the fifth day of initiation to establish a scheme for predicting an early warfarin maintenance dose. To test the validity of this scheme, 23 additional patients with nonrheumatic atrial fibrillation were given the predicted warfarin maintenance dose based on their INR on day 5 and were followed for 3 months. Although the characteristics of this additional group of patients were not stated, these subjects were enrolled according to the same criteria.
OUTCOMES MEASURED: The outcome of this study was to determine whether the INR on day 5 of warfarin treatment could predict an early warfarin maintenance dose. Major and minor bleeding episodes and thromboembolic complications were also measured.
RESULTS: Of 91 patients eligible to participate in the study, 61 were included in the analysis. Thirty patients could not be evaluated either because they failed to reach a therapeutic INR within 3 months or because they did not complete the follow-up period. The relationship between the weekly maintenance dose and the INR on day 5 followed a hyperbolic curve, demonstrating a direct relationship between the INR on day 5 and the weekly warfarin dose. During the evaluation phase that was conducted in 23 additional patients, the mean difference between the predicted and actual doses of warfarin was 1.6 mg/week (95% CI, .0007-3.195 mg) with a maximum difference of 9 mg/week. One minor bleeding episode was reported among the 61 initial patients and 23 additional patients. The dosing regimen, based on the INR after 4 days of 5 mg warfarin, is shown in the Table.
TABLE
WARFARIN DOSING REGIMEN USED IN STUDY
| INR on Day 5 | Approximate Daily Warfarin Dose (mg)* |
| 1.3 | 6 |
| 1.4 | 5 to 6 |
| 1.5 | 5 |
| 1.6 | 4 to 5 |
| 1.7 | 4 to 4.5 |
| 1.8 | 4 |
| 1.9 | 3.5 to 4 |
| 2.0 | 3.5 |
| *Doses are rounded and calculated from a cumulative weekly dose. | |
Starting outpatients with 5 mg per day of warfarin and basing a maintenance dose on the INR obtained on the fifth day is an effective way to initiate therapy. The difference between the actual and predicted maintenance doses was small, indicating that this simple scheme is a good model for predicting the warfarin maintenance dose. Although only 23 patients were tested using this warfarin dosage scheme, clinicians may consult it when choosing a warfarin maintenance dose rather than using the trial-and-error method that is often pursued in daily practice.