Cleveland Clinic Journal of Medicine

Yes. Growing evidence demonstrates that the human papillomavirus (HPV) DNA test is more sensitive than the Papanicolaou (Pap) test, with a better negative predictive value—ie, women who have negative test results can be more certain that they are truly free of cervical cancer.^1–3

On April 24, 2014, the US Food and Drug Administration (FDA) approved the Cobas HPV test developed by Roche for use as the first-line screening test for cervical cancer in women age 25 and older.⁴ The approval follows the unanimous recommendation from an independent panel of experts, the Microbiology Devices Panel of the FDA’s Medical Devices Advisory Committee, on March 12, 2014.

PAP-HPV COTESTING IS EFFECTIVE BUT NOT PERFECT

Based on conclusive evidence of a direct link between HPV infection (specifically, infection with certain high-risk HPV genotypes) and almost all cases of invasive cervical cancer,^5,6 the American Cancer Society (ACS), American Society for Colposcopy and Cervical Pathology (ASCCP), American Society for Clinical Pathology (ASCP), US Preventive Services Task Force (USPSTF), and American Congress of Obstetricians and Gynecologists (ACOG) issued a consensus recommendation for Pap-HPV cotesting as the preferred screening strategy starting at age 30 and continuing through age 65.^7–9

Compared with Pap testing alone, cotesting offers improved detection of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) and the ability to safely extend the screening interval to every 5 years in women who have negative results on both tests. It is an effective screening strategy and remains the standard of care today.

However, this strategy is not perfect and presents several problems for clinicians. The results of the two tests often conflict—the results of the Pap test might be positive while those of the HPV test are negative, or vice versa. Integrating the results of cotesting into triaging can be confusing and complicated. In addition, performing two tests on all women increases the cost of care. And furthermore, the cotesting strategy increases the number of women who require immediate or short-term follow-up,^1,2,10–12 such as colposcopy, which is unnecessary for many.

THE HPV TEST DETECTS 14 HIGH-RISK GENOTYPES

The FDA-approved HPV test detects 14 high-risk genotypes. The results for 12 of these are pooled and reported collectively as either positive or negative, while the other two—HPV 16 and HPV 18—are reported separately. (HPV 16 and HPV 18 are the highest-risk genotypes, and together they account for more than two-thirds of cases of invasive cervical cancer.)

ADVANTAGES OF HPV-ONLY TESTING: FINDINGS FROM THE ATHENA TRIAL

The FDA’s decision to approve the Cobas HPV test for use by itself for screening was based on the landmark ATHENA (Addressing the Need for Advanced HPV Diagnostics) trial.¹³ ATHENA, the largest prospective study of cervical cancer screening performed in the United States to date, enrolled 47,208 women at 61 sites in 23 states. The study revealed the following findings:

The FDA has approved the test for this indication, and guideline committees are reviewing the data

• The HPV DNA test had higher sensitivity for detecting CIN3+ (37% higher than the Pap test) and equivalent specificity.
• The HPV test’s positive predictive value was nearly twice as high (12.25% vs 6.47%), and it had a higher negative predictive value (99.58% vs 99.41%) in detecting CIN3+ than with the Pap test.
• HPV testing by itself performed better than Pap-HPV cotesting, with positive predictive values of 12.25% vs 11.04% and negative predictive values of 99.58% vs 99.52% (data presented to the FDA Medical Devices Advisory Committee, Microbiology Panel. March 12, 2014. FDA Executive Summary).

For women whose results were negative for HPV 16 and 18 but positive for the 12-genotype pooled panel, the sample was automatically submitted for cytologic (Pap) testing. Reserving Pap testing for samples in this category improved the specificity of the test and resulted in fewer colposcopy referrals. The ATHENA researchers found that 11.4% of the participants who tested positive for either HPV 16 or 18 had CIN2+.¹³ Other large cohort studies^14,15 also showed that the short-term risk of developing CIN3+ reached 10% over 1 to 5 years in women who tested positive for HPV 16 or 18.

The proposed algorithm for screening (Figure 1) takes advantage of the superior sensitivity of the HPV test, the built-in risk stratification of HPV 16 and 18 genotyping, and the excellent specificity of the Pap test in triaging women whose results are positive for high-risk HPV genotypes other than HPV 16 and 18. Thus, women who have a negative HPV test result can be assured of remaining disease-free for 3 years. The algorithm also identifies women who are at highest risk, ie, those who test positive for HPV 16 or 18. In contrast, the current cotesting approach uses the Qiagen Hybrid Capture HPV testing system, which is a panel of 13 high-risk genotypes, but, if the result is positive, it does not tell you which one the patient has. Furthermore, the new algorithm provides efficient triage, using the Pap test, for women who test positive for the 12 other high-risk HPV genotypes.

Data from large clinical trials other than ATHENA are limited.

FDA APPROVAL DOES NOT CHANGE THE GUIDELINES—YET

The cervical cancer screening guidelines are developed by several organizations other than the FDA. The current guidelines issued by the ACS, ASCCP, ASCP, USPSTF, and ACOG in 2012 call for Pap testing every 3 years in women younger than 30 and Pap-HPV cotesting every 5 years in women ages 30 to 65.^7–9 However, FDA approval of the new indication of the HPV DNA test as a stand-alone first-line screening test is an important milestone. It heralds the shifting of the practice paradigm from morphologically based Pap testing to molecular testing in cervical cancer screening.

The ACS and ASCCP have announced that they are reviewing the evidence and may issue updated guidelines for clinicians in the near future.^16,17 We anticipate that other organizations may take similar steps. As primary care physicians, we need to stay tuned and follow the most up-to-date evidence-based practice guidelines to provide the best care for our patients.

Yes. Growing evidence demonstrates that the human papillomavirus (HPV) DNA test is more sensitive than the Papanicolaou (Pap) test, with a better negative predictive value—ie, women who have negative test results can be more certain that they are truly free of cervical cancer.^1–3

On April 24, 2014, the US Food and Drug Administration (FDA) approved the Cobas HPV test developed by Roche for use as the first-line screening test for cervical cancer in women age 25 and older.⁴ The approval follows the unanimous recommendation from an independent panel of experts, the Microbiology Devices Panel of the FDA’s Medical Devices Advisory Committee, on March 12, 2014.

PAP-HPV COTESTING IS EFFECTIVE BUT NOT PERFECT

Based on conclusive evidence of a direct link between HPV infection (specifically, infection with certain high-risk HPV genotypes) and almost all cases of invasive cervical cancer,^5,6 the American Cancer Society (ACS), American Society for Colposcopy and Cervical Pathology (ASCCP), American Society for Clinical Pathology (ASCP), US Preventive Services Task Force (USPSTF), and American Congress of Obstetricians and Gynecologists (ACOG) issued a consensus recommendation for Pap-HPV cotesting as the preferred screening strategy starting at age 30 and continuing through age 65.^7–9

Compared with Pap testing alone, cotesting offers improved detection of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) and the ability to safely extend the screening interval to every 5 years in women who have negative results on both tests. It is an effective screening strategy and remains the standard of care today.

However, this strategy is not perfect and presents several problems for clinicians. The results of the two tests often conflict—the results of the Pap test might be positive while those of the HPV test are negative, or vice versa. Integrating the results of cotesting into triaging can be confusing and complicated. In addition, performing two tests on all women increases the cost of care. And furthermore, the cotesting strategy increases the number of women who require immediate or short-term follow-up,^1,2,10–12 such as colposcopy, which is unnecessary for many.

THE HPV TEST DETECTS 14 HIGH-RISK GENOTYPES

The FDA-approved HPV test detects 14 high-risk genotypes. The results for 12 of these are pooled and reported collectively as either positive or negative, while the other two—HPV 16 and HPV 18—are reported separately. (HPV 16 and HPV 18 are the highest-risk genotypes, and together they account for more than two-thirds of cases of invasive cervical cancer.)

ADVANTAGES OF HPV-ONLY TESTING: FINDINGS FROM THE ATHENA TRIAL

The FDA’s decision to approve the Cobas HPV test for use by itself for screening was based on the landmark ATHENA (Addressing the Need for Advanced HPV Diagnostics) trial.¹³ ATHENA, the largest prospective study of cervical cancer screening performed in the United States to date, enrolled 47,208 women at 61 sites in 23 states. The study revealed the following findings:

The FDA has approved the test for this indication, and guideline committees are reviewing the data

• The HPV DNA test had higher sensitivity for detecting CIN3+ (37% higher than the Pap test) and equivalent specificity.
• The HPV test’s positive predictive value was nearly twice as high (12.25% vs 6.47%), and it had a higher negative predictive value (99.58% vs 99.41%) in detecting CIN3+ than with the Pap test.
• HPV testing by itself performed better than Pap-HPV cotesting, with positive predictive values of 12.25% vs 11.04% and negative predictive values of 99.58% vs 99.52% (data presented to the FDA Medical Devices Advisory Committee, Microbiology Panel. March 12, 2014. FDA Executive Summary).

For women whose results were negative for HPV 16 and 18 but positive for the 12-genotype pooled panel, the sample was automatically submitted for cytologic (Pap) testing. Reserving Pap testing for samples in this category improved the specificity of the test and resulted in fewer colposcopy referrals. The ATHENA researchers found that 11.4% of the participants who tested positive for either HPV 16 or 18 had CIN2+.¹³ Other large cohort studies^14,15 also showed that the short-term risk of developing CIN3+ reached 10% over 1 to 5 years in women who tested positive for HPV 16 or 18.

The proposed algorithm for screening (Figure 1) takes advantage of the superior sensitivity of the HPV test, the built-in risk stratification of HPV 16 and 18 genotyping, and the excellent specificity of the Pap test in triaging women whose results are positive for high-risk HPV genotypes other than HPV 16 and 18. Thus, women who have a negative HPV test result can be assured of remaining disease-free for 3 years. The algorithm also identifies women who are at highest risk, ie, those who test positive for HPV 16 or 18. In contrast, the current cotesting approach uses the Qiagen Hybrid Capture HPV testing system, which is a panel of 13 high-risk genotypes, but, if the result is positive, it does not tell you which one the patient has. Furthermore, the new algorithm provides efficient triage, using the Pap test, for women who test positive for the 12 other high-risk HPV genotypes.

Data from large clinical trials other than ATHENA are limited.

FDA APPROVAL DOES NOT CHANGE THE GUIDELINES—YET

The cervical cancer screening guidelines are developed by several organizations other than the FDA. The current guidelines issued by the ACS, ASCCP, ASCP, USPSTF, and ACOG in 2012 call for Pap testing every 3 years in women younger than 30 and Pap-HPV cotesting every 5 years in women ages 30 to 65.^7–9 However, FDA approval of the new indication of the HPV DNA test as a stand-alone first-line screening test is an important milestone. It heralds the shifting of the practice paradigm from morphologically based Pap testing to molecular testing in cervical cancer screening.

The ACS and ASCCP have announced that they are reviewing the evidence and may issue updated guidelines for clinicians in the near future.^16,17 We anticipate that other organizations may take similar steps. As primary care physicians, we need to stay tuned and follow the most up-to-date evidence-based practice guidelines to provide the best care for our patients.

Yes. Growing evidence demonstrates that the human papillomavirus (HPV) DNA test is more sensitive than the Papanicolaou (Pap) test, with a better negative predictive value—ie, women who have negative test results can be more certain that they are truly free of cervical cancer.^1–3

On April 24, 2014, the US Food and Drug Administration (FDA) approved the Cobas HPV test developed by Roche for use as the first-line screening test for cervical cancer in women age 25 and older.⁴ The approval follows the unanimous recommendation from an independent panel of experts, the Microbiology Devices Panel of the FDA’s Medical Devices Advisory Committee, on March 12, 2014.

PAP-HPV COTESTING IS EFFECTIVE BUT NOT PERFECT

Based on conclusive evidence of a direct link between HPV infection (specifically, infection with certain high-risk HPV genotypes) and almost all cases of invasive cervical cancer,^5,6 the American Cancer Society (ACS), American Society for Colposcopy and Cervical Pathology (ASCCP), American Society for Clinical Pathology (ASCP), US Preventive Services Task Force (USPSTF), and American Congress of Obstetricians and Gynecologists (ACOG) issued a consensus recommendation for Pap-HPV cotesting as the preferred screening strategy starting at age 30 and continuing through age 65.^7–9

Compared with Pap testing alone, cotesting offers improved detection of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) and the ability to safely extend the screening interval to every 5 years in women who have negative results on both tests. It is an effective screening strategy and remains the standard of care today.

However, this strategy is not perfect and presents several problems for clinicians. The results of the two tests often conflict—the results of the Pap test might be positive while those of the HPV test are negative, or vice versa. Integrating the results of cotesting into triaging can be confusing and complicated. In addition, performing two tests on all women increases the cost of care. And furthermore, the cotesting strategy increases the number of women who require immediate or short-term follow-up,^1,2,10–12 such as colposcopy, which is unnecessary for many.

THE HPV TEST DETECTS 14 HIGH-RISK GENOTYPES

The FDA-approved HPV test detects 14 high-risk genotypes. The results for 12 of these are pooled and reported collectively as either positive or negative, while the other two—HPV 16 and HPV 18—are reported separately. (HPV 16 and HPV 18 are the highest-risk genotypes, and together they account for more than two-thirds of cases of invasive cervical cancer.)

ADVANTAGES OF HPV-ONLY TESTING: FINDINGS FROM THE ATHENA TRIAL

The FDA’s decision to approve the Cobas HPV test for use by itself for screening was based on the landmark ATHENA (Addressing the Need for Advanced HPV Diagnostics) trial.¹³ ATHENA, the largest prospective study of cervical cancer screening performed in the United States to date, enrolled 47,208 women at 61 sites in 23 states. The study revealed the following findings:

The FDA has approved the test for this indication, and guideline committees are reviewing the data

• The HPV DNA test had higher sensitivity for detecting CIN3+ (37% higher than the Pap test) and equivalent specificity.
• The HPV test’s positive predictive value was nearly twice as high (12.25% vs 6.47%), and it had a higher negative predictive value (99.58% vs 99.41%) in detecting CIN3+ than with the Pap test.
• HPV testing by itself performed better than Pap-HPV cotesting, with positive predictive values of 12.25% vs 11.04% and negative predictive values of 99.58% vs 99.52% (data presented to the FDA Medical Devices Advisory Committee, Microbiology Panel. March 12, 2014. FDA Executive Summary).

For women whose results were negative for HPV 16 and 18 but positive for the 12-genotype pooled panel, the sample was automatically submitted for cytologic (Pap) testing. Reserving Pap testing for samples in this category improved the specificity of the test and resulted in fewer colposcopy referrals. The ATHENA researchers found that 11.4% of the participants who tested positive for either HPV 16 or 18 had CIN2+.¹³ Other large cohort studies^14,15 also showed that the short-term risk of developing CIN3+ reached 10% over 1 to 5 years in women who tested positive for HPV 16 or 18.

The proposed algorithm for screening (Figure 1) takes advantage of the superior sensitivity of the HPV test, the built-in risk stratification of HPV 16 and 18 genotyping, and the excellent specificity of the Pap test in triaging women whose results are positive for high-risk HPV genotypes other than HPV 16 and 18. Thus, women who have a negative HPV test result can be assured of remaining disease-free for 3 years. The algorithm also identifies women who are at highest risk, ie, those who test positive for HPV 16 or 18. In contrast, the current cotesting approach uses the Qiagen Hybrid Capture HPV testing system, which is a panel of 13 high-risk genotypes, but, if the result is positive, it does not tell you which one the patient has. Furthermore, the new algorithm provides efficient triage, using the Pap test, for women who test positive for the 12 other high-risk HPV genotypes.

Data from large clinical trials other than ATHENA are limited.

FDA APPROVAL DOES NOT CHANGE THE GUIDELINES—YET

The cervical cancer screening guidelines are developed by several organizations other than the FDA. The current guidelines issued by the ACS, ASCCP, ASCP, USPSTF, and ACOG in 2012 call for Pap testing every 3 years in women younger than 30 and Pap-HPV cotesting every 5 years in women ages 30 to 65.^7–9 However, FDA approval of the new indication of the HPV DNA test as a stand-alone first-line screening test is an important milestone. It heralds the shifting of the practice paradigm from morphologically based Pap testing to molecular testing in cervical cancer screening.

The ACS and ASCCP have announced that they are reviewing the evidence and may issue updated guidelines for clinicians in the near future.^16,17 We anticipate that other organizations may take similar steps. As primary care physicians, we need to stay tuned and follow the most up-to-date evidence-based practice guidelines to provide the best care for our patients.

A 44-year-old man presented with a 3-week history of a painless, nonhealing ulcer affecting the mucosa in the right angle of the mouth. He reported no fever, weight loss, or systemic symptoms of chronic disease. His medical history included chronic hepatitis C infection and human immunodeficiency virus (HIV) infection; his antiretroviral regimen for HIV was abacavir, lamivudine, and darunavir. His CD4+ T-cell count was 153 cells/mm³, and his viral load was 154.88 copies/mL. He formerly used injected drugs, and he currently smoked 20 cigarettes a day. He had no history of periodontal disease.

Oral examination showed poor oral hygiene and a solitary ulcerated lesion with an infiltrated base and indurated borders in the right oral commissure (Figure 1). There was also soft-tissue induration in the ipsilateral cheek. He had no other oral lesions or signs of neck lymphadenopathy.

Based on the clinical examination, a provisional diagnosis of malignancy was suspected, and an incisional biopsy of the ulcer was done. The findings on histopathologic study of the biopsy specimen (below; Figure 2) led to additional evaluation with chest radiography and thoracic computed tomography (Figure 3).

FURTHER WORKUP

Histologic study of the biopsy specimen showed ulcerated mucosa with extensive granulomatous inflammation and with caseation necrosis. Ziehl-Neelsen staining demonstrated a few acid-fast bacilli. The patient was then evaluated for pulmonary tuberculosis.

Chest radiography showed pulmonary infiltrates in both bases and the upper right lobe and cavitation in the upper left lobe. Thoracic computed tomography confirmed the presence of multiple cavitated lesions in both left and right lung fields. Sputum cultures were positive for Mycobacterium tuberculosis, an organism sensitive to several agents. Laboratory investigations that included blood cell counts, biochemical tests, and liver and kidney function tests were normal, with the exception of a low lymphocyte count.

ORAL TUBERCULOSIS SECONDARY TO ACTIVE PULMONARY TUBERCULOSIS

Even though the incidence of extrapulmonary tuberculosis has been increasing worldwide in recent years, cutaneous manifestations are uncommon (2% to 10%) and are seen mainly in immunosuppressed patients with coexisting tuberculosis infection of internal organs.¹ Oral manifestations of tuberculosis are extremely rare, accounting for 2% of cases of cutaneous manifestations.^1,2 For this reason and because of its clinical heterogeneity, oral tuberculosis is often not considered in the differential diagnosis of oral lesions.

The differential diagnosis of oral ulcers in patients with HIV includes adverse drug reactions (eg, nevirapine-induced Stevens-Johnson syndrome); oral ulcers and necrotizing gingivitis related to HIV-associated neutropenia; aphthous ulcers; oral ulcers in reactive arthritis; malignancies such as lymphoma, Kaposi sarcoma, and squamous cell carcinoma; and infections such as candidiasis, herpes simplex virus, cytomegalovirus, primary syphilis, mucosal leishmaniasis, histoplasmosis, and periorificial tuberculosis. Periorificial tuberculosis is more commonly seen in HIV patients, in whom extrapulmonary forms of tuberculosis are frequent.³

Oral tuberculosis is often mistaken for a malignancy such as squamous cell carcinoma; in fact, carcinoma coexists with tubercular ulcer in up to 3% of patients.² The typical clinical presentation of oral tuberculosis is one or more painful or painless ulcers with irregular borders, usually localized on the tongue (nearly half of cases⁴), and less frequently affecting the lip, buccal mucosa, gingiva, soft palate, and extraction sockets. It can also present as a nodule, fissure, vesicle, tuberculoma, tubercular papilloma, or periapical granuloma.^2,5

Oral tuberculosis may be primary but is more commonly secondary to internal-organ tuberculosis. Secondary disease is seen in patients with pulmonary forms (affecting 0.05% to 1.5% of patients with pulmonary tuberculosis^1,2) because of autoinoculation by infected sputum or hematogenous spread.^1,4,5

Clinicians should consider oral tuberculosis in the differential diagnosis of a nonhealing ulcer of the mouth, particularly in an immunosuppressed patient such as ours. It is also important to highlight the necessity of searching for a primary site of infection, more frequently in the lungs.

A 44-year-old man presented with a 3-week history of a painless, nonhealing ulcer affecting the mucosa in the right angle of the mouth. He reported no fever, weight loss, or systemic symptoms of chronic disease. His medical history included chronic hepatitis C infection and human immunodeficiency virus (HIV) infection; his antiretroviral regimen for HIV was abacavir, lamivudine, and darunavir. His CD4+ T-cell count was 153 cells/mm³, and his viral load was 154.88 copies/mL. He formerly used injected drugs, and he currently smoked 20 cigarettes a day. He had no history of periodontal disease.

Oral examination showed poor oral hygiene and a solitary ulcerated lesion with an infiltrated base and indurated borders in the right oral commissure (Figure 1). There was also soft-tissue induration in the ipsilateral cheek. He had no other oral lesions or signs of neck lymphadenopathy.

Based on the clinical examination, a provisional diagnosis of malignancy was suspected, and an incisional biopsy of the ulcer was done. The findings on histopathologic study of the biopsy specimen (below; Figure 2) led to additional evaluation with chest radiography and thoracic computed tomography (Figure 3).

FURTHER WORKUP

Histologic study of the biopsy specimen showed ulcerated mucosa with extensive granulomatous inflammation and with caseation necrosis. Ziehl-Neelsen staining demonstrated a few acid-fast bacilli. The patient was then evaluated for pulmonary tuberculosis.

Chest radiography showed pulmonary infiltrates in both bases and the upper right lobe and cavitation in the upper left lobe. Thoracic computed tomography confirmed the presence of multiple cavitated lesions in both left and right lung fields. Sputum cultures were positive for Mycobacterium tuberculosis, an organism sensitive to several agents. Laboratory investigations that included blood cell counts, biochemical tests, and liver and kidney function tests were normal, with the exception of a low lymphocyte count.

ORAL TUBERCULOSIS SECONDARY TO ACTIVE PULMONARY TUBERCULOSIS

Even though the incidence of extrapulmonary tuberculosis has been increasing worldwide in recent years, cutaneous manifestations are uncommon (2% to 10%) and are seen mainly in immunosuppressed patients with coexisting tuberculosis infection of internal organs.¹ Oral manifestations of tuberculosis are extremely rare, accounting for 2% of cases of cutaneous manifestations.^1,2 For this reason and because of its clinical heterogeneity, oral tuberculosis is often not considered in the differential diagnosis of oral lesions.

The differential diagnosis of oral ulcers in patients with HIV includes adverse drug reactions (eg, nevirapine-induced Stevens-Johnson syndrome); oral ulcers and necrotizing gingivitis related to HIV-associated neutropenia; aphthous ulcers; oral ulcers in reactive arthritis; malignancies such as lymphoma, Kaposi sarcoma, and squamous cell carcinoma; and infections such as candidiasis, herpes simplex virus, cytomegalovirus, primary syphilis, mucosal leishmaniasis, histoplasmosis, and periorificial tuberculosis. Periorificial tuberculosis is more commonly seen in HIV patients, in whom extrapulmonary forms of tuberculosis are frequent.³

Oral tuberculosis is often mistaken for a malignancy such as squamous cell carcinoma; in fact, carcinoma coexists with tubercular ulcer in up to 3% of patients.² The typical clinical presentation of oral tuberculosis is one or more painful or painless ulcers with irregular borders, usually localized on the tongue (nearly half of cases⁴), and less frequently affecting the lip, buccal mucosa, gingiva, soft palate, and extraction sockets. It can also present as a nodule, fissure, vesicle, tuberculoma, tubercular papilloma, or periapical granuloma.^2,5

Oral tuberculosis may be primary but is more commonly secondary to internal-organ tuberculosis. Secondary disease is seen in patients with pulmonary forms (affecting 0.05% to 1.5% of patients with pulmonary tuberculosis^1,2) because of autoinoculation by infected sputum or hematogenous spread.^1,4,5

Clinicians should consider oral tuberculosis in the differential diagnosis of a nonhealing ulcer of the mouth, particularly in an immunosuppressed patient such as ours. It is also important to highlight the necessity of searching for a primary site of infection, more frequently in the lungs.

A 44-year-old man presented with a 3-week history of a painless, nonhealing ulcer affecting the mucosa in the right angle of the mouth. He reported no fever, weight loss, or systemic symptoms of chronic disease. His medical history included chronic hepatitis C infection and human immunodeficiency virus (HIV) infection; his antiretroviral regimen for HIV was abacavir, lamivudine, and darunavir. His CD4+ T-cell count was 153 cells/mm³, and his viral load was 154.88 copies/mL. He formerly used injected drugs, and he currently smoked 20 cigarettes a day. He had no history of periodontal disease.

Oral examination showed poor oral hygiene and a solitary ulcerated lesion with an infiltrated base and indurated borders in the right oral commissure (Figure 1). There was also soft-tissue induration in the ipsilateral cheek. He had no other oral lesions or signs of neck lymphadenopathy.

Based on the clinical examination, a provisional diagnosis of malignancy was suspected, and an incisional biopsy of the ulcer was done. The findings on histopathologic study of the biopsy specimen (below; Figure 2) led to additional evaluation with chest radiography and thoracic computed tomography (Figure 3).

FURTHER WORKUP

Histologic study of the biopsy specimen showed ulcerated mucosa with extensive granulomatous inflammation and with caseation necrosis. Ziehl-Neelsen staining demonstrated a few acid-fast bacilli. The patient was then evaluated for pulmonary tuberculosis.

Chest radiography showed pulmonary infiltrates in both bases and the upper right lobe and cavitation in the upper left lobe. Thoracic computed tomography confirmed the presence of multiple cavitated lesions in both left and right lung fields. Sputum cultures were positive for Mycobacterium tuberculosis, an organism sensitive to several agents. Laboratory investigations that included blood cell counts, biochemical tests, and liver and kidney function tests were normal, with the exception of a low lymphocyte count.

ORAL TUBERCULOSIS SECONDARY TO ACTIVE PULMONARY TUBERCULOSIS

Even though the incidence of extrapulmonary tuberculosis has been increasing worldwide in recent years, cutaneous manifestations are uncommon (2% to 10%) and are seen mainly in immunosuppressed patients with coexisting tuberculosis infection of internal organs.¹ Oral manifestations of tuberculosis are extremely rare, accounting for 2% of cases of cutaneous manifestations.^1,2 For this reason and because of its clinical heterogeneity, oral tuberculosis is often not considered in the differential diagnosis of oral lesions.

The differential diagnosis of oral ulcers in patients with HIV includes adverse drug reactions (eg, nevirapine-induced Stevens-Johnson syndrome); oral ulcers and necrotizing gingivitis related to HIV-associated neutropenia; aphthous ulcers; oral ulcers in reactive arthritis; malignancies such as lymphoma, Kaposi sarcoma, and squamous cell carcinoma; and infections such as candidiasis, herpes simplex virus, cytomegalovirus, primary syphilis, mucosal leishmaniasis, histoplasmosis, and periorificial tuberculosis. Periorificial tuberculosis is more commonly seen in HIV patients, in whom extrapulmonary forms of tuberculosis are frequent.³

Oral tuberculosis is often mistaken for a malignancy such as squamous cell carcinoma; in fact, carcinoma coexists with tubercular ulcer in up to 3% of patients.² The typical clinical presentation of oral tuberculosis is one or more painful or painless ulcers with irregular borders, usually localized on the tongue (nearly half of cases⁴), and less frequently affecting the lip, buccal mucosa, gingiva, soft palate, and extraction sockets. It can also present as a nodule, fissure, vesicle, tuberculoma, tubercular papilloma, or periapical granuloma.^2,5

Oral tuberculosis may be primary but is more commonly secondary to internal-organ tuberculosis. Secondary disease is seen in patients with pulmonary forms (affecting 0.05% to 1.5% of patients with pulmonary tuberculosis^1,2) because of autoinoculation by infected sputum or hematogenous spread.^1,4,5

Clinicians should consider oral tuberculosis in the differential diagnosis of a nonhealing ulcer of the mouth, particularly in an immunosuppressed patient such as ours. It is also important to highlight the necessity of searching for a primary site of infection, more frequently in the lungs.

An obese 50-year-old man with hypertension, hyperlipidemia, recently diagnosed diabetes, and a history of grand mal seizures presented to the emergency room complaining of skin rash for 1 week. He denied having fever, chills, myalgia, abdominal pain, visual changes, recent changes in medications, or contact with anyone with similar symptoms.

He was a smoker, with a history of 20 pack-years; he denied abusing alcohol and taking illicit drugs.

He had no family history of diabetes, peripheral vascular disease, or coronary artery disease. His medications included lisinopril, simvastatin, niacin, metformin, and phenytoin.

On physical examination, the lesions were small, reddish-yellow, nonpruritic tender papules covering the extensor surfaces of the knees, the forearms, the abdomen, and the back (Figure 1). Laboratory test results:

• Total cholesterol 1,045 mg/dL (reference range 100–199)
• Triglycerides 7,855 mg/dL (30–149)
• Thyroid-stimulating hormone 0.52 mIU/L (0.4–5.5)
• Fasting blood glucose 441 mg/dL (65–100)
• Hemoglobin A_1c 12.6% (4.0–6.0)
• Total protein 7.2 g/dL (6.0–8.4)
• Albumin 4 g/dL (3.5–5.0)
• Creatinine 1 mg/dL (0.70–1.40)
• Glomerular filtration rate 79 mL/min/1.73 m² (> 60)
• Urinalysis showed no proteinuria.

Histologic analysis of a lesion-biopsy specimen showed dermal foamy macrophages and loose lipids, which confirmed the suspicion of eruptive xanthoma.

The patient was started on strict glycemic and lipid control. Metformin and statin doses were increased and insulin was added. Three months later, laboratory results showed total cholesterol 128 mg/dL, triglycerides 164 mg/dL, fasting blood glucose 88 mg/dL, and hemoglobin A_1c 5.5%. This was accompanied by  marked improvement of the skin lesions (Figure  2).

CAUSES AND DIFFERENTIAL DIAGNOSIS

Eruptive xanthoma is a cutaneous disease most commonly arising over the extensor surfaces of the extremities and on the buttocks and shoulders, and it can be caused by high levels of serum triglycerides and uncontrolled diabetes mellitus.¹ Hypothyroidism, end-stage renal disease, and nephrotic syndrome can cause secondary hypertriglyceridemia,² which can cause eruptive xanthoma in severe cases. Patients with eruptive xanthoma may also have ophthalmologic and gastrointestinal involvement, such as lipemia retinalis (salmon-colored retina with creamy-white retinal vessels), abdominal pain, and hepatosplenomegaly.³

Other types of xanthoma associated with dyslipidemia include tuberous, tendinous, and plane xanthoma. Tuberous xanthoma is a firm, painless, deeper, red-yellow, larger nodular lesion, and the size may vary.⁴ Tendinous xanthoma is a slowly enlarging subcutaneous nodule typically located near tendons or ligaments in the hands, feet, and the Achilles tendon. Plane xanthoma is a flat papule or patch that can occur anywhere on the body.

Eruptive xanthoma most commonly arises over extensor surfaces of the extremities, and on the buttocks and shoulders

The differential diagnosis includes disseminated granuloma annulare, non-Langerhans cell histiocytosis (xanthoma disseminatum, micronodular form of juvenile xanthogranuloma), and generalized eruptive histiocytoma. Eruptive xanthoma is differentiated from disseminated granuloma annulare by the abundance of perivascular histiocytes and xanthomized histiocytes, the presence of lipid deposits, and the deposition of hyaluronic acid on the edges.⁵ Xanthoma disseminatum consists of numerous, small, red-brown papules that are evenly spread on the face, skin-folds, trunk, and proximal extremities.⁶ Juvenile xanthogranuloma occurs mostly in children and is characterized by discrete orange-yellow nodules, which commonly appear on the scalp, face, and upper trunk. It is in most cases a solitary lesion, but multiple lesions may occur.⁷ Lesions of generalized eruptive histiocytoma are firm, erythematous or brownish papules that appear in successive crops over the face, trunk, and proximal surfaces of the limbs.

TREATMENT

Treatment of eruptive xanthoma involves dietary restriction, exercise, and drug therapy to control the hyperlipidemia and the diabetes.² Early recognition and proper control of hypertriglyceridemia can prevent sequelae such as acute pancreatitis.³

An obese 50-year-old man with hypertension, hyperlipidemia, recently diagnosed diabetes, and a history of grand mal seizures presented to the emergency room complaining of skin rash for 1 week. He denied having fever, chills, myalgia, abdominal pain, visual changes, recent changes in medications, or contact with anyone with similar symptoms.

He was a smoker, with a history of 20 pack-years; he denied abusing alcohol and taking illicit drugs.

He had no family history of diabetes, peripheral vascular disease, or coronary artery disease. His medications included lisinopril, simvastatin, niacin, metformin, and phenytoin.

On physical examination, the lesions were small, reddish-yellow, nonpruritic tender papules covering the extensor surfaces of the knees, the forearms, the abdomen, and the back (Figure 1). Laboratory test results:

• Total cholesterol 1,045 mg/dL (reference range 100–199)
• Triglycerides 7,855 mg/dL (30–149)
• Thyroid-stimulating hormone 0.52 mIU/L (0.4–5.5)
• Fasting blood glucose 441 mg/dL (65–100)
• Hemoglobin A_1c 12.6% (4.0–6.0)
• Total protein 7.2 g/dL (6.0–8.4)
• Albumin 4 g/dL (3.5–5.0)
• Creatinine 1 mg/dL (0.70–1.40)
• Glomerular filtration rate 79 mL/min/1.73 m² (> 60)
• Urinalysis showed no proteinuria.

Histologic analysis of a lesion-biopsy specimen showed dermal foamy macrophages and loose lipids, which confirmed the suspicion of eruptive xanthoma.

The patient was started on strict glycemic and lipid control. Metformin and statin doses were increased and insulin was added. Three months later, laboratory results showed total cholesterol 128 mg/dL, triglycerides 164 mg/dL, fasting blood glucose 88 mg/dL, and hemoglobin A_1c 5.5%. This was accompanied by  marked improvement of the skin lesions (Figure  2).

CAUSES AND DIFFERENTIAL DIAGNOSIS

Eruptive xanthoma is a cutaneous disease most commonly arising over the extensor surfaces of the extremities and on the buttocks and shoulders, and it can be caused by high levels of serum triglycerides and uncontrolled diabetes mellitus.¹ Hypothyroidism, end-stage renal disease, and nephrotic syndrome can cause secondary hypertriglyceridemia,² which can cause eruptive xanthoma in severe cases. Patients with eruptive xanthoma may also have ophthalmologic and gastrointestinal involvement, such as lipemia retinalis (salmon-colored retina with creamy-white retinal vessels), abdominal pain, and hepatosplenomegaly.³

Other types of xanthoma associated with dyslipidemia include tuberous, tendinous, and plane xanthoma. Tuberous xanthoma is a firm, painless, deeper, red-yellow, larger nodular lesion, and the size may vary.⁴ Tendinous xanthoma is a slowly enlarging subcutaneous nodule typically located near tendons or ligaments in the hands, feet, and the Achilles tendon. Plane xanthoma is a flat papule or patch that can occur anywhere on the body.

Eruptive xanthoma most commonly arises over extensor surfaces of the extremities, and on the buttocks and shoulders

The differential diagnosis includes disseminated granuloma annulare, non-Langerhans cell histiocytosis (xanthoma disseminatum, micronodular form of juvenile xanthogranuloma), and generalized eruptive histiocytoma. Eruptive xanthoma is differentiated from disseminated granuloma annulare by the abundance of perivascular histiocytes and xanthomized histiocytes, the presence of lipid deposits, and the deposition of hyaluronic acid on the edges.⁵ Xanthoma disseminatum consists of numerous, small, red-brown papules that are evenly spread on the face, skin-folds, trunk, and proximal extremities.⁶ Juvenile xanthogranuloma occurs mostly in children and is characterized by discrete orange-yellow nodules, which commonly appear on the scalp, face, and upper trunk. It is in most cases a solitary lesion, but multiple lesions may occur.⁷ Lesions of generalized eruptive histiocytoma are firm, erythematous or brownish papules that appear in successive crops over the face, trunk, and proximal surfaces of the limbs.

TREATMENT

Treatment of eruptive xanthoma involves dietary restriction, exercise, and drug therapy to control the hyperlipidemia and the diabetes.² Early recognition and proper control of hypertriglyceridemia can prevent sequelae such as acute pancreatitis.³

An obese 50-year-old man with hypertension, hyperlipidemia, recently diagnosed diabetes, and a history of grand mal seizures presented to the emergency room complaining of skin rash for 1 week. He denied having fever, chills, myalgia, abdominal pain, visual changes, recent changes in medications, or contact with anyone with similar symptoms.

He was a smoker, with a history of 20 pack-years; he denied abusing alcohol and taking illicit drugs.

He had no family history of diabetes, peripheral vascular disease, or coronary artery disease. His medications included lisinopril, simvastatin, niacin, metformin, and phenytoin.

On physical examination, the lesions were small, reddish-yellow, nonpruritic tender papules covering the extensor surfaces of the knees, the forearms, the abdomen, and the back (Figure 1). Laboratory test results:

• Total cholesterol 1,045 mg/dL (reference range 100–199)
• Triglycerides 7,855 mg/dL (30–149)
• Thyroid-stimulating hormone 0.52 mIU/L (0.4–5.5)
• Fasting blood glucose 441 mg/dL (65–100)
• Hemoglobin A_1c 12.6% (4.0–6.0)
• Total protein 7.2 g/dL (6.0–8.4)
• Albumin 4 g/dL (3.5–5.0)
• Creatinine 1 mg/dL (0.70–1.40)
• Glomerular filtration rate 79 mL/min/1.73 m² (> 60)
• Urinalysis showed no proteinuria.

Histologic analysis of a lesion-biopsy specimen showed dermal foamy macrophages and loose lipids, which confirmed the suspicion of eruptive xanthoma.

The patient was started on strict glycemic and lipid control. Metformin and statin doses were increased and insulin was added. Three months later, laboratory results showed total cholesterol 128 mg/dL, triglycerides 164 mg/dL, fasting blood glucose 88 mg/dL, and hemoglobin A_1c 5.5%. This was accompanied by  marked improvement of the skin lesions (Figure  2).

CAUSES AND DIFFERENTIAL DIAGNOSIS

Eruptive xanthoma is a cutaneous disease most commonly arising over the extensor surfaces of the extremities and on the buttocks and shoulders, and it can be caused by high levels of serum triglycerides and uncontrolled diabetes mellitus.¹ Hypothyroidism, end-stage renal disease, and nephrotic syndrome can cause secondary hypertriglyceridemia,² which can cause eruptive xanthoma in severe cases. Patients with eruptive xanthoma may also have ophthalmologic and gastrointestinal involvement, such as lipemia retinalis (salmon-colored retina with creamy-white retinal vessels), abdominal pain, and hepatosplenomegaly.³

Other types of xanthoma associated with dyslipidemia include tuberous, tendinous, and plane xanthoma. Tuberous xanthoma is a firm, painless, deeper, red-yellow, larger nodular lesion, and the size may vary.⁴ Tendinous xanthoma is a slowly enlarging subcutaneous nodule typically located near tendons or ligaments in the hands, feet, and the Achilles tendon. Plane xanthoma is a flat papule or patch that can occur anywhere on the body.

Eruptive xanthoma most commonly arises over extensor surfaces of the extremities, and on the buttocks and shoulders

The differential diagnosis includes disseminated granuloma annulare, non-Langerhans cell histiocytosis (xanthoma disseminatum, micronodular form of juvenile xanthogranuloma), and generalized eruptive histiocytoma. Eruptive xanthoma is differentiated from disseminated granuloma annulare by the abundance of perivascular histiocytes and xanthomized histiocytes, the presence of lipid deposits, and the deposition of hyaluronic acid on the edges.⁵ Xanthoma disseminatum consists of numerous, small, red-brown papules that are evenly spread on the face, skin-folds, trunk, and proximal extremities.⁶ Juvenile xanthogranuloma occurs mostly in children and is characterized by discrete orange-yellow nodules, which commonly appear on the scalp, face, and upper trunk. It is in most cases a solitary lesion, but multiple lesions may occur.⁷ Lesions of generalized eruptive histiocytoma are firm, erythematous or brownish papules that appear in successive crops over the face, trunk, and proximal surfaces of the limbs.

TREATMENT

Treatment of eruptive xanthoma involves dietary restriction, exercise, and drug therapy to control the hyperlipidemia and the diabetes.² Early recognition and proper control of hypertriglyceridemia can prevent sequelae such as acute pancreatitis.³

A 76-year-old man presented to the emergency department with right-sided exertional chest pain radiating to the right shoulder and arm associated with shortness of breath. His vital signs were normal.  On clinical examination, the cardiac apex was palpated on the right side, 9 cm from the midsternal line in the fifth intercostal space.

A standard left-sided 12-lead electrocardiogram (ECG) showed right-axis deviation and inverted P, QRS, and T waves in leads I and aVL (Figure 1). Although these changes are also seen when the right and left arm electrode wires are transposed, the precordial lead morphology in such a situation would usually be normal. In our patient, the precordial leads showed the absence or even slight reversal of R-wave progression, a feature indicative of dextrocardia.^1,2

In patients with dextrocardia, right-sided hookup of the electrodes is usually necessary for proper interpretation of the ECG. When this was done in our patient, the ECG showed a normal cardiac axis, a negative QRS complex in lead aVR, a positive P wave and other complexes in lead I, and normal R-wave progression in the precordial leads—findings suggestive of dextrocardia (Figure 2).

Chest radiography showed a right-sided cardiac silhouette (Figure 3), and computed tomography of the abdomen (Figure 4) revealed the liver positioned on the left side and the spleen on the right, confirming the diagnosis of situs inversus totalis. The ECG showed dextrocardia, but no other abnormalities. The patient eventually underwent coronary angiography, which showed nonobstructive coronary artery disease.

DEXTROCARDIA, OTHER CONGENITAL CARDIOVASCULAR MALFORMATIONS

Dextrocardia was first described in early 17th century.¹ Situs solitus is the normal position of the heart and viscera, whereas situs inversus is a mirror-image anatomic arrangement of the organs. Situs inversus with dextrocardia, also called situs inversus totalis, is a rare condition (with a prevalence of 1 in 8,000) in which the heart and descending aorta are on the right and the thoracic and abdominal viscera are usually mirror images of the normal morphology.^1,3,4 A mirror-image sinus node lies at the junction of the left superior vena cava and the left-sided (morphologic right) atrium.¹ People with situs inversus with dextrocardia are usually asymptomatic and have a normal life expectancy.^1,2 Situs inversus with levocardia is a rare condition in which the heart is in the normal position but the viscera are in the dextro-position. This anomaly has a prevalence of 1 in 22,000.⁵

Atrial situs almost always corresponds to visceral situs. However, when the alignment of the atria and viscera is inconsistent and situs cannot be determined clearly because of the malpositioning of organs, the condition is called “situs ambiguous.” This is very rare, with a prevalence of 1 in 40,000.⁶

Risk factors

The cause of congenital cardiovascular malformations such as these is not known, but risk factors include positive family history, maternal diabetes, and cocaine use in the first trimester.⁷

Negative complexes in lead I, positive complexes in aVR, and slight reversal of R-wave progression indicate dextrocardia

The prevalence of congenital heart disease in patients with situs inversus with dextrocardia is low and ranges from 2% to 5%. This is in contrast to situs solitus with dextrocardia (isolated dextrocardia), which is almost always associated with cardiovascular anomalies.^2,4 Kartagener syndrome—the triad of situs inversus, sinusitis, and bronchiectasis—occurs in 25% of people with situs inversus with dextrocardia.⁴ Situs inversus with levocardia is also frequently associated with cardiac anomalies.⁵

The major features of dextrocardia on ECG are:

• Negative P wave, QRS complex, and T wave in lead I
• Positive QRS complex in aVR
• Right-axis deviation
• Reversal of R-wave progression in the precordial leads.

Ventricular activation and repolarization are reversed, resulting in a negative QRS complex and an inverted T wave in lead I. The absence of R-wave progression in the precordial leads helps differentiate mirror-image dextrocardia from erroneously reversed limb-electrode placement, which shows normal R-wave progression from V₁ to V₆ while showing similar features to those seen in dextrocardia in the limb leads.² In right-sided hookup, the limb electrodes are reversed, and the chest electrodes are recorded from the right precordium.

CORONARY INTERVENTIONS REQUIRE SPECIAL CONSIDERATION

In patients with dextrocardia, coronary interventions can be challenging because of the mirror-image position of the coronary ostia and the aortic arch.⁸ These patients also need careful imaging, consideration of other associated congenital cardiac abnormalities, and detailed planning before cardiac surgery, including coronary artery bypass grafting.⁹

Patients with dextrocardia may present with cardiac symptoms localized to the right side of the body and have confusing clinical and diagnostic findings. Keeping dextrocardia and other such anomalies in mind can prevent delay in appropriately directed interventions. In a patient such as ours, the heart on the right side of the chest may indeed be “right.” Still, diagnostic tests to look for disorders encountered with dextrocardia may be necessary.

A 76-year-old man presented to the emergency department with right-sided exertional chest pain radiating to the right shoulder and arm associated with shortness of breath. His vital signs were normal.  On clinical examination, the cardiac apex was palpated on the right side, 9 cm from the midsternal line in the fifth intercostal space.

A standard left-sided 12-lead electrocardiogram (ECG) showed right-axis deviation and inverted P, QRS, and T waves in leads I and aVL (Figure 1). Although these changes are also seen when the right and left arm electrode wires are transposed, the precordial lead morphology in such a situation would usually be normal. In our patient, the precordial leads showed the absence or even slight reversal of R-wave progression, a feature indicative of dextrocardia.^1,2

In patients with dextrocardia, right-sided hookup of the electrodes is usually necessary for proper interpretation of the ECG. When this was done in our patient, the ECG showed a normal cardiac axis, a negative QRS complex in lead aVR, a positive P wave and other complexes in lead I, and normal R-wave progression in the precordial leads—findings suggestive of dextrocardia (Figure 2).

Chest radiography showed a right-sided cardiac silhouette (Figure 3), and computed tomography of the abdomen (Figure 4) revealed the liver positioned on the left side and the spleen on the right, confirming the diagnosis of situs inversus totalis. The ECG showed dextrocardia, but no other abnormalities. The patient eventually underwent coronary angiography, which showed nonobstructive coronary artery disease.

DEXTROCARDIA, OTHER CONGENITAL CARDIOVASCULAR MALFORMATIONS

Dextrocardia was first described in early 17th century.¹ Situs solitus is the normal position of the heart and viscera, whereas situs inversus is a mirror-image anatomic arrangement of the organs. Situs inversus with dextrocardia, also called situs inversus totalis, is a rare condition (with a prevalence of 1 in 8,000) in which the heart and descending aorta are on the right and the thoracic and abdominal viscera are usually mirror images of the normal morphology.^1,3,4 A mirror-image sinus node lies at the junction of the left superior vena cava and the left-sided (morphologic right) atrium.¹ People with situs inversus with dextrocardia are usually asymptomatic and have a normal life expectancy.^1,2 Situs inversus with levocardia is a rare condition in which the heart is in the normal position but the viscera are in the dextro-position. This anomaly has a prevalence of 1 in 22,000.⁵

Atrial situs almost always corresponds to visceral situs. However, when the alignment of the atria and viscera is inconsistent and situs cannot be determined clearly because of the malpositioning of organs, the condition is called “situs ambiguous.” This is very rare, with a prevalence of 1 in 40,000.⁶

Risk factors

The cause of congenital cardiovascular malformations such as these is not known, but risk factors include positive family history, maternal diabetes, and cocaine use in the first trimester.⁷

Negative complexes in lead I, positive complexes in aVR, and slight reversal of R-wave progression indicate dextrocardia

The prevalence of congenital heart disease in patients with situs inversus with dextrocardia is low and ranges from 2% to 5%. This is in contrast to situs solitus with dextrocardia (isolated dextrocardia), which is almost always associated with cardiovascular anomalies.^2,4 Kartagener syndrome—the triad of situs inversus, sinusitis, and bronchiectasis—occurs in 25% of people with situs inversus with dextrocardia.⁴ Situs inversus with levocardia is also frequently associated with cardiac anomalies.⁵

The major features of dextrocardia on ECG are:

• Negative P wave, QRS complex, and T wave in lead I
• Positive QRS complex in aVR
• Right-axis deviation
• Reversal of R-wave progression in the precordial leads.

Ventricular activation and repolarization are reversed, resulting in a negative QRS complex and an inverted T wave in lead I. The absence of R-wave progression in the precordial leads helps differentiate mirror-image dextrocardia from erroneously reversed limb-electrode placement, which shows normal R-wave progression from V₁ to V₆ while showing similar features to those seen in dextrocardia in the limb leads.² In right-sided hookup, the limb electrodes are reversed, and the chest electrodes are recorded from the right precordium.

CORONARY INTERVENTIONS REQUIRE SPECIAL CONSIDERATION

In patients with dextrocardia, coronary interventions can be challenging because of the mirror-image position of the coronary ostia and the aortic arch.⁸ These patients also need careful imaging, consideration of other associated congenital cardiac abnormalities, and detailed planning before cardiac surgery, including coronary artery bypass grafting.⁹

Patients with dextrocardia may present with cardiac symptoms localized to the right side of the body and have confusing clinical and diagnostic findings. Keeping dextrocardia and other such anomalies in mind can prevent delay in appropriately directed interventions. In a patient such as ours, the heart on the right side of the chest may indeed be “right.” Still, diagnostic tests to look for disorders encountered with dextrocardia may be necessary.

A 76-year-old man presented to the emergency department with right-sided exertional chest pain radiating to the right shoulder and arm associated with shortness of breath. His vital signs were normal.  On clinical examination, the cardiac apex was palpated on the right side, 9 cm from the midsternal line in the fifth intercostal space.

A standard left-sided 12-lead electrocardiogram (ECG) showed right-axis deviation and inverted P, QRS, and T waves in leads I and aVL (Figure 1). Although these changes are also seen when the right and left arm electrode wires are transposed, the precordial lead morphology in such a situation would usually be normal. In our patient, the precordial leads showed the absence or even slight reversal of R-wave progression, a feature indicative of dextrocardia.^1,2

In patients with dextrocardia, right-sided hookup of the electrodes is usually necessary for proper interpretation of the ECG. When this was done in our patient, the ECG showed a normal cardiac axis, a negative QRS complex in lead aVR, a positive P wave and other complexes in lead I, and normal R-wave progression in the precordial leads—findings suggestive of dextrocardia (Figure 2).

Chest radiography showed a right-sided cardiac silhouette (Figure 3), and computed tomography of the abdomen (Figure 4) revealed the liver positioned on the left side and the spleen on the right, confirming the diagnosis of situs inversus totalis. The ECG showed dextrocardia, but no other abnormalities. The patient eventually underwent coronary angiography, which showed nonobstructive coronary artery disease.

DEXTROCARDIA, OTHER CONGENITAL CARDIOVASCULAR MALFORMATIONS

Dextrocardia was first described in early 17th century.¹ Situs solitus is the normal position of the heart and viscera, whereas situs inversus is a mirror-image anatomic arrangement of the organs. Situs inversus with dextrocardia, also called situs inversus totalis, is a rare condition (with a prevalence of 1 in 8,000) in which the heart and descending aorta are on the right and the thoracic and abdominal viscera are usually mirror images of the normal morphology.^1,3,4 A mirror-image sinus node lies at the junction of the left superior vena cava and the left-sided (morphologic right) atrium.¹ People with situs inversus with dextrocardia are usually asymptomatic and have a normal life expectancy.^1,2 Situs inversus with levocardia is a rare condition in which the heart is in the normal position but the viscera are in the dextro-position. This anomaly has a prevalence of 1 in 22,000.⁵

Atrial situs almost always corresponds to visceral situs. However, when the alignment of the atria and viscera is inconsistent and situs cannot be determined clearly because of the malpositioning of organs, the condition is called “situs ambiguous.” This is very rare, with a prevalence of 1 in 40,000.⁶

Risk factors

The cause of congenital cardiovascular malformations such as these is not known, but risk factors include positive family history, maternal diabetes, and cocaine use in the first trimester.⁷

Negative complexes in lead I, positive complexes in aVR, and slight reversal of R-wave progression indicate dextrocardia

The prevalence of congenital heart disease in patients with situs inversus with dextrocardia is low and ranges from 2% to 5%. This is in contrast to situs solitus with dextrocardia (isolated dextrocardia), which is almost always associated with cardiovascular anomalies.^2,4 Kartagener syndrome—the triad of situs inversus, sinusitis, and bronchiectasis—occurs in 25% of people with situs inversus with dextrocardia.⁴ Situs inversus with levocardia is also frequently associated with cardiac anomalies.⁵

The major features of dextrocardia on ECG are:

• Negative P wave, QRS complex, and T wave in lead I
• Positive QRS complex in aVR
• Right-axis deviation
• Reversal of R-wave progression in the precordial leads.

Ventricular activation and repolarization are reversed, resulting in a negative QRS complex and an inverted T wave in lead I. The absence of R-wave progression in the precordial leads helps differentiate mirror-image dextrocardia from erroneously reversed limb-electrode placement, which shows normal R-wave progression from V₁ to V₆ while showing similar features to those seen in dextrocardia in the limb leads.² In right-sided hookup, the limb electrodes are reversed, and the chest electrodes are recorded from the right precordium.

CORONARY INTERVENTIONS REQUIRE SPECIAL CONSIDERATION

In patients with dextrocardia, coronary interventions can be challenging because of the mirror-image position of the coronary ostia and the aortic arch.⁸ These patients also need careful imaging, consideration of other associated congenital cardiac abnormalities, and detailed planning before cardiac surgery, including coronary artery bypass grafting.⁹

Patients with dextrocardia may present with cardiac symptoms localized to the right side of the body and have confusing clinical and diagnostic findings. Keeping dextrocardia and other such anomalies in mind can prevent delay in appropriately directed interventions. In a patient such as ours, the heart on the right side of the chest may indeed be “right.” Still, diagnostic tests to look for disorders encountered with dextrocardia may be necessary.

The article by Dr. Alison Colantino et al in this issue on when to resume anticoagulation after a hemorrhagic event is relevant to the discussion of clinical decision-making that I started here last month. My thoughts then were prompted by a commentary by Dr. Vinay Prasad on incorporating appropriate study outcomes in clinical decision-making (Cleve Clin J Med 2015; 82:146–150).

In the clinic or hospital, we make many decisions without being able to cite specific applicable clinical studies. I base some decisions on my overall impression from the literature (including formal trials), some on general recall of a specific study (which I hopefully either find time to review afterwards, or ask one of our trainees to read and discuss with our team the next day), and others on my knowledge of clinical guidelines or clearly accepted practice. Most clinical decisions are made without any directly applicable data from available clinical studies. This is the “art” of medicine.

Should this art make its way into our clinical journals, and if so, how extensively, and how should it be framed? It is relatively easy when we are talking about the science of clinical practice. Journals receive the (hopefully complete) data, get peer reviews to improve the paper, and publish it with the authors’ opinions presented in the discussion section. Then, dialogue ensues in the published literature, in educational lectures, and in blogs posted on the Internet. But where does the art go? Does it belong in our traditionally conservative textbooks or newer go-to online resources, which emphasize the need for authors to provide updated specific references for their treatment recommendations? We believe that after our best efforts at peer review it is appropriate to publish it in the CCJM because hopefully it can provide additional perspective on how we deliver care to our patients.

In the arena of new therapies, regulatory approval requires hard data documenting efficacy and safety. And that often leaves me without approved or sometimes even “proven effective” therapies to use when treating patients with relatively uncommon conditions, such as refractory uveitis with threatened visual loss or idiopathic aortitis. Yet I still need to treat the patient.

Another aspect of the art of medicine relates to how best to use therapies that have been approved. We have had antibiotics for many decades, but data are still being generated on how long to treat specific infections, and relatively few scenarios have been studied. Huge media coverage and (mostly) appropriate hype were generated over the need to treat patients with postmenopausal osteoporosis as diagnosed by dual-energy x-ray absorptiometry. But even after evidence emerged regarding atypical femoral fractures in patients receiving long-term bisphosphonate therapy, the question of how long treatment should continue remains more art than science.

The field of anticoagulation has seen many recent advances. We have new heparins, new target-specific oral anticoagulants, and a lot of new science on the natural history of some thrombotic disorders and the efficacy and safety of these new agents. But how long to treat specific thrombotic conditions, which agent to use, how intense the anticoagulation needs to be, when to use bridging therapy, and, as discussed by Dr. Colantino et al, when to resume anticoagulation after a hemorrhagic event mostly remain part of the art of medicine.

I highlight the Colantino paper in the context of both clinical and editorial decision-making because it is an example of experienced clinical authors discussing their solutions to thorny clinical scenarios we often face with inadequate data. While some journals avoid this approach, we embrace the opportunity to provide thoughtful expert opinions to our readers. We push authors from the start of the editorial process and through aggressive peer review to provide evidence to support their practice recommendations when appropriate. But we also encourage them to make recommendations and describe their own decision-making process in situations that may not be fully described in the literature.

Most of our readers do not have ready access to consultants who have had years of experience within multidisciplinary teams at referral institutions regularly managing patients with permutations of these complex clinical problems. Though generic consultation advice must be evaluated within the context of the specific patient, we hope that by framing the clinical issues with relevant clinical science the opinions of experienced authors will be of use in guiding your (and my) approach to similar clinical scenarios.

If you think we are not striking the right balance between the science and the art of medical practice, please let me know.

The article by Dr. Alison Colantino et al in this issue on when to resume anticoagulation after a hemorrhagic event is relevant to the discussion of clinical decision-making that I started here last month. My thoughts then were prompted by a commentary by Dr. Vinay Prasad on incorporating appropriate study outcomes in clinical decision-making (Cleve Clin J Med 2015; 82:146–150).

In the clinic or hospital, we make many decisions without being able to cite specific applicable clinical studies. I base some decisions on my overall impression from the literature (including formal trials), some on general recall of a specific study (which I hopefully either find time to review afterwards, or ask one of our trainees to read and discuss with our team the next day), and others on my knowledge of clinical guidelines or clearly accepted practice. Most clinical decisions are made without any directly applicable data from available clinical studies. This is the “art” of medicine.

Should this art make its way into our clinical journals, and if so, how extensively, and how should it be framed? It is relatively easy when we are talking about the science of clinical practice. Journals receive the (hopefully complete) data, get peer reviews to improve the paper, and publish it with the authors’ opinions presented in the discussion section. Then, dialogue ensues in the published literature, in educational lectures, and in blogs posted on the Internet. But where does the art go? Does it belong in our traditionally conservative textbooks or newer go-to online resources, which emphasize the need for authors to provide updated specific references for their treatment recommendations? We believe that after our best efforts at peer review it is appropriate to publish it in the CCJM because hopefully it can provide additional perspective on how we deliver care to our patients.

In the arena of new therapies, regulatory approval requires hard data documenting efficacy and safety. And that often leaves me without approved or sometimes even “proven effective” therapies to use when treating patients with relatively uncommon conditions, such as refractory uveitis with threatened visual loss or idiopathic aortitis. Yet I still need to treat the patient.

Another aspect of the art of medicine relates to how best to use therapies that have been approved. We have had antibiotics for many decades, but data are still being generated on how long to treat specific infections, and relatively few scenarios have been studied. Huge media coverage and (mostly) appropriate hype were generated over the need to treat patients with postmenopausal osteoporosis as diagnosed by dual-energy x-ray absorptiometry. But even after evidence emerged regarding atypical femoral fractures in patients receiving long-term bisphosphonate therapy, the question of how long treatment should continue remains more art than science.

The field of anticoagulation has seen many recent advances. We have new heparins, new target-specific oral anticoagulants, and a lot of new science on the natural history of some thrombotic disorders and the efficacy and safety of these new agents. But how long to treat specific thrombotic conditions, which agent to use, how intense the anticoagulation needs to be, when to use bridging therapy, and, as discussed by Dr. Colantino et al, when to resume anticoagulation after a hemorrhagic event mostly remain part of the art of medicine.

I highlight the Colantino paper in the context of both clinical and editorial decision-making because it is an example of experienced clinical authors discussing their solutions to thorny clinical scenarios we often face with inadequate data. While some journals avoid this approach, we embrace the opportunity to provide thoughtful expert opinions to our readers. We push authors from the start of the editorial process and through aggressive peer review to provide evidence to support their practice recommendations when appropriate. But we also encourage them to make recommendations and describe their own decision-making process in situations that may not be fully described in the literature.

Most of our readers do not have ready access to consultants who have had years of experience within multidisciplinary teams at referral institutions regularly managing patients with permutations of these complex clinical problems. Though generic consultation advice must be evaluated within the context of the specific patient, we hope that by framing the clinical issues with relevant clinical science the opinions of experienced authors will be of use in guiding your (and my) approach to similar clinical scenarios.

If you think we are not striking the right balance between the science and the art of medical practice, please let me know.

The article by Dr. Alison Colantino et al in this issue on when to resume anticoagulation after a hemorrhagic event is relevant to the discussion of clinical decision-making that I started here last month. My thoughts then were prompted by a commentary by Dr. Vinay Prasad on incorporating appropriate study outcomes in clinical decision-making (Cleve Clin J Med 2015; 82:146–150).

In the clinic or hospital, we make many decisions without being able to cite specific applicable clinical studies. I base some decisions on my overall impression from the literature (including formal trials), some on general recall of a specific study (which I hopefully either find time to review afterwards, or ask one of our trainees to read and discuss with our team the next day), and others on my knowledge of clinical guidelines or clearly accepted practice. Most clinical decisions are made without any directly applicable data from available clinical studies. This is the “art” of medicine.

Should this art make its way into our clinical journals, and if so, how extensively, and how should it be framed? It is relatively easy when we are talking about the science of clinical practice. Journals receive the (hopefully complete) data, get peer reviews to improve the paper, and publish it with the authors’ opinions presented in the discussion section. Then, dialogue ensues in the published literature, in educational lectures, and in blogs posted on the Internet. But where does the art go? Does it belong in our traditionally conservative textbooks or newer go-to online resources, which emphasize the need for authors to provide updated specific references for their treatment recommendations? We believe that after our best efforts at peer review it is appropriate to publish it in the CCJM because hopefully it can provide additional perspective on how we deliver care to our patients.

In the arena of new therapies, regulatory approval requires hard data documenting efficacy and safety. And that often leaves me without approved or sometimes even “proven effective” therapies to use when treating patients with relatively uncommon conditions, such as refractory uveitis with threatened visual loss or idiopathic aortitis. Yet I still need to treat the patient.

Another aspect of the art of medicine relates to how best to use therapies that have been approved. We have had antibiotics for many decades, but data are still being generated on how long to treat specific infections, and relatively few scenarios have been studied. Huge media coverage and (mostly) appropriate hype were generated over the need to treat patients with postmenopausal osteoporosis as diagnosed by dual-energy x-ray absorptiometry. But even after evidence emerged regarding atypical femoral fractures in patients receiving long-term bisphosphonate therapy, the question of how long treatment should continue remains more art than science.

The field of anticoagulation has seen many recent advances. We have new heparins, new target-specific oral anticoagulants, and a lot of new science on the natural history of some thrombotic disorders and the efficacy and safety of these new agents. But how long to treat specific thrombotic conditions, which agent to use, how intense the anticoagulation needs to be, when to use bridging therapy, and, as discussed by Dr. Colantino et al, when to resume anticoagulation after a hemorrhagic event mostly remain part of the art of medicine.

I highlight the Colantino paper in the context of both clinical and editorial decision-making because it is an example of experienced clinical authors discussing their solutions to thorny clinical scenarios we often face with inadequate data. While some journals avoid this approach, we embrace the opportunity to provide thoughtful expert opinions to our readers. We push authors from the start of the editorial process and through aggressive peer review to provide evidence to support their practice recommendations when appropriate. But we also encourage them to make recommendations and describe their own decision-making process in situations that may not be fully described in the literature.

Most of our readers do not have ready access to consultants who have had years of experience within multidisciplinary teams at referral institutions regularly managing patients with permutations of these complex clinical problems. Though generic consultation advice must be evaluated within the context of the specific patient, we hope that by framing the clinical issues with relevant clinical science the opinions of experienced authors will be of use in guiding your (and my) approach to similar clinical scenarios.

If you think we are not striking the right balance between the science and the art of medical practice, please let me know.

If a patient receiving anticoagulant therapy suffers a bleeding event, the patient and physician must decide whether and how soon to restart the therapy, and with what agent.

Foremost on our minds tends to be the risk of another hemorrhage. Subtler to appreciate immediately after an event is the continued risk of thrombosis, often from the same medical condition that prompted anticoagulation therapy in the first place (Table 1).

Complicating the decision, there may be a rebound effect: some thrombotic events such as pulmonary embolism and atrial fibrillation-related stroke may be more likely to occur in the first weeks after stopping warfarin than during similar intervals in patients who have not been taking it.^1–3 The same thing may happen with the newer, target-specific oral anticoagulants.^4–6

Although we have evidence-based guidelines for initiating and managing anticoagulant therapy, ample data on adverse events, and protocols for reversing anticoagulation if bleeding occurs, we do not have clear guidelines on restarting anticoagulation after a hemorrhagic event.

In this article, we outline a practical framework for approaching this clinical dilemma. Used in conjunction with consideration of a patient’s values and preferences as well as input from experts, this framework can help clinicians guide their patients through this challenging clinical decision. It consists of five questions:

• Why is the patient on anticoagulation, and what is the risk of thromboembolism without it?
• What was the clinical impact of the hemorrhage, and what is the risk of rebleeding if anticoagulation is resumed?
• What additional patient factors should be taken into consideration?
• How long should we wait before restarting anticoagulation?
• Would a newer drug be a better choice?

BLEEDING OCCURS IN 2% TO 3% OF PATIENTS PER YEAR

Most of our information on anticoagulation is about vitamin K antagonists—principally warfarin, in use since the 1950s. Among patients taking warfarin outside of clinical trials, the risk of major bleeding is estimated at 2% to 3% per year.⁷

However, the target-specific oral anticoagulants rivaroxaban (Xarelto), apixaban (Eliquis),  dabigatran (Pradaxa) and edoxaban (Savaysa) are being used more and more, and we include them in our discussion insofar as we have information on them. The rates of bleeding with these new drugs in clinical trials have been comparable to or lower than those with warfarin.⁸ Postmarketing surveillance is under way.

WHY IS THE PATIENT ON ANTICOAGULATION? WHAT IS THE RISK WITHOUT IT?

Common, evidence-based indications for anticoagulation are to prevent complications in patients with venous thromboembolism and to prevent stroke in patients with atrial fibrillation or a mechanical heart valve. Other uses, such as in heart failure and its sequelae, pulmonary hypertension, and splanchnic or hepatic vein thrombosis, have less robust evidence to support them.

When anticoagulation-related bleeding occurs, it is essential to review why the patient is taking the drug and the risk of thromboembolism without it. Some indications pose a higher risk of thromboembolism than others and so argue more strongly for continuing the treatment.

Douketis et al⁹ developed a risk-stratification scheme for perioperative thromboembolism. We have modified it by adding the CHA₂DS₂-VASc score (Table 2),^9–11 and believe it can be used more widely.

High-risk indications

Conditions that pose a high risk of thrombosis almost always require restarting anticoagulation. Here, the most appropriate question nearly always is not if anticoagulation should be restarted, but when. Examples:

• A mechanical mitral valve
• Antiphospholipid antibody syndrome with recurrent thromboembolic events.

Lower-risk indications

Lower-risk indications allow more leeway in determining if anticoagulation should be resumed. The most straightforward cases fall well within established guidelines. Examples:

• Atrial fibrillation and a CHA₂DS₂-VASc score of 1. The 2014 guidelines from the American College of Cardiology, American Heart Association, and Heart Rhythm Society¹⁰ suggest that patients with nonvalvular atrial fibrillation and a CHA₂DS₂-VASc score of 1 have three options: an oral anticoagulant, aspirin, and no antithrombotic therapy. If such a patient on anticoagulant therapy subsequently experiences a major gastrointestinal hemorrhage requiring transfusion and intensive care and no definitively treatable source of bleeding is found on endoscopy, one can argue that the risks of continued anticoagulation (recurrent bleeding) now exceed the benefits and that the patient would be better served by aspirin or even no antithrombotic therapy.

• After 6 months of anticoagulation for unprovoked deep vein thrombosis. Several studies showed that aspirin reduced the risk of recurrent venous thromboembolism in patients who completed an initial 6-month course of anticoagulation.^12–15 Though these studies did not specifically compare aspirin with warfarin or target-specific oral anticoagulants in preventing recurrent venous thromboembolism after a hemorrhage, it is reasonable to extrapolate their results to this situation.

If the risk of recurrent hemorrhage on anticoagulation is considered to be too great, then aspirin is an alternative to no anticoagulation, as it reduces the risk of recurrent venous thromboembolism.¹⁶ However, we advise caution if the bleeding lesion may be specifically exacerbated by aspirin, particularly upper gastrointestinal ulcers.

Moderate-risk indications

• After a partial course of anticoagulation for provoked venous thromboembolism. Suppose a patient in the 10th week of a planned 12-week course of anticoagulation for a surgically provoked, first deep vein thrombosis presents with abdominal pain and is found to have a retroperitoneal hematoma. In light of the risk of recurrent bleeding vs the benefit of resuming anticoagulation for the limited remaining period, her 12-week treatment course can reasonably be shortened to 10 weeks.

The risk of recurrent venous thromboembolism when a patient is off anticoagulation decreases with time from the initial event. The highest risk, estimated at 0.3% to 1.3% per day, is in the first 4 weeks, falling to 0.03% to 0.2% per day in weeks 5 through 12, and 0.05% per day thereafter.^17–20

The risk of recurrent venous thromboembolism is greatest immediately after the event and decreases over time

Additionally, a pooled analysis of seven randomized trials suggests that patients with isolated, distal deep vein thrombosis provoked by a temporary risk factor did not have a high risk of recurrence after being treated for 4 to 6 weeks.²¹ These analyses are based on vitamin K antagonists, though it seems reasonable to extrapolate this information to the target-specific oral anticoagulants.

More challenging are situations in which the evidence supporting the initial or continued need for anticoagulation is less robust, such as in heart failure, pulmonary hypertension, or splanchnic and hepatic vein thrombosis. In these cases, the lack of strong evidence supporting the use of anticoagulation should make us hesitate to resume it after bleeding.

WHAT WAS THE CLINICAL IMPACT? WHAT IS THE RISK OF REBLEEDING?

Different groups have defined major and minor bleeding in different ways.^22,23 Several have proposed criteria to standardize how bleeding events (on warfarin and otherwise) are classified,^23–25 but the definitions differ.

Specifically, all agree that a “major” bleeding event is one that is fatal, involves bleeding into a major organ, or leads to a substantial decline in hemoglobin level. However, the Thrombolysis in Myocardial Infarction trials use a decline of more than 5 g/dL in their definition,^23,25 while the International Society on Thrombosis and Haemostasis uses 2 g/dL.²⁴

Here, we review the clinical impact of the most common sources of anticoagulation-related hemorrhage—gastrointestinal, soft tissue, and urinary tract²⁶—as well as intracerebral hemorrhage, a less common but more uniformly devastating event.²⁷

Clinical impact of gastrointestinal hemorrhage

Each year, about 4.5% of patients taking warfarin have a gastrointestinal hemorrhage, though not all of these events are major.²⁸ Evolving data suggest that the newer agents (particularly dabigatran, rivaroxaban, and edoxaban) pose a higher risk of gastrointestinal bleeding than warfarin.²⁹ Patients may need plasma and blood transfusions and intravenous phytonadione, all of which carry risks, albeit small.

Frequently, endoscopy is needed to find the source of bleeding and to control it. If this does not work, angiographic intervention to infuse vasoconstrictors or embolic coils into the culprit artery may be required, and some patients need surgery. Each intervention carries its own risk.

Clinical impact of soft-tissue hemorrhage

Soft-tissue hemorrhage accounts for more than 20% of warfarin-related bleeding events²⁶; as yet, we know of no data on the rate with the new drugs. Soft-tissue hemorrhage is often localized to the large muscles of the retroperitoneum and legs. Though retroperitoneal hemorrhage accounts for a relatively small portion of soft-tissue hemorrhages, it is associated with high rates of morbidity and death and will therefore be our focus.²⁶

Some indications for anticoagulation pose a higher risk of thromboembolism than others

Much of the clinical impact of retroperitoneal hemorrhage is from a mass effect that causes abdominal compartment syndrome, hydroureter, ileus, abscess formation, and acute and chronic pain. At least 20% of cases are associated with femoral neuropathy. It can also lead to deep vein thrombosis from venous compression, coupled with hypercoagulability in response to bleeding. Brisk bleeding can lead to shock and death, and the mortality rate in retroperitoneal hemorrhage is estimated at 20% or higher.³⁰

In many cases, the retroperitoneal hemorrhage will self-tamponade and the blood will be reabsorbed once the bleeding has stopped, but uncontrolled bleeding may require surgical or angiographic intervention.³⁰

Clinical impact of urinary tract hemorrhage

Gross or microscopic hematuria can be found in an estimated 2% to 24% of patients taking warfarin^31–33; data are lacking for the target-specific oral anticoagulants. Interventions required to manage urinary tract bleeding include bladder irrigation and, less often, transfusion.³¹ Since a significant number of cases of hematuria are due to neoplastic disease,³² a diagnostic workup with radiographic imaging of the upper tract and cystoscopy of the lower tract is usually required.³¹ While life-threatening hemorrhage is uncommon, complications such as transient urinary obstruction from clots may occur.

Clinical impact of intracranial hemorrhage

Intracranial hemorrhage is the most feared and deadly of the bleeding complications of anticoagulation. The incidence in patients on warfarin is estimated at 2% to 3% per year, which is markedly higher than the estimated incidence of 25 per 100,000 person-years in the general population.³⁴ Emerging data indicate that the newer drugs are also associated with a risk of intracranial hemorrhage, though the risk is about half that with vitamin K antagonists.³⁵ Intracranial hemorrhage leads to death or disability in 76% of cases, compared with 3% of cases of bleeding from the gastrointestinal or urinary tract.²⁷

Regardless of the source of bleeding, hospitalization is likely to be required and may be  prolonged, with attendant risks of nosocomial harms such as infection.

Risk of rebleeding

Given the scope and severity of anticoagulation-related bleeding, there is strong interest in predicting and preventing it. By some estimates, the incidence of recurrent bleeding after resuming vitamin K antagonists is 8% to 13%.²² Although there are several indices for predicting the risk of major bleeding when starting anticoagulation, there are currently no validated tools to estimate a patient’s risk of rebleeding.³⁶

The patient factor that most consistently predicts major bleeding is a history of bleeding, particularly from the gastrointestinal tract. Finding and controlling the source of bleeding is important.^26,37 For example, a patient with gross hematuria who is found on cystoscopy to have a urothelial papilloma is unlikely to have rebleeding if the tumor is successfully resected and serial follow-up shows no regrowth. In contrast, consider a patient with a major gastrointestinal hemorrhage, the source of which remains elusive after upper, lower, and capsule endoscopy or, alternatively, is suspected to be from one of multiple angiodysplastic lesions. Without definitive source management, this patient faces a high risk of rebleeding.

With or without anticoagulation, after a first intracranial hemorrhage the risk of another one is estimated at 2% to 4% per year.³⁴ An observational study found a recurrence rate of 7.5% when vitamin K antagonist therapy was started after an intracranial hemorrhage (though not all patients were on a vitamin K antagonist at the time of the first hemorrhage).³⁸

Evolving data suggest the newer oral agents pose a higher risk of GI bleeding

Patients with lobar hemorrhage and those with suspected cerebral amyloid angiopathy may be at particularly high risk if anticoagulation is resumed. Conversely, initial events attributed to uncontrolled hypertension that subsequently can be well controlled may portend a lower risk of rebleeding.³⁴ For other types of intracranial hemorrhage, recurrence rates can be even higher. Irrespective of anticoagulation, one prospective study estimated the crude annual rebleeding rate with untreated arteriovenous malformations to be 7%.³⁹ In chronic subdural hematoma, the recurrence rate after initial drainage has been estimated at 9.2% to 26.5%, with use of anticoagulants (in this case, vitamin K antagonists) being an independent predictor of recurrence.⁴⁰

WHAT OTHER PATIENT FACTORS NEED CONSIDERATION?

Target INR on warfarin

An important factor influencing the risk of bleeding with warfarin is the intensity of this therapy.³⁷ A meta-analysis⁴¹ found that the risks of major hemorrhage and thromboembolism are minimized if the goal international normalized ratio (INR) is 2.0 to 3.0. When considering resuming anticoagulation after bleeding, make sure the therapeutic target is appropriate.³⁷

Table 3 summarizes recommended therapeutic ranges for frequently encountered indications for warfarin.^36,42,43

INR at time of the event and challenges in controlling it

The decision to resume anticoagulation in patients who bled while using warfarin must take into account the actual INR at the time of the event.

For example, consider a patient whose INR values are consistently in the therapeutic range.  While on vacation, he receives ciprofloxacin for acute prostatitis from an urgent care team, and no adjustment to INR monitoring or warfarin dose is made. Several days later, he presents with lower gastrointestinal bleeding. His INR is 8, and colonoscopy reveals diverticulosis with a bleeding vessel, responsive to endoscopic therapy. After controlling the source of bleeding and reinforcing the need to always review new medications for potential interactions with anticoagulation, it is reasonable to expect that he once again will be able to keep his INR in the therapeutic range.

A patient on anticoagulation for the same indication but who has a history of repeated supratherapeutic levels, poor adherence, or poor access to INR monitoring poses very different concerns about resuming anticoagulation (as well as which agent to use, as we discuss below).

Of note, a high INR alone does not explain bleeding. It is estimated that a workup for gastrointestinal bleeding and gross hematuria uncovers previously undetected lesions in approximately one-third of cases involving warfarin.²⁶ A similar malignancy-unmasking effect is now recognized in patients using the target-specific oral agents who experience gastrointestinal bleeding.⁴⁴ Accordingly, we recommend a comprehensive source evaluation for any anticoagulation-related hemorrhage.

Comorbid conditions

Comorbid conditions associated with bleeding include cancer, end-stage renal disease, liver disease, arterial hypertension, prior stroke, and alcohol abuse.^37,45 Gait instability, regardless of cause, may also increase the risk of trauma-related hemorrhage, but some have estimated that a patient would need to fall multiple times per week to contraindicate anticoagulation on the basis of falls alone.⁴⁶

Concurrent medications

Concomitant therapies, including antiplatelet drugs and nonsteroidal anti-inflammatory drugs, increase bleeding risk.^47,48 Aspirin and the nonsteroidals, in addition to having antiplatelet effects, also can cause gastric erosion.³⁷ In evaluating whether and when to restart anticoagulation, it is advisable to review the role that concomitant therapies may have had in the index bleeding event and to evaluate the risks and benefits of these other agents.

The factor that most consistently predicts major bleeding is a history of bleeding, particularly gastrointestinal bleeding

Additionally, warfarin has many interactions. Although the newer drugs are lauded for having fewer interactions, they are not completely free of them, and the potential for interactions must always be reviewed.⁴⁹ Further, unlike warfarin therapy, therapy with the newer agents is not routinely monitored with laboratory tests, so toxicity (or underdosing) may not be recognized until an adverse clinical event occurs. Ultimately, it may be safer to resume anticoagulation after a contributing drug can be safely discontinued.

Advanced age

The influence that the patient’s age should have on the decision to restart anticoagulation is unclear. Although the risk of intracranial hemorrhage increases with age, particularly after age 80, limited data exist in this population, particularly with regard to rebleeding. Further, age is a major risk factor for most thrombotic events, including venous thromboembolism and stroke from atrial fibrillation, so although the risks of anticoagulation may be higher, the benefits may also be higher than in younger patients.^37,46 We discourage using age alone as a reason to withhold anticoagulation after a hemorrhage.

HOW LONG SHOULD WE WAIT TO RESTART ANTICOAGULATION?

We lack conclusive data on how long to wait to restart anticoagulation after an anticoagulation-associated hemorrhage.

The decision is complicated by evidence suggesting a rebound effect, with an increased risk of pulmonary embolism and atrial fibrillation-related stroke during the first 90 days of interruption of therapy with warfarin as well as with target-specific oral anticoagulants.^3–8 In anticoagulation-associated retroperitoneal bleeding, there is increased risk of deep vein thrombosis from compression, even if venous thromboembolism was not the initial indication for anticoagulation.³⁰

In patients with intracranial hemorrhage, evidence suggests that the intracranial hemorrhage itself increases the risk of arterial and venous thromboembolic events. Irrespective of whether a patient was previously on anticoagulation, the risk of arterial and venous thromboembolic events approaches 7% during the initial intracranial hemorrhage-related hospitalization and 9% during the first 90 days.^34,50,51

To date, the only information we have about when to resume anticoagulation comes from patients taking vitamin K antagonists.

Timing after gastrointestinal bleeding

Small case series suggest that in the first 2 months after warfarin-associated gastrointestinal bleeding, there is substantial risk of rebleeding when anticoagulation is resumed—and of thrombosis when it is not.^52,53 Two retrospective cohort studies may provide some guidance in this dilemma.^28,54

A workup for GI bleeding and gross hematuria uncovers previously undetected lesions in about one-third of cases involving warfarin

Witt et al²⁸ followed 442 patients who presented with gastrointestinal bleeding from any site during warfarin therapy for varied indications for up to 90 days after the index bleeding event. The risk of death was three times lower in patients who restarted warfarin than in those who did not, and their rate of thrombotic events was 10 times lower. The risk of recurrent gastrointestinal bleeding was statistically insignificant, and there were no fatal bleeding events. Anticoagulant therapy was generally resumed within 1 week of the bleeding event, at a median of 4 days.^28,55

Qureshi et al⁵⁴ performed a retrospective cohort study of 1,329 patients with  nonvalvular atrial fibrillation who had experienced a gastrointestinal hemorrhage while taking warfarin. They found that resuming warfarin after 7 days was not associated with a higher risk of recurrent gastrointestinal bleeding and that the rates of death and thromboembolism were lower than in patients who resumed warfarin after 30 days. On the other hand, the risk of recurrent gastrointestinal bleeding was significantly greater if therapy was resumed within the first week.

In view of these studies, we believe that most patients should resume anticoagulation after 4 to 7 days of interruption after gastrointestinal bleeding.⁵⁵

Timing after soft-tissue hemorrhage

The literature on resuming anticoagulation after soft-tissue hemorrhage is sparse. A retrospective study⁵² looked at this question in patients with spontaneous rectal sheath hematoma who had been receiving  antiplatelet drugs, intravenous heparin, vitamin K antagonists, or a combination of these, but not target-specific agents. More than half of the patients were on vitamin K antagonists at the time of hemorrhage. Analysis suggested that when benefits of resuming anticoagulation are believed to outweigh risks, it is reasonable to resume anticoagulation 4 days after the index event.⁵⁶

Timing after intracranial hemorrhage

Anticoagulation should not be considered within the first 24 hours after intracranial hemorrhage, as over 70% of patients develop some amount of hematoma expansion during this time.^34,57 The period thereafter poses a challenge, as the risk of hematoma expansion decreases while the risk of arterial and venous thromboembolism is ongoing and cumulative.⁵⁰

Perhaps surprisingly, national guidelines suggest starting prophylactic-dosed anticoagulation early in all intracranial hemorrhage patients, including those not previously on warfarin.^58,59 In a randomized trial, Boeer et al⁶⁰ concluded that starting low-dose subcutaneous heparin the day after an intracranial hemorrhage decreased the risk of thromboembolism without increasing the risk of rebleeding.⁶⁰ Dickmann et al⁶¹ similarly concluded that there was no increased risk of rebleeding with early prophylactic-dosed subcutaneous heparin.⁶¹ Optimal mechanical thromboprophylaxis, including graduated compression stockings and intermittent pneumatic compression stockings, is also encouraged.³⁴

We discourage using age alone as a reason to withhold anticoagulation after a hemorrhage

Expert opinion remains divided on when and if anticoagulants should be resumed.^34,62 The American Heart Association suggests that in nonvalvular atrial fibrillation, long-term anticoagulation should be avoided after spontaneous lobar hemorrhage; antiplatelet agents can be considered instead.⁵⁸ In nonlobar hemorrhage, the American Heart Association suggests that anticoagulation be considered, depending on strength of indication, 7 to 10 days after the onset.⁵⁸ The European Stroke Initiative suggests patients with strong indications for anticoagulation be restarted on warfarin 10 to 14 days after the event, depending on the risk of thromboembolism and recurrent intracranial hemorrhage.⁵⁹ Others suggest delaying resumption to 10 to 30 weeks after an index intracranial hemorrhage.⁶³

Overall, in the immediate acute period of intracranial hemorrhage, most patients will likely benefit from acute reversal of anticoagulation, followed by institution of prophylactic-dose anticoagulation after the first 24 hours. Going forward, patients who remain at higher risk of a recurrence of anticoagulant-related intracranial hemorrhage (such as those with lobar hemorrhage, suspected cerebral amyloid angiopathy, and other high-risk factors) than of thromboembolic events may be best managed without anticoagulants. Alternatively, patients with deep hemispheric intracranial hemorrhage, hypertension that can be well controlled, and a high risk of serious thromboembolism may experience net benefit from restarting anticoagulation.³⁴

We recommend considering restarting anticoagulation 7 days after the onset of intracranial hemorrhage in patients at high risk of thromboembolism and after at least 14 days for patients at lower risk (Table 2). Discussions with neurologic and neurosurgical consultants should also inform this timing decision.

WOULD A NEWER DRUG BE A BETTER CHOICE?

The emergence of target-specific oral anticoagulants, including factor Xa inhibitors such as rivaroxaban, apixaban, and edoxaban and the direct thrombin inhibitor dabigatran etexilate, presents further challenges in managing anticoagulation after hemorrhage. Table 4 summarizes the current FDA-approved indications.^64–67

These newer agents are attractive because, compared with warfarin, they have wider therapeutic windows, faster onset and offset of action, and fewer drug and food interactions.⁶⁸ A meta-analysis of data available to date suggests that the new drugs, compared with warfarin, show a favorable risk-benefit profile with reductions in stroke, intracranial hemorrhage, and mortality with similar overall major bleeding rates, except for a possible increase in gastrointestinal bleeding.⁶⁸

However, when managing anticoagulation after a bleeding event, the newer agents are challenging for two reasons: they may be associated with a higher incidence of gastrointestinal bleeding than warfarin, and they lack the typical reversal agents that can be used to manage an acute bleeding event.^68,69

In individual studies comparing warfarin with dabigatran,⁷⁰ rivaroxaban,⁷¹ apixaban,⁷² or edoxaban⁷³ for stroke prevention in patients with atrial fibrillation, there was no significant difference in the rate of major bleeding between dabigatran in its higher dose (150 mg twice a day) or rivaroxaban compared with warfarin.^70,71 The risk of major bleeding was actually lower with apixaban⁷² and edoxaban.⁷³

In regard to specific types of major bleeding, the rate of intracranial hemorrhage was significantly lower with dabigatran, rivaroxaban, apixaban, and edoxaban than with warfarin.^35,68–73 Some have proposed that since the brain is high in tissue factor, inhibition of tissue factor-factor VIIa complexes by vitamin K antagonists leaves the brain vulnerable to hemorrhage. Others suggest that the targeted mechanism of target-specific agents, as opposed to the multiple pathways in both the intrinsic and extrinsic coagulation cascade that vitamin K antagonists affect, may explain this difference.^35,74,75

However, some studies suggest that rivaroxaban and the higher doses of dabigatran and edoxaban are associated with higher rates of major gastrointestinal bleeding compared with warfarin.^69–71,76 But apixaban demonstrated no significant difference in gastrointestinal bleeding, and instead demonstrated rates of gastrointestinal bleeding comparable to that with aspirin for stroke prevention in atrial fibrillation.⁷²

The new oral anticoagulants lack antidotes or reversal agents such as phytonadione and fresh-frozen plasma that are available to manage warfarin-associated bleeding events. Other proposed reversal options for the new agents include activated charcoal (if the drugs were taken recently enough to remain in the gastrointestinal tract) and concentrated clotting factor product, though research is ongoing in regards to the most appropriate use in clinical practice.^37,69 Unlike rivaroxaban and apixaban, dabigatran has low plasma protein binding and is dialyzable, which provides another strategy in managing dabigatran-related bleeding.⁶⁹

We believe most patients should resume anticoagulation after 4 to 7 days of interruption after GI bleeding

Of note, the above bleeding risk calculations relate to the first anticoagulant-related bleeding event, though presumably the same risk comparison across agents may be applicable to rebleeding events. Given the data above, when anticoagulation is to be resumed after an intracranial hemorrhage, the risk of rebleeding, particularly in the form of recurrent intracranial hemorrhage, may be lower if a target-specific oral anticoagulant is used.⁷⁵ Similarly, when anticoagulation is to be resumed after a gastrointestinal bleeding event, reinitiation with warfarin or apixaban therapy may present the lowest risk of recurrent gastrointestinal rebleeding. In other sources of bleeding, such as retroperitoneal bleeding, we suggest consideration of transitioning to warfarin, given the availability of reversal agents in the event of recurrent bleeding.

Other important drug-specific factors that must be noted when selecting an agent with which to resume anticoagulation after a hemorrhage include the following:

• In patients with significant renal impairment, the choice of agent will be limited to a vitamin K antagonist.⁷⁷
• A meta-analysis of randomized clinical trials suggests that in the elderly (age 75 and older) target-specific oral anticoagulants did not cause excess bleeding and were associated with at least equal efficacy compared with vitamin K antagonists.⁷⁸
• Target-specific oral anticoagulants may be beneficial in patients who have challenges in achieving INR targets, as evidence suggests that switching to them is associated with a reduction in bleeding for patients who struggle to maintain an appropriately therapeutic INR.⁶⁸ On the other hand, if there is concern that a patient may occasionally miss doses of an anticoagulant, given the rapid onset and offset of action of target-specific agents compared with warfarin, a missed dose of a target-specific agent may result in faster dissolution of anticoagulant effect and increased risk of thrombotic events, and lapses in anticoagulation will not be identified by routine drug monitoring.^6–8,75 As such, it is vital to have a frank discussion with any patient who has difficulty maintaining therapeutic INRs on warfarin treatment to make sure that he or she is not missing doses.
• If there is no clear and compelling reason to select a particular agent, cost considerations should be taken into account. We have included estimated 30-day pricing for the various agents in Table 4. 

If a patient receiving anticoagulant therapy suffers a bleeding event, the patient and physician must decide whether and how soon to restart the therapy, and with what agent.

Foremost on our minds tends to be the risk of another hemorrhage. Subtler to appreciate immediately after an event is the continued risk of thrombosis, often from the same medical condition that prompted anticoagulation therapy in the first place (Table 1).

Complicating the decision, there may be a rebound effect: some thrombotic events such as pulmonary embolism and atrial fibrillation-related stroke may be more likely to occur in the first weeks after stopping warfarin than during similar intervals in patients who have not been taking it.^1–3 The same thing may happen with the newer, target-specific oral anticoagulants.^4–6

Although we have evidence-based guidelines for initiating and managing anticoagulant therapy, ample data on adverse events, and protocols for reversing anticoagulation if bleeding occurs, we do not have clear guidelines on restarting anticoagulation after a hemorrhagic event.

In this article, we outline a practical framework for approaching this clinical dilemma. Used in conjunction with consideration of a patient’s values and preferences as well as input from experts, this framework can help clinicians guide their patients through this challenging clinical decision. It consists of five questions:

• Why is the patient on anticoagulation, and what is the risk of thromboembolism without it?
• What was the clinical impact of the hemorrhage, and what is the risk of rebleeding if anticoagulation is resumed?
• What additional patient factors should be taken into consideration?
• How long should we wait before restarting anticoagulation?
• Would a newer drug be a better choice?

BLEEDING OCCURS IN 2% TO 3% OF PATIENTS PER YEAR

Most of our information on anticoagulation is about vitamin K antagonists—principally warfarin, in use since the 1950s. Among patients taking warfarin outside of clinical trials, the risk of major bleeding is estimated at 2% to 3% per year.⁷

However, the target-specific oral anticoagulants rivaroxaban (Xarelto), apixaban (Eliquis),  dabigatran (Pradaxa) and edoxaban (Savaysa) are being used more and more, and we include them in our discussion insofar as we have information on them. The rates of bleeding with these new drugs in clinical trials have been comparable to or lower than those with warfarin.⁸ Postmarketing surveillance is under way.

WHY IS THE PATIENT ON ANTICOAGULATION? WHAT IS THE RISK WITHOUT IT?

Common, evidence-based indications for anticoagulation are to prevent complications in patients with venous thromboembolism and to prevent stroke in patients with atrial fibrillation or a mechanical heart valve. Other uses, such as in heart failure and its sequelae, pulmonary hypertension, and splanchnic or hepatic vein thrombosis, have less robust evidence to support them.

When anticoagulation-related bleeding occurs, it is essential to review why the patient is taking the drug and the risk of thromboembolism without it. Some indications pose a higher risk of thromboembolism than others and so argue more strongly for continuing the treatment.

Douketis et al⁹ developed a risk-stratification scheme for perioperative thromboembolism. We have modified it by adding the CHA₂DS₂-VASc score (Table 2),^9–11 and believe it can be used more widely.

High-risk indications

Conditions that pose a high risk of thrombosis almost always require restarting anticoagulation. Here, the most appropriate question nearly always is not if anticoagulation should be restarted, but when. Examples:

• A mechanical mitral valve
• Antiphospholipid antibody syndrome with recurrent thromboembolic events.

Lower-risk indications

Lower-risk indications allow more leeway in determining if anticoagulation should be resumed. The most straightforward cases fall well within established guidelines. Examples:

• Atrial fibrillation and a CHA₂DS₂-VASc score of 1. The 2014 guidelines from the American College of Cardiology, American Heart Association, and Heart Rhythm Society¹⁰ suggest that patients with nonvalvular atrial fibrillation and a CHA₂DS₂-VASc score of 1 have three options: an oral anticoagulant, aspirin, and no antithrombotic therapy. If such a patient on anticoagulant therapy subsequently experiences a major gastrointestinal hemorrhage requiring transfusion and intensive care and no definitively treatable source of bleeding is found on endoscopy, one can argue that the risks of continued anticoagulation (recurrent bleeding) now exceed the benefits and that the patient would be better served by aspirin or even no antithrombotic therapy.

• After 6 months of anticoagulation for unprovoked deep vein thrombosis. Several studies showed that aspirin reduced the risk of recurrent venous thromboembolism in patients who completed an initial 6-month course of anticoagulation.^12–15 Though these studies did not specifically compare aspirin with warfarin or target-specific oral anticoagulants in preventing recurrent venous thromboembolism after a hemorrhage, it is reasonable to extrapolate their results to this situation.

If the risk of recurrent hemorrhage on anticoagulation is considered to be too great, then aspirin is an alternative to no anticoagulation, as it reduces the risk of recurrent venous thromboembolism.¹⁶ However, we advise caution if the bleeding lesion may be specifically exacerbated by aspirin, particularly upper gastrointestinal ulcers.

Moderate-risk indications

• After a partial course of anticoagulation for provoked venous thromboembolism. Suppose a patient in the 10th week of a planned 12-week course of anticoagulation for a surgically provoked, first deep vein thrombosis presents with abdominal pain and is found to have a retroperitoneal hematoma. In light of the risk of recurrent bleeding vs the benefit of resuming anticoagulation for the limited remaining period, her 12-week treatment course can reasonably be shortened to 10 weeks.

The risk of recurrent venous thromboembolism when a patient is off anticoagulation decreases with time from the initial event. The highest risk, estimated at 0.3% to 1.3% per day, is in the first 4 weeks, falling to 0.03% to 0.2% per day in weeks 5 through 12, and 0.05% per day thereafter.^17–20

The risk of recurrent venous thromboembolism is greatest immediately after the event and decreases over time

Additionally, a pooled analysis of seven randomized trials suggests that patients with isolated, distal deep vein thrombosis provoked by a temporary risk factor did not have a high risk of recurrence after being treated for 4 to 6 weeks.²¹ These analyses are based on vitamin K antagonists, though it seems reasonable to extrapolate this information to the target-specific oral anticoagulants.

More challenging are situations in which the evidence supporting the initial or continued need for anticoagulation is less robust, such as in heart failure, pulmonary hypertension, or splanchnic and hepatic vein thrombosis. In these cases, the lack of strong evidence supporting the use of anticoagulation should make us hesitate to resume it after bleeding.

WHAT WAS THE CLINICAL IMPACT? WHAT IS THE RISK OF REBLEEDING?

Different groups have defined major and minor bleeding in different ways.^22,23 Several have proposed criteria to standardize how bleeding events (on warfarin and otherwise) are classified,^23–25 but the definitions differ.

Specifically, all agree that a “major” bleeding event is one that is fatal, involves bleeding into a major organ, or leads to a substantial decline in hemoglobin level. However, the Thrombolysis in Myocardial Infarction trials use a decline of more than 5 g/dL in their definition,^23,25 while the International Society on Thrombosis and Haemostasis uses 2 g/dL.²⁴

Here, we review the clinical impact of the most common sources of anticoagulation-related hemorrhage—gastrointestinal, soft tissue, and urinary tract²⁶—as well as intracerebral hemorrhage, a less common but more uniformly devastating event.²⁷

Clinical impact of gastrointestinal hemorrhage

Each year, about 4.5% of patients taking warfarin have a gastrointestinal hemorrhage, though not all of these events are major.²⁸ Evolving data suggest that the newer agents (particularly dabigatran, rivaroxaban, and edoxaban) pose a higher risk of gastrointestinal bleeding than warfarin.²⁹ Patients may need plasma and blood transfusions and intravenous phytonadione, all of which carry risks, albeit small.

Frequently, endoscopy is needed to find the source of bleeding and to control it. If this does not work, angiographic intervention to infuse vasoconstrictors or embolic coils into the culprit artery may be required, and some patients need surgery. Each intervention carries its own risk.

Clinical impact of soft-tissue hemorrhage

Soft-tissue hemorrhage accounts for more than 20% of warfarin-related bleeding events²⁶; as yet, we know of no data on the rate with the new drugs. Soft-tissue hemorrhage is often localized to the large muscles of the retroperitoneum and legs. Though retroperitoneal hemorrhage accounts for a relatively small portion of soft-tissue hemorrhages, it is associated with high rates of morbidity and death and will therefore be our focus.²⁶

Some indications for anticoagulation pose a higher risk of thromboembolism than others

Much of the clinical impact of retroperitoneal hemorrhage is from a mass effect that causes abdominal compartment syndrome, hydroureter, ileus, abscess formation, and acute and chronic pain. At least 20% of cases are associated with femoral neuropathy. It can also lead to deep vein thrombosis from venous compression, coupled with hypercoagulability in response to bleeding. Brisk bleeding can lead to shock and death, and the mortality rate in retroperitoneal hemorrhage is estimated at 20% or higher.³⁰

In many cases, the retroperitoneal hemorrhage will self-tamponade and the blood will be reabsorbed once the bleeding has stopped, but uncontrolled bleeding may require surgical or angiographic intervention.³⁰

Clinical impact of urinary tract hemorrhage

Gross or microscopic hematuria can be found in an estimated 2% to 24% of patients taking warfarin^31–33; data are lacking for the target-specific oral anticoagulants. Interventions required to manage urinary tract bleeding include bladder irrigation and, less often, transfusion.³¹ Since a significant number of cases of hematuria are due to neoplastic disease,³² a diagnostic workup with radiographic imaging of the upper tract and cystoscopy of the lower tract is usually required.³¹ While life-threatening hemorrhage is uncommon, complications such as transient urinary obstruction from clots may occur.

Clinical impact of intracranial hemorrhage

Intracranial hemorrhage is the most feared and deadly of the bleeding complications of anticoagulation. The incidence in patients on warfarin is estimated at 2% to 3% per year, which is markedly higher than the estimated incidence of 25 per 100,000 person-years in the general population.³⁴ Emerging data indicate that the newer drugs are also associated with a risk of intracranial hemorrhage, though the risk is about half that with vitamin K antagonists.³⁵ Intracranial hemorrhage leads to death or disability in 76% of cases, compared with 3% of cases of bleeding from the gastrointestinal or urinary tract.²⁷

Regardless of the source of bleeding, hospitalization is likely to be required and may be  prolonged, with attendant risks of nosocomial harms such as infection.

Risk of rebleeding

Given the scope and severity of anticoagulation-related bleeding, there is strong interest in predicting and preventing it. By some estimates, the incidence of recurrent bleeding after resuming vitamin K antagonists is 8% to 13%.²² Although there are several indices for predicting the risk of major bleeding when starting anticoagulation, there are currently no validated tools to estimate a patient’s risk of rebleeding.³⁶

The patient factor that most consistently predicts major bleeding is a history of bleeding, particularly from the gastrointestinal tract. Finding and controlling the source of bleeding is important.^26,37 For example, a patient with gross hematuria who is found on cystoscopy to have a urothelial papilloma is unlikely to have rebleeding if the tumor is successfully resected and serial follow-up shows no regrowth. In contrast, consider a patient with a major gastrointestinal hemorrhage, the source of which remains elusive after upper, lower, and capsule endoscopy or, alternatively, is suspected to be from one of multiple angiodysplastic lesions. Without definitive source management, this patient faces a high risk of rebleeding.

With or without anticoagulation, after a first intracranial hemorrhage the risk of another one is estimated at 2% to 4% per year.³⁴ An observational study found a recurrence rate of 7.5% when vitamin K antagonist therapy was started after an intracranial hemorrhage (though not all patients were on a vitamin K antagonist at the time of the first hemorrhage).³⁸

Evolving data suggest the newer oral agents pose a higher risk of GI bleeding

Patients with lobar hemorrhage and those with suspected cerebral amyloid angiopathy may be at particularly high risk if anticoagulation is resumed. Conversely, initial events attributed to uncontrolled hypertension that subsequently can be well controlled may portend a lower risk of rebleeding.³⁴ For other types of intracranial hemorrhage, recurrence rates can be even higher. Irrespective of anticoagulation, one prospective study estimated the crude annual rebleeding rate with untreated arteriovenous malformations to be 7%.³⁹ In chronic subdural hematoma, the recurrence rate after initial drainage has been estimated at 9.2% to 26.5%, with use of anticoagulants (in this case, vitamin K antagonists) being an independent predictor of recurrence.⁴⁰

WHAT OTHER PATIENT FACTORS NEED CONSIDERATION?

Target INR on warfarin

An important factor influencing the risk of bleeding with warfarin is the intensity of this therapy.³⁷ A meta-analysis⁴¹ found that the risks of major hemorrhage and thromboembolism are minimized if the goal international normalized ratio (INR) is 2.0 to 3.0. When considering resuming anticoagulation after bleeding, make sure the therapeutic target is appropriate.³⁷

Table 3 summarizes recommended therapeutic ranges for frequently encountered indications for warfarin.^36,42,43

INR at time of the event and challenges in controlling it

The decision to resume anticoagulation in patients who bled while using warfarin must take into account the actual INR at the time of the event.

For example, consider a patient whose INR values are consistently in the therapeutic range.  While on vacation, he receives ciprofloxacin for acute prostatitis from an urgent care team, and no adjustment to INR monitoring or warfarin dose is made. Several days later, he presents with lower gastrointestinal bleeding. His INR is 8, and colonoscopy reveals diverticulosis with a bleeding vessel, responsive to endoscopic therapy. After controlling the source of bleeding and reinforcing the need to always review new medications for potential interactions with anticoagulation, it is reasonable to expect that he once again will be able to keep his INR in the therapeutic range.

A patient on anticoagulation for the same indication but who has a history of repeated supratherapeutic levels, poor adherence, or poor access to INR monitoring poses very different concerns about resuming anticoagulation (as well as which agent to use, as we discuss below).

Of note, a high INR alone does not explain bleeding. It is estimated that a workup for gastrointestinal bleeding and gross hematuria uncovers previously undetected lesions in approximately one-third of cases involving warfarin.²⁶ A similar malignancy-unmasking effect is now recognized in patients using the target-specific oral agents who experience gastrointestinal bleeding.⁴⁴ Accordingly, we recommend a comprehensive source evaluation for any anticoagulation-related hemorrhage.

Comorbid conditions

Comorbid conditions associated with bleeding include cancer, end-stage renal disease, liver disease, arterial hypertension, prior stroke, and alcohol abuse.^37,45 Gait instability, regardless of cause, may also increase the risk of trauma-related hemorrhage, but some have estimated that a patient would need to fall multiple times per week to contraindicate anticoagulation on the basis of falls alone.⁴⁶

Concurrent medications

Concomitant therapies, including antiplatelet drugs and nonsteroidal anti-inflammatory drugs, increase bleeding risk.^47,48 Aspirin and the nonsteroidals, in addition to having antiplatelet effects, also can cause gastric erosion.³⁷ In evaluating whether and when to restart anticoagulation, it is advisable to review the role that concomitant therapies may have had in the index bleeding event and to evaluate the risks and benefits of these other agents.

The factor that most consistently predicts major bleeding is a history of bleeding, particularly gastrointestinal bleeding

Additionally, warfarin has many interactions. Although the newer drugs are lauded for having fewer interactions, they are not completely free of them, and the potential for interactions must always be reviewed.⁴⁹ Further, unlike warfarin therapy, therapy with the newer agents is not routinely monitored with laboratory tests, so toxicity (or underdosing) may not be recognized until an adverse clinical event occurs. Ultimately, it may be safer to resume anticoagulation after a contributing drug can be safely discontinued.

Advanced age

The influence that the patient’s age should have on the decision to restart anticoagulation is unclear. Although the risk of intracranial hemorrhage increases with age, particularly after age 80, limited data exist in this population, particularly with regard to rebleeding. Further, age is a major risk factor for most thrombotic events, including venous thromboembolism and stroke from atrial fibrillation, so although the risks of anticoagulation may be higher, the benefits may also be higher than in younger patients.^37,46 We discourage using age alone as a reason to withhold anticoagulation after a hemorrhage.

HOW LONG SHOULD WE WAIT TO RESTART ANTICOAGULATION?

We lack conclusive data on how long to wait to restart anticoagulation after an anticoagulation-associated hemorrhage.

The decision is complicated by evidence suggesting a rebound effect, with an increased risk of pulmonary embolism and atrial fibrillation-related stroke during the first 90 days of interruption of therapy with warfarin as well as with target-specific oral anticoagulants.^3–8 In anticoagulation-associated retroperitoneal bleeding, there is increased risk of deep vein thrombosis from compression, even if venous thromboembolism was not the initial indication for anticoagulation.³⁰

In patients with intracranial hemorrhage, evidence suggests that the intracranial hemorrhage itself increases the risk of arterial and venous thromboembolic events. Irrespective of whether a patient was previously on anticoagulation, the risk of arterial and venous thromboembolic events approaches 7% during the initial intracranial hemorrhage-related hospitalization and 9% during the first 90 days.^34,50,51

To date, the only information we have about when to resume anticoagulation comes from patients taking vitamin K antagonists.

Timing after gastrointestinal bleeding

Small case series suggest that in the first 2 months after warfarin-associated gastrointestinal bleeding, there is substantial risk of rebleeding when anticoagulation is resumed—and of thrombosis when it is not.^52,53 Two retrospective cohort studies may provide some guidance in this dilemma.^28,54

A workup for GI bleeding and gross hematuria uncovers previously undetected lesions in about one-third of cases involving warfarin

Witt et al²⁸ followed 442 patients who presented with gastrointestinal bleeding from any site during warfarin therapy for varied indications for up to 90 days after the index bleeding event. The risk of death was three times lower in patients who restarted warfarin than in those who did not, and their rate of thrombotic events was 10 times lower. The risk of recurrent gastrointestinal bleeding was statistically insignificant, and there were no fatal bleeding events. Anticoagulant therapy was generally resumed within 1 week of the bleeding event, at a median of 4 days.^28,55

Qureshi et al⁵⁴ performed a retrospective cohort study of 1,329 patients with  nonvalvular atrial fibrillation who had experienced a gastrointestinal hemorrhage while taking warfarin. They found that resuming warfarin after 7 days was not associated with a higher risk of recurrent gastrointestinal bleeding and that the rates of death and thromboembolism were lower than in patients who resumed warfarin after 30 days. On the other hand, the risk of recurrent gastrointestinal bleeding was significantly greater if therapy was resumed within the first week.

In view of these studies, we believe that most patients should resume anticoagulation after 4 to 7 days of interruption after gastrointestinal bleeding.⁵⁵

Timing after soft-tissue hemorrhage

The literature on resuming anticoagulation after soft-tissue hemorrhage is sparse. A retrospective study⁵² looked at this question in patients with spontaneous rectal sheath hematoma who had been receiving  antiplatelet drugs, intravenous heparin, vitamin K antagonists, or a combination of these, but not target-specific agents. More than half of the patients were on vitamin K antagonists at the time of hemorrhage. Analysis suggested that when benefits of resuming anticoagulation are believed to outweigh risks, it is reasonable to resume anticoagulation 4 days after the index event.⁵⁶

Timing after intracranial hemorrhage

Anticoagulation should not be considered within the first 24 hours after intracranial hemorrhage, as over 70% of patients develop some amount of hematoma expansion during this time.^34,57 The period thereafter poses a challenge, as the risk of hematoma expansion decreases while the risk of arterial and venous thromboembolism is ongoing and cumulative.⁵⁰

Perhaps surprisingly, national guidelines suggest starting prophylactic-dosed anticoagulation early in all intracranial hemorrhage patients, including those not previously on warfarin.^58,59 In a randomized trial, Boeer et al⁶⁰ concluded that starting low-dose subcutaneous heparin the day after an intracranial hemorrhage decreased the risk of thromboembolism without increasing the risk of rebleeding.⁶⁰ Dickmann et al⁶¹ similarly concluded that there was no increased risk of rebleeding with early prophylactic-dosed subcutaneous heparin.⁶¹ Optimal mechanical thromboprophylaxis, including graduated compression stockings and intermittent pneumatic compression stockings, is also encouraged.³⁴

We discourage using age alone as a reason to withhold anticoagulation after a hemorrhage

Expert opinion remains divided on when and if anticoagulants should be resumed.^34,62 The American Heart Association suggests that in nonvalvular atrial fibrillation, long-term anticoagulation should be avoided after spontaneous lobar hemorrhage; antiplatelet agents can be considered instead.⁵⁸ In nonlobar hemorrhage, the American Heart Association suggests that anticoagulation be considered, depending on strength of indication, 7 to 10 days after the onset.⁵⁸ The European Stroke Initiative suggests patients with strong indications for anticoagulation be restarted on warfarin 10 to 14 days after the event, depending on the risk of thromboembolism and recurrent intracranial hemorrhage.⁵⁹ Others suggest delaying resumption to 10 to 30 weeks after an index intracranial hemorrhage.⁶³

Overall, in the immediate acute period of intracranial hemorrhage, most patients will likely benefit from acute reversal of anticoagulation, followed by institution of prophylactic-dose anticoagulation after the first 24 hours. Going forward, patients who remain at higher risk of a recurrence of anticoagulant-related intracranial hemorrhage (such as those with lobar hemorrhage, suspected cerebral amyloid angiopathy, and other high-risk factors) than of thromboembolic events may be best managed without anticoagulants. Alternatively, patients with deep hemispheric intracranial hemorrhage, hypertension that can be well controlled, and a high risk of serious thromboembolism may experience net benefit from restarting anticoagulation.³⁴

We recommend considering restarting anticoagulation 7 days after the onset of intracranial hemorrhage in patients at high risk of thromboembolism and after at least 14 days for patients at lower risk (Table 2). Discussions with neurologic and neurosurgical consultants should also inform this timing decision.

WOULD A NEWER DRUG BE A BETTER CHOICE?

The emergence of target-specific oral anticoagulants, including factor Xa inhibitors such as rivaroxaban, apixaban, and edoxaban and the direct thrombin inhibitor dabigatran etexilate, presents further challenges in managing anticoagulation after hemorrhage. Table 4 summarizes the current FDA-approved indications.^64–67

These newer agents are attractive because, compared with warfarin, they have wider therapeutic windows, faster onset and offset of action, and fewer drug and food interactions.⁶⁸ A meta-analysis of data available to date suggests that the new drugs, compared with warfarin, show a favorable risk-benefit profile with reductions in stroke, intracranial hemorrhage, and mortality with similar overall major bleeding rates, except for a possible increase in gastrointestinal bleeding.⁶⁸

However, when managing anticoagulation after a bleeding event, the newer agents are challenging for two reasons: they may be associated with a higher incidence of gastrointestinal bleeding than warfarin, and they lack the typical reversal agents that can be used to manage an acute bleeding event.^68,69

In individual studies comparing warfarin with dabigatran,⁷⁰ rivaroxaban,⁷¹ apixaban,⁷² or edoxaban⁷³ for stroke prevention in patients with atrial fibrillation, there was no significant difference in the rate of major bleeding between dabigatran in its higher dose (150 mg twice a day) or rivaroxaban compared with warfarin.^70,71 The risk of major bleeding was actually lower with apixaban⁷² and edoxaban.⁷³

In regard to specific types of major bleeding, the rate of intracranial hemorrhage was significantly lower with dabigatran, rivaroxaban, apixaban, and edoxaban than with warfarin.^35,68–73 Some have proposed that since the brain is high in tissue factor, inhibition of tissue factor-factor VIIa complexes by vitamin K antagonists leaves the brain vulnerable to hemorrhage. Others suggest that the targeted mechanism of target-specific agents, as opposed to the multiple pathways in both the intrinsic and extrinsic coagulation cascade that vitamin K antagonists affect, may explain this difference.^35,74,75

However, some studies suggest that rivaroxaban and the higher doses of dabigatran and edoxaban are associated with higher rates of major gastrointestinal bleeding compared with warfarin.^69–71,76 But apixaban demonstrated no significant difference in gastrointestinal bleeding, and instead demonstrated rates of gastrointestinal bleeding comparable to that with aspirin for stroke prevention in atrial fibrillation.⁷²

The new oral anticoagulants lack antidotes or reversal agents such as phytonadione and fresh-frozen plasma that are available to manage warfarin-associated bleeding events. Other proposed reversal options for the new agents include activated charcoal (if the drugs were taken recently enough to remain in the gastrointestinal tract) and concentrated clotting factor product, though research is ongoing in regards to the most appropriate use in clinical practice.^37,69 Unlike rivaroxaban and apixaban, dabigatran has low plasma protein binding and is dialyzable, which provides another strategy in managing dabigatran-related bleeding.⁶⁹

We believe most patients should resume anticoagulation after 4 to 7 days of interruption after GI bleeding

Of note, the above bleeding risk calculations relate to the first anticoagulant-related bleeding event, though presumably the same risk comparison across agents may be applicable to rebleeding events. Given the data above, when anticoagulation is to be resumed after an intracranial hemorrhage, the risk of rebleeding, particularly in the form of recurrent intracranial hemorrhage, may be lower if a target-specific oral anticoagulant is used.⁷⁵ Similarly, when anticoagulation is to be resumed after a gastrointestinal bleeding event, reinitiation with warfarin or apixaban therapy may present the lowest risk of recurrent gastrointestinal rebleeding. In other sources of bleeding, such as retroperitoneal bleeding, we suggest consideration of transitioning to warfarin, given the availability of reversal agents in the event of recurrent bleeding.

Other important drug-specific factors that must be noted when selecting an agent with which to resume anticoagulation after a hemorrhage include the following:

• In patients with significant renal impairment, the choice of agent will be limited to a vitamin K antagonist.⁷⁷
• A meta-analysis of randomized clinical trials suggests that in the elderly (age 75 and older) target-specific oral anticoagulants did not cause excess bleeding and were associated with at least equal efficacy compared with vitamin K antagonists.⁷⁸
• Target-specific oral anticoagulants may be beneficial in patients who have challenges in achieving INR targets, as evidence suggests that switching to them is associated with a reduction in bleeding for patients who struggle to maintain an appropriately therapeutic INR.⁶⁸ On the other hand, if there is concern that a patient may occasionally miss doses of an anticoagulant, given the rapid onset and offset of action of target-specific agents compared with warfarin, a missed dose of a target-specific agent may result in faster dissolution of anticoagulant effect and increased risk of thrombotic events, and lapses in anticoagulation will not be identified by routine drug monitoring.^6–8,75 As such, it is vital to have a frank discussion with any patient who has difficulty maintaining therapeutic INRs on warfarin treatment to make sure that he or she is not missing doses.
• If there is no clear and compelling reason to select a particular agent, cost considerations should be taken into account. We have included estimated 30-day pricing for the various agents in Table 4. 

If a patient receiving anticoagulant therapy suffers a bleeding event, the patient and physician must decide whether and how soon to restart the therapy, and with what agent.

Foremost on our minds tends to be the risk of another hemorrhage. Subtler to appreciate immediately after an event is the continued risk of thrombosis, often from the same medical condition that prompted anticoagulation therapy in the first place (Table 1).

Complicating the decision, there may be a rebound effect: some thrombotic events such as pulmonary embolism and atrial fibrillation-related stroke may be more likely to occur in the first weeks after stopping warfarin than during similar intervals in patients who have not been taking it.^1–3 The same thing may happen with the newer, target-specific oral anticoagulants.^4–6

Although we have evidence-based guidelines for initiating and managing anticoagulant therapy, ample data on adverse events, and protocols for reversing anticoagulation if bleeding occurs, we do not have clear guidelines on restarting anticoagulation after a hemorrhagic event.

In this article, we outline a practical framework for approaching this clinical dilemma. Used in conjunction with consideration of a patient’s values and preferences as well as input from experts, this framework can help clinicians guide their patients through this challenging clinical decision. It consists of five questions:

• Why is the patient on anticoagulation, and what is the risk of thromboembolism without it?
• What was the clinical impact of the hemorrhage, and what is the risk of rebleeding if anticoagulation is resumed?
• What additional patient factors should be taken into consideration?
• How long should we wait before restarting anticoagulation?
• Would a newer drug be a better choice?

BLEEDING OCCURS IN 2% TO 3% OF PATIENTS PER YEAR

Most of our information on anticoagulation is about vitamin K antagonists—principally warfarin, in use since the 1950s. Among patients taking warfarin outside of clinical trials, the risk of major bleeding is estimated at 2% to 3% per year.⁷

However, the target-specific oral anticoagulants rivaroxaban (Xarelto), apixaban (Eliquis),  dabigatran (Pradaxa) and edoxaban (Savaysa) are being used more and more, and we include them in our discussion insofar as we have information on them. The rates of bleeding with these new drugs in clinical trials have been comparable to or lower than those with warfarin.⁸ Postmarketing surveillance is under way.

WHY IS THE PATIENT ON ANTICOAGULATION? WHAT IS THE RISK WITHOUT IT?

Common, evidence-based indications for anticoagulation are to prevent complications in patients with venous thromboembolism and to prevent stroke in patients with atrial fibrillation or a mechanical heart valve. Other uses, such as in heart failure and its sequelae, pulmonary hypertension, and splanchnic or hepatic vein thrombosis, have less robust evidence to support them.

When anticoagulation-related bleeding occurs, it is essential to review why the patient is taking the drug and the risk of thromboembolism without it. Some indications pose a higher risk of thromboembolism than others and so argue more strongly for continuing the treatment.

Douketis et al⁹ developed a risk-stratification scheme for perioperative thromboembolism. We have modified it by adding the CHA₂DS₂-VASc score (Table 2),^9–11 and believe it can be used more widely.

High-risk indications

Conditions that pose a high risk of thrombosis almost always require restarting anticoagulation. Here, the most appropriate question nearly always is not if anticoagulation should be restarted, but when. Examples:

• A mechanical mitral valve
• Antiphospholipid antibody syndrome with recurrent thromboembolic events.

Lower-risk indications

Lower-risk indications allow more leeway in determining if anticoagulation should be resumed. The most straightforward cases fall well within established guidelines. Examples:

• Atrial fibrillation and a CHA₂DS₂-VASc score of 1. The 2014 guidelines from the American College of Cardiology, American Heart Association, and Heart Rhythm Society¹⁰ suggest that patients with nonvalvular atrial fibrillation and a CHA₂DS₂-VASc score of 1 have three options: an oral anticoagulant, aspirin, and no antithrombotic therapy. If such a patient on anticoagulant therapy subsequently experiences a major gastrointestinal hemorrhage requiring transfusion and intensive care and no definitively treatable source of bleeding is found on endoscopy, one can argue that the risks of continued anticoagulation (recurrent bleeding) now exceed the benefits and that the patient would be better served by aspirin or even no antithrombotic therapy.

• After 6 months of anticoagulation for unprovoked deep vein thrombosis. Several studies showed that aspirin reduced the risk of recurrent venous thromboembolism in patients who completed an initial 6-month course of anticoagulation.^12–15 Though these studies did not specifically compare aspirin with warfarin or target-specific oral anticoagulants in preventing recurrent venous thromboembolism after a hemorrhage, it is reasonable to extrapolate their results to this situation.

If the risk of recurrent hemorrhage on anticoagulation is considered to be too great, then aspirin is an alternative to no anticoagulation, as it reduces the risk of recurrent venous thromboembolism.¹⁶ However, we advise caution if the bleeding lesion may be specifically exacerbated by aspirin, particularly upper gastrointestinal ulcers.

Moderate-risk indications

• After a partial course of anticoagulation for provoked venous thromboembolism. Suppose a patient in the 10th week of a planned 12-week course of anticoagulation for a surgically provoked, first deep vein thrombosis presents with abdominal pain and is found to have a retroperitoneal hematoma. In light of the risk of recurrent bleeding vs the benefit of resuming anticoagulation for the limited remaining period, her 12-week treatment course can reasonably be shortened to 10 weeks.

The risk of recurrent venous thromboembolism when a patient is off anticoagulation decreases with time from the initial event. The highest risk, estimated at 0.3% to 1.3% per day, is in the first 4 weeks, falling to 0.03% to 0.2% per day in weeks 5 through 12, and 0.05% per day thereafter.^17–20

The risk of recurrent venous thromboembolism is greatest immediately after the event and decreases over time

Additionally, a pooled analysis of seven randomized trials suggests that patients with isolated, distal deep vein thrombosis provoked by a temporary risk factor did not have a high risk of recurrence after being treated for 4 to 6 weeks.²¹ These analyses are based on vitamin K antagonists, though it seems reasonable to extrapolate this information to the target-specific oral anticoagulants.

More challenging are situations in which the evidence supporting the initial or continued need for anticoagulation is less robust, such as in heart failure, pulmonary hypertension, or splanchnic and hepatic vein thrombosis. In these cases, the lack of strong evidence supporting the use of anticoagulation should make us hesitate to resume it after bleeding.

WHAT WAS THE CLINICAL IMPACT? WHAT IS THE RISK OF REBLEEDING?

Different groups have defined major and minor bleeding in different ways.^22,23 Several have proposed criteria to standardize how bleeding events (on warfarin and otherwise) are classified,^23–25 but the definitions differ.

Specifically, all agree that a “major” bleeding event is one that is fatal, involves bleeding into a major organ, or leads to a substantial decline in hemoglobin level. However, the Thrombolysis in Myocardial Infarction trials use a decline of more than 5 g/dL in their definition,^23,25 while the International Society on Thrombosis and Haemostasis uses 2 g/dL.²⁴

Here, we review the clinical impact of the most common sources of anticoagulation-related hemorrhage—gastrointestinal, soft tissue, and urinary tract²⁶—as well as intracerebral hemorrhage, a less common but more uniformly devastating event.²⁷

Clinical impact of gastrointestinal hemorrhage

Each year, about 4.5% of patients taking warfarin have a gastrointestinal hemorrhage, though not all of these events are major.²⁸ Evolving data suggest that the newer agents (particularly dabigatran, rivaroxaban, and edoxaban) pose a higher risk of gastrointestinal bleeding than warfarin.²⁹ Patients may need plasma and blood transfusions and intravenous phytonadione, all of which carry risks, albeit small.

Frequently, endoscopy is needed to find the source of bleeding and to control it. If this does not work, angiographic intervention to infuse vasoconstrictors or embolic coils into the culprit artery may be required, and some patients need surgery. Each intervention carries its own risk.

Clinical impact of soft-tissue hemorrhage

Soft-tissue hemorrhage accounts for more than 20% of warfarin-related bleeding events²⁶; as yet, we know of no data on the rate with the new drugs. Soft-tissue hemorrhage is often localized to the large muscles of the retroperitoneum and legs. Though retroperitoneal hemorrhage accounts for a relatively small portion of soft-tissue hemorrhages, it is associated with high rates of morbidity and death and will therefore be our focus.²⁶

Some indications for anticoagulation pose a higher risk of thromboembolism than others

Much of the clinical impact of retroperitoneal hemorrhage is from a mass effect that causes abdominal compartment syndrome, hydroureter, ileus, abscess formation, and acute and chronic pain. At least 20% of cases are associated with femoral neuropathy. It can also lead to deep vein thrombosis from venous compression, coupled with hypercoagulability in response to bleeding. Brisk bleeding can lead to shock and death, and the mortality rate in retroperitoneal hemorrhage is estimated at 20% or higher.³⁰

In many cases, the retroperitoneal hemorrhage will self-tamponade and the blood will be reabsorbed once the bleeding has stopped, but uncontrolled bleeding may require surgical or angiographic intervention.³⁰

Clinical impact of urinary tract hemorrhage

Gross or microscopic hematuria can be found in an estimated 2% to 24% of patients taking warfarin^31–33; data are lacking for the target-specific oral anticoagulants. Interventions required to manage urinary tract bleeding include bladder irrigation and, less often, transfusion.³¹ Since a significant number of cases of hematuria are due to neoplastic disease,³² a diagnostic workup with radiographic imaging of the upper tract and cystoscopy of the lower tract is usually required.³¹ While life-threatening hemorrhage is uncommon, complications such as transient urinary obstruction from clots may occur.

Clinical impact of intracranial hemorrhage

Intracranial hemorrhage is the most feared and deadly of the bleeding complications of anticoagulation. The incidence in patients on warfarin is estimated at 2% to 3% per year, which is markedly higher than the estimated incidence of 25 per 100,000 person-years in the general population.³⁴ Emerging data indicate that the newer drugs are also associated with a risk of intracranial hemorrhage, though the risk is about half that with vitamin K antagonists.³⁵ Intracranial hemorrhage leads to death or disability in 76% of cases, compared with 3% of cases of bleeding from the gastrointestinal or urinary tract.²⁷

Regardless of the source of bleeding, hospitalization is likely to be required and may be  prolonged, with attendant risks of nosocomial harms such as infection.

Risk of rebleeding

Given the scope and severity of anticoagulation-related bleeding, there is strong interest in predicting and preventing it. By some estimates, the incidence of recurrent bleeding after resuming vitamin K antagonists is 8% to 13%.²² Although there are several indices for predicting the risk of major bleeding when starting anticoagulation, there are currently no validated tools to estimate a patient’s risk of rebleeding.³⁶

The patient factor that most consistently predicts major bleeding is a history of bleeding, particularly from the gastrointestinal tract. Finding and controlling the source of bleeding is important.^26,37 For example, a patient with gross hematuria who is found on cystoscopy to have a urothelial papilloma is unlikely to have rebleeding if the tumor is successfully resected and serial follow-up shows no regrowth. In contrast, consider a patient with a major gastrointestinal hemorrhage, the source of which remains elusive after upper, lower, and capsule endoscopy or, alternatively, is suspected to be from one of multiple angiodysplastic lesions. Without definitive source management, this patient faces a high risk of rebleeding.

With or without anticoagulation, after a first intracranial hemorrhage the risk of another one is estimated at 2% to 4% per year.³⁴ An observational study found a recurrence rate of 7.5% when vitamin K antagonist therapy was started after an intracranial hemorrhage (though not all patients were on a vitamin K antagonist at the time of the first hemorrhage).³⁸

Evolving data suggest the newer oral agents pose a higher risk of GI bleeding

Patients with lobar hemorrhage and those with suspected cerebral amyloid angiopathy may be at particularly high risk if anticoagulation is resumed. Conversely, initial events attributed to uncontrolled hypertension that subsequently can be well controlled may portend a lower risk of rebleeding.³⁴ For other types of intracranial hemorrhage, recurrence rates can be even higher. Irrespective of anticoagulation, one prospective study estimated the crude annual rebleeding rate with untreated arteriovenous malformations to be 7%.³⁹ In chronic subdural hematoma, the recurrence rate after initial drainage has been estimated at 9.2% to 26.5%, with use of anticoagulants (in this case, vitamin K antagonists) being an independent predictor of recurrence.⁴⁰

WHAT OTHER PATIENT FACTORS NEED CONSIDERATION?

Target INR on warfarin

An important factor influencing the risk of bleeding with warfarin is the intensity of this therapy.³⁷ A meta-analysis⁴¹ found that the risks of major hemorrhage and thromboembolism are minimized if the goal international normalized ratio (INR) is 2.0 to 3.0. When considering resuming anticoagulation after bleeding, make sure the therapeutic target is appropriate.³⁷

Table 3 summarizes recommended therapeutic ranges for frequently encountered indications for warfarin.^36,42,43

INR at time of the event and challenges in controlling it

The decision to resume anticoagulation in patients who bled while using warfarin must take into account the actual INR at the time of the event.

For example, consider a patient whose INR values are consistently in the therapeutic range.  While on vacation, he receives ciprofloxacin for acute prostatitis from an urgent care team, and no adjustment to INR monitoring or warfarin dose is made. Several days later, he presents with lower gastrointestinal bleeding. His INR is 8, and colonoscopy reveals diverticulosis with a bleeding vessel, responsive to endoscopic therapy. After controlling the source of bleeding and reinforcing the need to always review new medications for potential interactions with anticoagulation, it is reasonable to expect that he once again will be able to keep his INR in the therapeutic range.

A patient on anticoagulation for the same indication but who has a history of repeated supratherapeutic levels, poor adherence, or poor access to INR monitoring poses very different concerns about resuming anticoagulation (as well as which agent to use, as we discuss below).

Of note, a high INR alone does not explain bleeding. It is estimated that a workup for gastrointestinal bleeding and gross hematuria uncovers previously undetected lesions in approximately one-third of cases involving warfarin.²⁶ A similar malignancy-unmasking effect is now recognized in patients using the target-specific oral agents who experience gastrointestinal bleeding.⁴⁴ Accordingly, we recommend a comprehensive source evaluation for any anticoagulation-related hemorrhage.

Comorbid conditions

Comorbid conditions associated with bleeding include cancer, end-stage renal disease, liver disease, arterial hypertension, prior stroke, and alcohol abuse.^37,45 Gait instability, regardless of cause, may also increase the risk of trauma-related hemorrhage, but some have estimated that a patient would need to fall multiple times per week to contraindicate anticoagulation on the basis of falls alone.⁴⁶

Concurrent medications

Concomitant therapies, including antiplatelet drugs and nonsteroidal anti-inflammatory drugs, increase bleeding risk.^47,48 Aspirin and the nonsteroidals, in addition to having antiplatelet effects, also can cause gastric erosion.³⁷ In evaluating whether and when to restart anticoagulation, it is advisable to review the role that concomitant therapies may have had in the index bleeding event and to evaluate the risks and benefits of these other agents.

The factor that most consistently predicts major bleeding is a history of bleeding, particularly gastrointestinal bleeding

Additionally, warfarin has many interactions. Although the newer drugs are lauded for having fewer interactions, they are not completely free of them, and the potential for interactions must always be reviewed.⁴⁹ Further, unlike warfarin therapy, therapy with the newer agents is not routinely monitored with laboratory tests, so toxicity (or underdosing) may not be recognized until an adverse clinical event occurs. Ultimately, it may be safer to resume anticoagulation after a contributing drug can be safely discontinued.

Advanced age

The influence that the patient’s age should have on the decision to restart anticoagulation is unclear. Although the risk of intracranial hemorrhage increases with age, particularly after age 80, limited data exist in this population, particularly with regard to rebleeding. Further, age is a major risk factor for most thrombotic events, including venous thromboembolism and stroke from atrial fibrillation, so although the risks of anticoagulation may be higher, the benefits may also be higher than in younger patients.^37,46 We discourage using age alone as a reason to withhold anticoagulation after a hemorrhage.

HOW LONG SHOULD WE WAIT TO RESTART ANTICOAGULATION?

We lack conclusive data on how long to wait to restart anticoagulation after an anticoagulation-associated hemorrhage.

The decision is complicated by evidence suggesting a rebound effect, with an increased risk of pulmonary embolism and atrial fibrillation-related stroke during the first 90 days of interruption of therapy with warfarin as well as with target-specific oral anticoagulants.^3–8 In anticoagulation-associated retroperitoneal bleeding, there is increased risk of deep vein thrombosis from compression, even if venous thromboembolism was not the initial indication for anticoagulation.³⁰

In patients with intracranial hemorrhage, evidence suggests that the intracranial hemorrhage itself increases the risk of arterial and venous thromboembolic events. Irrespective of whether a patient was previously on anticoagulation, the risk of arterial and venous thromboembolic events approaches 7% during the initial intracranial hemorrhage-related hospitalization and 9% during the first 90 days.^34,50,51

To date, the only information we have about when to resume anticoagulation comes from patients taking vitamin K antagonists.

Timing after gastrointestinal bleeding

Small case series suggest that in the first 2 months after warfarin-associated gastrointestinal bleeding, there is substantial risk of rebleeding when anticoagulation is resumed—and of thrombosis when it is not.^52,53 Two retrospective cohort studies may provide some guidance in this dilemma.^28,54

A workup for GI bleeding and gross hematuria uncovers previously undetected lesions in about one-third of cases involving warfarin

Witt et al²⁸ followed 442 patients who presented with gastrointestinal bleeding from any site during warfarin therapy for varied indications for up to 90 days after the index bleeding event. The risk of death was three times lower in patients who restarted warfarin than in those who did not, and their rate of thrombotic events was 10 times lower. The risk of recurrent gastrointestinal bleeding was statistically insignificant, and there were no fatal bleeding events. Anticoagulant therapy was generally resumed within 1 week of the bleeding event, at a median of 4 days.^28,55

Qureshi et al⁵⁴ performed a retrospective cohort study of 1,329 patients with  nonvalvular atrial fibrillation who had experienced a gastrointestinal hemorrhage while taking warfarin. They found that resuming warfarin after 7 days was not associated with a higher risk of recurrent gastrointestinal bleeding and that the rates of death and thromboembolism were lower than in patients who resumed warfarin after 30 days. On the other hand, the risk of recurrent gastrointestinal bleeding was significantly greater if therapy was resumed within the first week.

In view of these studies, we believe that most patients should resume anticoagulation after 4 to 7 days of interruption after gastrointestinal bleeding.⁵⁵

Timing after soft-tissue hemorrhage

The literature on resuming anticoagulation after soft-tissue hemorrhage is sparse. A retrospective study⁵² looked at this question in patients with spontaneous rectal sheath hematoma who had been receiving  antiplatelet drugs, intravenous heparin, vitamin K antagonists, or a combination of these, but not target-specific agents. More than half of the patients were on vitamin K antagonists at the time of hemorrhage. Analysis suggested that when benefits of resuming anticoagulation are believed to outweigh risks, it is reasonable to resume anticoagulation 4 days after the index event.⁵⁶

Timing after intracranial hemorrhage

Anticoagulation should not be considered within the first 24 hours after intracranial hemorrhage, as over 70% of patients develop some amount of hematoma expansion during this time.^34,57 The period thereafter poses a challenge, as the risk of hematoma expansion decreases while the risk of arterial and venous thromboembolism is ongoing and cumulative.⁵⁰

Perhaps surprisingly, national guidelines suggest starting prophylactic-dosed anticoagulation early in all intracranial hemorrhage patients, including those not previously on warfarin.^58,59 In a randomized trial, Boeer et al⁶⁰ concluded that starting low-dose subcutaneous heparin the day after an intracranial hemorrhage decreased the risk of thromboembolism without increasing the risk of rebleeding.⁶⁰ Dickmann et al⁶¹ similarly concluded that there was no increased risk of rebleeding with early prophylactic-dosed subcutaneous heparin.⁶¹ Optimal mechanical thromboprophylaxis, including graduated compression stockings and intermittent pneumatic compression stockings, is also encouraged.³⁴

We discourage using age alone as a reason to withhold anticoagulation after a hemorrhage

Expert opinion remains divided on when and if anticoagulants should be resumed.^34,62 The American Heart Association suggests that in nonvalvular atrial fibrillation, long-term anticoagulation should be avoided after spontaneous lobar hemorrhage; antiplatelet agents can be considered instead.⁵⁸ In nonlobar hemorrhage, the American Heart Association suggests that anticoagulation be considered, depending on strength of indication, 7 to 10 days after the onset.⁵⁸ The European Stroke Initiative suggests patients with strong indications for anticoagulation be restarted on warfarin 10 to 14 days after the event, depending on the risk of thromboembolism and recurrent intracranial hemorrhage.⁵⁹ Others suggest delaying resumption to 10 to 30 weeks after an index intracranial hemorrhage.⁶³

Overall, in the immediate acute period of intracranial hemorrhage, most patients will likely benefit from acute reversal of anticoagulation, followed by institution of prophylactic-dose anticoagulation after the first 24 hours. Going forward, patients who remain at higher risk of a recurrence of anticoagulant-related intracranial hemorrhage (such as those with lobar hemorrhage, suspected cerebral amyloid angiopathy, and other high-risk factors) than of thromboembolic events may be best managed without anticoagulants. Alternatively, patients with deep hemispheric intracranial hemorrhage, hypertension that can be well controlled, and a high risk of serious thromboembolism may experience net benefit from restarting anticoagulation.³⁴

We recommend considering restarting anticoagulation 7 days after the onset of intracranial hemorrhage in patients at high risk of thromboembolism and after at least 14 days for patients at lower risk (Table 2). Discussions with neurologic and neurosurgical consultants should also inform this timing decision.

WOULD A NEWER DRUG BE A BETTER CHOICE?

The emergence of target-specific oral anticoagulants, including factor Xa inhibitors such as rivaroxaban, apixaban, and edoxaban and the direct thrombin inhibitor dabigatran etexilate, presents further challenges in managing anticoagulation after hemorrhage. Table 4 summarizes the current FDA-approved indications.^64–67

These newer agents are attractive because, compared with warfarin, they have wider therapeutic windows, faster onset and offset of action, and fewer drug and food interactions.⁶⁸ A meta-analysis of data available to date suggests that the new drugs, compared with warfarin, show a favorable risk-benefit profile with reductions in stroke, intracranial hemorrhage, and mortality with similar overall major bleeding rates, except for a possible increase in gastrointestinal bleeding.⁶⁸

However, when managing anticoagulation after a bleeding event, the newer agents are challenging for two reasons: they may be associated with a higher incidence of gastrointestinal bleeding than warfarin, and they lack the typical reversal agents that can be used to manage an acute bleeding event.^68,69

In individual studies comparing warfarin with dabigatran,⁷⁰ rivaroxaban,⁷¹ apixaban,⁷² or edoxaban⁷³ for stroke prevention in patients with atrial fibrillation, there was no significant difference in the rate of major bleeding between dabigatran in its higher dose (150 mg twice a day) or rivaroxaban compared with warfarin.^70,71 The risk of major bleeding was actually lower with apixaban⁷² and edoxaban.⁷³

In regard to specific types of major bleeding, the rate of intracranial hemorrhage was significantly lower with dabigatran, rivaroxaban, apixaban, and edoxaban than with warfarin.^35,68–73 Some have proposed that since the brain is high in tissue factor, inhibition of tissue factor-factor VIIa complexes by vitamin K antagonists leaves the brain vulnerable to hemorrhage. Others suggest that the targeted mechanism of target-specific agents, as opposed to the multiple pathways in both the intrinsic and extrinsic coagulation cascade that vitamin K antagonists affect, may explain this difference.^35,74,75

However, some studies suggest that rivaroxaban and the higher doses of dabigatran and edoxaban are associated with higher rates of major gastrointestinal bleeding compared with warfarin.^69–71,76 But apixaban demonstrated no significant difference in gastrointestinal bleeding, and instead demonstrated rates of gastrointestinal bleeding comparable to that with aspirin for stroke prevention in atrial fibrillation.⁷²

The new oral anticoagulants lack antidotes or reversal agents such as phytonadione and fresh-frozen plasma that are available to manage warfarin-associated bleeding events. Other proposed reversal options for the new agents include activated charcoal (if the drugs were taken recently enough to remain in the gastrointestinal tract) and concentrated clotting factor product, though research is ongoing in regards to the most appropriate use in clinical practice.^37,69 Unlike rivaroxaban and apixaban, dabigatran has low plasma protein binding and is dialyzable, which provides another strategy in managing dabigatran-related bleeding.⁶⁹

We believe most patients should resume anticoagulation after 4 to 7 days of interruption after GI bleeding

Of note, the above bleeding risk calculations relate to the first anticoagulant-related bleeding event, though presumably the same risk comparison across agents may be applicable to rebleeding events. Given the data above, when anticoagulation is to be resumed after an intracranial hemorrhage, the risk of rebleeding, particularly in the form of recurrent intracranial hemorrhage, may be lower if a target-specific oral anticoagulant is used.⁷⁵ Similarly, when anticoagulation is to be resumed after a gastrointestinal bleeding event, reinitiation with warfarin or apixaban therapy may present the lowest risk of recurrent gastrointestinal rebleeding. In other sources of bleeding, such as retroperitoneal bleeding, we suggest consideration of transitioning to warfarin, given the availability of reversal agents in the event of recurrent bleeding.

Other important drug-specific factors that must be noted when selecting an agent with which to resume anticoagulation after a hemorrhage include the following:

• In patients with significant renal impairment, the choice of agent will be limited to a vitamin K antagonist.⁷⁷
• A meta-analysis of randomized clinical trials suggests that in the elderly (age 75 and older) target-specific oral anticoagulants did not cause excess bleeding and were associated with at least equal efficacy compared with vitamin K antagonists.⁷⁸
• Target-specific oral anticoagulants may be beneficial in patients who have challenges in achieving INR targets, as evidence suggests that switching to them is associated with a reduction in bleeding for patients who struggle to maintain an appropriately therapeutic INR.⁶⁸ On the other hand, if there is concern that a patient may occasionally miss doses of an anticoagulant, given the rapid onset and offset of action of target-specific agents compared with warfarin, a missed dose of a target-specific agent may result in faster dissolution of anticoagulant effect and increased risk of thrombotic events, and lapses in anticoagulation will not be identified by routine drug monitoring.^6–8,75 As such, it is vital to have a frank discussion with any patient who has difficulty maintaining therapeutic INRs on warfarin treatment to make sure that he or she is not missing doses.
• If there is no clear and compelling reason to select a particular agent, cost considerations should be taken into account. We have included estimated 30-day pricing for the various agents in Table 4.