Vascular

Sickle cell disease is a common genetic disorder in the United States that disproportionately affects people of African ancestry. The characteristic sickling of red blood cells under conditions of reduced oxygen tension leads to intravascular hemolysis and vaso-occlusive events, which in turn cause tissue ischemia-reperfusion injury affecting multiple organs, including the genitourinary system.^1–3

In this paper, we review the genitourinary effects of sickle cell disease, focusing on sickle cell nephropathy, priapism, and renal medullary carcinoma.

THE WIDE-RANGING EFFECTS OF SICKLE CELL DISEASE

In the United States, sickle cell disease affects 1 of every 500 blacks and 1 of every 36,000 Hispanics.¹ The term describes hemoglobinopathies associated with sickling of red blood cells.

Sickling of red blood cells results from a single base-pair change in the beta-globin gene from glutamic acid to valine at position 6, causing abnormal hemoglobin (hemoglobin S), which polymerizes under conditions of reduced oxygen tension and alters the biconcave disk shape into a rigid, irregular, unstable cell. The sickle-shaped cells are prone to intravascular hemolysis,² causing intermittent vaso-occlusive events that result in tissue ischemia-reperfusion injury. Genitourinary problems include impaired ability to concentrate urine, hematuria, renal medullary carcinoma, and increased frequency of urinary tract infection.

SICKLE CELL NEPHROPATHY

Signs of kidney involvement may appear in early childhood

The kidney is one of the most frequently affected organs in sickle cell disease. Renal manifestations begin to appear in early childhood, with impaired medullary concentrating ability and ischemic damage to the tubular cells caused by sickling within the vasa recta renis precipitated by the acidic, hypoxic, and hypertonic environment in the renal medulla.

As in early diabetic nephropathy, renal blood flow is enhanced and the glomerular filtration rate (GFR) is increased. Increased cardiac output as a result of anemia, localized release of prostaglandins, and a hypoxia-induced increase in nitric oxide synthesis all play a role in the increase in GFR.^4,5

Oxidative stress, an increase in markers of inflammation, and local activation of the renin-angiotensin system contribute to renal damage in sickle cell disease.^5–7 The resulting hyperfiltration injury leads to microalbuminuria, which occurs in 20% to 40% of children with sickle cell anemia^8,9 and in as many as 60% of adults.

The glomerular lesions associated with sickle cell disease vary from glomerulopathy in the early stages to secondary focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis, and glomerular thrombotic microangiopathy.¹⁰

Clinical presentations and workup

Clinical presentations are not limited to glomerular disease but include hyperchloremic metabolic acidosis and hyperkalemia resulting from defects in potassium secretion and renal acidification.

Hyperphosphatemia—a result of increased reabsorption of phosphorus, increased secretion of uric acid, and increased creatinine clearance—is seen in patients with sickle cell disease.^11,12 About 10% of patients can develop an acute kidney injury as a result of volume depletion, rhabdomyolysis, renal vein thrombosis, papillary necrosis, and urinary tract obstruction secondary to blood clots.^11,13

Up to 30% of adult patients with sickle cell disease develop chronic kidney disease. Predictors include severe anemia, hypertension, proteinuria, nephrotic syndrome, and microscopic hematuria.¹⁴ From 4% to 12% of patients go on to develop end-stage renal disease, but with a 1-year mortality rate three times higher than in patients without sickle cell disease.¹⁵

In general, patients with sickle cell anemia have blood pressures below those of age- and sex-matched individuals, but elevated blood pressure and low GFR are not uncommon in affected children. In a cohort of 48 children ages 3 to 18, 8.3% had an estimated GFR less than 90 mL/min/1.73 m², and 16.7% had elevated blood pressure (prehypertension and hypertension).¹⁶

In patients with sickle cell disease, evaluation of proteinuria, hematuria, hypertension, and renal failure should take into consideration the unique renal physiologic and pathologic processes involved. Recent evidence^17,18 suggests that the Chronic Kidney Disease Epidemiology Collaboration equation provides a better estimate of GFR than the Modification of Diet in Renal Disease and Cockcroft-Gault equations, although all three creatinine-based methods overestimate GFR in patients with sickle cell disease when compared with GFR measured with technetium-99m-labeled diethylenetriamine penta-acetic acid renal scanning.

Treatment options

Treatment of sickle cell nephropathy includes adequate fluid intake (given the loss of concentrating ability), adequate blood pressure control, use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) in patients who have microalbuminuria or proteinuria (or both)^9,11,19 and hydroxyurea. Treatment with enalapril has been shown to decrease proteinuria in patients with sickle cell nephropathy.⁹ In a cohort of children with sickle cell disease, four of nine patients treated with an ACE inhibitor developed hyperkalemia, leading to discontinuation of the drug in three patients.⁹

ACE inhibitors and ARBs must be used cautiously in these patients because they have defects in potassium secretion. Hydroxyurea has also been shown to decrease hyperfiltration and microalbuminuria in recent studies,^20,21 and this could protect against the development of overt nephropathy.

Higher mortality rates have been reported in patients with sickle cell disease who developed end-stage renal disease than in patients with end-stage renal disease without sickle cell disease. Sickle cell disease also increases the risk of pulmonary hypertension and the vaso-occlusive complication known as acute chest syndrome, contributing to increased mortality rates. Of note, in a study that looked at the association between mortality rates and pre-end-stage care of renal disease using data from the Centers for Medicare and Medicaid Services, patients with sickle cell disease who had had predialysis nephrology care had lower mortality rates.¹⁵

Treatments for end-stage renal disease are also effective in patients with sickle cell disease and include hemodialysis, peritoneal dialysis, and transplantation

Treatments for end-stage renal disease are also effective in patients with sickle cell disease and include hemodialysis, peritoneal dialysis, and renal transplantation. Data from the Organ Procurement and Transplantation Network and the United Network for Organ Sharing show that from 2000 to 2011, African American kidney recipients with sickle cell disease had better survival rates than patients who had undergone transplantation from 1988 to 1999, although rates of long-term survival and graft survival were lower than in transplant recipients with other diagnoses.²²

It is important to note that complications as a result of vaso-occlusive events and thrombosis can lead to graft loss; therefore, sickle cell crisis after transplantation requires careful management.

Take-home messages

• Loss of urine-concentrating ability and hyperfiltration are the earliest pathologic changes in sickle cell disease.
• Microalbuminuria as seen in diabetic nephropathy is the earliest manifestation of sickle cell nephropathy, and the prevalence increases as these patients get older and live longer.
• ACE inhibitors or ARBs should be used with caution, given the heightened risk of hyperkalemia in sickle cell disease.
• Recent results with hydroxyurea in decreasing hyperfiltration and microalbuminuria are encouraging.
• Early referral for predialysis nephrologic care is needed in sickle cell patients with chronic kidney disease.

PRIAPISM IN SICKLE CELL DISEASE

Priapism was formerly defined as a full, painful erection lasting more than 4 hours and unrelated to sexual stimulation or orgasm. But priapism is now recognized as two separate disorders—ischemic (veno-occlusive, low-flow) priapism and nonischemic (arterial, high-flow) priapism. The new definition includes both disorders: ie, a full or partial erection lasting more than 4 hours and unrelated to sexual stimulation or orgasm.

Ischemic priapism

Hematologic disorders are major contributors to ischemic priapism and include sickle cell disease, multiple myeloma, fat emboli (hyperalimentation),²³ glucose-6-phosphate dehydrogenase deficiency, and hemoglobin Olmsted variant.²⁴

Ischemic priapism is often seen in sickle cell disease and is considered an emergency. It is characterized by an abnormally rigid erection not involving the glans penis. Entrapment of blood in the corpora cavernosa leads to hypoxia, hypercarbia, and acidosis, which in turn leads to a painful compartment syndrome that, if untreated, results in smooth muscle necrosis and subsequent fibrosis. The results are a smaller penis and erectile dysfunction that is unresponsive to any treatment other than implantation of a penile prosthesis. However, scarring of the corpora cavernosa can make this procedure exceedingly difficult, requiring advanced techniques such as corporeal excavation.²⁵

Men with a subtype of ischemic priapism called “stuttering” priapism²⁶ suffer recurrent prolonged erections during sleep. The patient awakens with a painful erection that usually subsides, but sometimes only after several hours. Patients with this disorder suffer from sleep deprivation. Stuttering priapism may lead to full-blown ischemic priapism that does not resolve without intervention.

Nonischemic priapism

In nonischemic priapism, the corpora are engorged but not rigid. The condition results from unregulated arterial inflow and thus is not painful and does not result in damage to the corporeal smooth muscle.

Most cases of nonischemic priapism follow blunt perineal trauma or trauma associated with needle insertion into the corpora. This form of priapism is not associated with sickle cell disease. Because tissue damage does not occur, nonischemic or arterial priapism is not considered an emergency.

Treatment guidelines

Differentiating ischemic from nonischemic priapism is usually straightforward, based on the history, physical examination, corporeal blood gases, and duplex ultrasonography.²⁷

Ischemic priapism is an emergency. After needle aspiration of blood from the corpora cavernosa, phenylephrine is diluted with normal saline to a concentration of 100 to 500 µg/mL and is injected in 1-mL amounts repeatedly at 3- to 5-minute intervals until the erection subsides or until a 1-hour time limit is reached. Blood pressure and pulse are monitored during these injections. If aspiration and phenylephrine irrigation fail, surgical shunting is performed.²⁷

Measures to treat sickle cell disease (hydration, oxygen, exchange transfusions) may be employed simultaneously but should never delay aspiration and phenylephrine injections.²⁵

Early referral for predialysis nephrologic care is needed in sickle cell patients with chronic kidney disease

As nonischemic priapism is not considered an emergency, management begins with observation. Patients eventually become dissatisfied with their constant partial erection, and they then present for treatment. Most cases resolve after selective catheterization of the internal pudendal artery and embolization of the fistula with absorbable material. If this fails, surgical exploration with ligation of the vessels leading to the fistula is indicated.

Prevalence in sickle cell trait vs sickle cell disease

Ischemic priapism is uncommon in men with sickle cell trait, but prevalence rates in men with sickle cell disease are as high as 42%.²⁸ In a study of 130 men with sickle cell disease, 35% had a history of prolonged ischemic priapism, 72% had a history of stuttering priapism, and 75% of men with stuttering priapism had their first episode before age 20.²⁹

Rates of erectile dysfunction increase with the duration of ischemic episodes and range from 20% to 90%.^28,30 In childhood, sickle cell disease accounts for 63% of the cases of ischemic priapism, and in adults it accounts for 23% of cases.³¹

Take-home messages

• Sickle cell disease accounts for two-thirds of cases of ischemic priapism in children, and one-fourth of adult cases.
• Ischemic priapism is a medical emergency.
• Treatment with aspiration and phenylephrine injections should begin immediately and should not await treatment measures for sickle cell disease (hydration, oxygen, exchange transfusions).

OTHER UROLOGIC COMPLICATIONS OF SICKLE CELL DISEASE

Other urologic complications of sickle cell trait and sickle cell disease include microscopic hematuria, gross hematuria, and renal colic. A formal evaluation of any patient with persistent microscopic hematuria or gross hematuria should consist of urinalysis, computed tomography, and cystoscopy. This approach assesses the upper and lower genitourinary system for treatable causes. Renal ultrasonography can be used instead of computed tomography but tends to provide less information.

Special considerations

In patients with sickle cell trait and sickle cell disease, chronic hypoxia and subsequent sickling of erythrocytes in the renal medulla can lead to papillary hypertrophy and papillary necrosis. In papillary hypertrophy, friable blood vessels can rupture, resulting in microscopic and gross hematuria. In papillary necrosis, the papilla can slough off and become lodged in the ureter.

Nevertheless, hematuria and renal colic in patients with sickle cell disease or trait are most often attributable to common causes such as infection and stones. A finding of hydronephrosis in the absence of a stone, however, suggests obstruction due to a clot or a sloughed papilla. Ureteroscopy, fulguration, and ureteral stent placement can stop the bleeding and alleviate obstruction in these cases.

Renal medullary carcinoma

Another important reason to order imaging in patients with sickle cell disease or trait who present with urologic symptoms is to rule out renal medullary carcinoma, a rare but aggressive cancer that arises from the collecting duct epithelium. This cancer is twice as likely to occur in males than in females; it has been reported in patients ranging in age from 10 to 40, with a median age at presentation of 26.³²

When patients present with symptomatic renal medullary cancer, in most cases the cancer has already metastasized.

On computed tomography, the tumor tends to occupy a central location in the kidney and appears to infiltrate and replace adjacent kidney tissue. Retroperitoneal lymphadenopathy and metastasis are common.

Treatment typically entails radical nephrectomy, chemotherapy, and in some circumstances, radiotherapy. Case reports have shown promising tumor responses to carboplatin and paclitaxel regimens.^33,34 Also, a low threshold for imaging in patients with sickle cell disease and trait may increase the odds of early detection of this aggressive cancer.

Sickle cell disease is a common genetic disorder in the United States that disproportionately affects people of African ancestry. The characteristic sickling of red blood cells under conditions of reduced oxygen tension leads to intravascular hemolysis and vaso-occlusive events, which in turn cause tissue ischemia-reperfusion injury affecting multiple organs, including the genitourinary system.^1–3

In this paper, we review the genitourinary effects of sickle cell disease, focusing on sickle cell nephropathy, priapism, and renal medullary carcinoma.

THE WIDE-RANGING EFFECTS OF SICKLE CELL DISEASE

In the United States, sickle cell disease affects 1 of every 500 blacks and 1 of every 36,000 Hispanics.¹ The term describes hemoglobinopathies associated with sickling of red blood cells.

Sickling of red blood cells results from a single base-pair change in the beta-globin gene from glutamic acid to valine at position 6, causing abnormal hemoglobin (hemoglobin S), which polymerizes under conditions of reduced oxygen tension and alters the biconcave disk shape into a rigid, irregular, unstable cell. The sickle-shaped cells are prone to intravascular hemolysis,² causing intermittent vaso-occlusive events that result in tissue ischemia-reperfusion injury. Genitourinary problems include impaired ability to concentrate urine, hematuria, renal medullary carcinoma, and increased frequency of urinary tract infection.

SICKLE CELL NEPHROPATHY

Signs of kidney involvement may appear in early childhood

The kidney is one of the most frequently affected organs in sickle cell disease. Renal manifestations begin to appear in early childhood, with impaired medullary concentrating ability and ischemic damage to the tubular cells caused by sickling within the vasa recta renis precipitated by the acidic, hypoxic, and hypertonic environment in the renal medulla.

As in early diabetic nephropathy, renal blood flow is enhanced and the glomerular filtration rate (GFR) is increased. Increased cardiac output as a result of anemia, localized release of prostaglandins, and a hypoxia-induced increase in nitric oxide synthesis all play a role in the increase in GFR.^4,5

Oxidative stress, an increase in markers of inflammation, and local activation of the renin-angiotensin system contribute to renal damage in sickle cell disease.^5–7 The resulting hyperfiltration injury leads to microalbuminuria, which occurs in 20% to 40% of children with sickle cell anemia^8,9 and in as many as 60% of adults.

The glomerular lesions associated with sickle cell disease vary from glomerulopathy in the early stages to secondary focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis, and glomerular thrombotic microangiopathy.¹⁰

Clinical presentations and workup

Clinical presentations are not limited to glomerular disease but include hyperchloremic metabolic acidosis and hyperkalemia resulting from defects in potassium secretion and renal acidification.

Hyperphosphatemia—a result of increased reabsorption of phosphorus, increased secretion of uric acid, and increased creatinine clearance—is seen in patients with sickle cell disease.^11,12 About 10% of patients can develop an acute kidney injury as a result of volume depletion, rhabdomyolysis, renal vein thrombosis, papillary necrosis, and urinary tract obstruction secondary to blood clots.^11,13

Up to 30% of adult patients with sickle cell disease develop chronic kidney disease. Predictors include severe anemia, hypertension, proteinuria, nephrotic syndrome, and microscopic hematuria.¹⁴ From 4% to 12% of patients go on to develop end-stage renal disease, but with a 1-year mortality rate three times higher than in patients without sickle cell disease.¹⁵

In general, patients with sickle cell anemia have blood pressures below those of age- and sex-matched individuals, but elevated blood pressure and low GFR are not uncommon in affected children. In a cohort of 48 children ages 3 to 18, 8.3% had an estimated GFR less than 90 mL/min/1.73 m², and 16.7% had elevated blood pressure (prehypertension and hypertension).¹⁶

In patients with sickle cell disease, evaluation of proteinuria, hematuria, hypertension, and renal failure should take into consideration the unique renal physiologic and pathologic processes involved. Recent evidence^17,18 suggests that the Chronic Kidney Disease Epidemiology Collaboration equation provides a better estimate of GFR than the Modification of Diet in Renal Disease and Cockcroft-Gault equations, although all three creatinine-based methods overestimate GFR in patients with sickle cell disease when compared with GFR measured with technetium-99m-labeled diethylenetriamine penta-acetic acid renal scanning.

Treatment options

Treatment of sickle cell nephropathy includes adequate fluid intake (given the loss of concentrating ability), adequate blood pressure control, use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) in patients who have microalbuminuria or proteinuria (or both)^9,11,19 and hydroxyurea. Treatment with enalapril has been shown to decrease proteinuria in patients with sickle cell nephropathy.⁹ In a cohort of children with sickle cell disease, four of nine patients treated with an ACE inhibitor developed hyperkalemia, leading to discontinuation of the drug in three patients.⁹

ACE inhibitors and ARBs must be used cautiously in these patients because they have defects in potassium secretion. Hydroxyurea has also been shown to decrease hyperfiltration and microalbuminuria in recent studies,^20,21 and this could protect against the development of overt nephropathy.

Higher mortality rates have been reported in patients with sickle cell disease who developed end-stage renal disease than in patients with end-stage renal disease without sickle cell disease. Sickle cell disease also increases the risk of pulmonary hypertension and the vaso-occlusive complication known as acute chest syndrome, contributing to increased mortality rates. Of note, in a study that looked at the association between mortality rates and pre-end-stage care of renal disease using data from the Centers for Medicare and Medicaid Services, patients with sickle cell disease who had had predialysis nephrology care had lower mortality rates.¹⁵

Treatments for end-stage renal disease are also effective in patients with sickle cell disease and include hemodialysis, peritoneal dialysis, and transplantation

Treatments for end-stage renal disease are also effective in patients with sickle cell disease and include hemodialysis, peritoneal dialysis, and renal transplantation. Data from the Organ Procurement and Transplantation Network and the United Network for Organ Sharing show that from 2000 to 2011, African American kidney recipients with sickle cell disease had better survival rates than patients who had undergone transplantation from 1988 to 1999, although rates of long-term survival and graft survival were lower than in transplant recipients with other diagnoses.²²

It is important to note that complications as a result of vaso-occlusive events and thrombosis can lead to graft loss; therefore, sickle cell crisis after transplantation requires careful management.

Take-home messages

• Loss of urine-concentrating ability and hyperfiltration are the earliest pathologic changes in sickle cell disease.
• Microalbuminuria as seen in diabetic nephropathy is the earliest manifestation of sickle cell nephropathy, and the prevalence increases as these patients get older and live longer.
• ACE inhibitors or ARBs should be used with caution, given the heightened risk of hyperkalemia in sickle cell disease.
• Recent results with hydroxyurea in decreasing hyperfiltration and microalbuminuria are encouraging.
• Early referral for predialysis nephrologic care is needed in sickle cell patients with chronic kidney disease.

PRIAPISM IN SICKLE CELL DISEASE

Priapism was formerly defined as a full, painful erection lasting more than 4 hours and unrelated to sexual stimulation or orgasm. But priapism is now recognized as two separate disorders—ischemic (veno-occlusive, low-flow) priapism and nonischemic (arterial, high-flow) priapism. The new definition includes both disorders: ie, a full or partial erection lasting more than 4 hours and unrelated to sexual stimulation or orgasm.

Ischemic priapism

Hematologic disorders are major contributors to ischemic priapism and include sickle cell disease, multiple myeloma, fat emboli (hyperalimentation),²³ glucose-6-phosphate dehydrogenase deficiency, and hemoglobin Olmsted variant.²⁴

Ischemic priapism is often seen in sickle cell disease and is considered an emergency. It is characterized by an abnormally rigid erection not involving the glans penis. Entrapment of blood in the corpora cavernosa leads to hypoxia, hypercarbia, and acidosis, which in turn leads to a painful compartment syndrome that, if untreated, results in smooth muscle necrosis and subsequent fibrosis. The results are a smaller penis and erectile dysfunction that is unresponsive to any treatment other than implantation of a penile prosthesis. However, scarring of the corpora cavernosa can make this procedure exceedingly difficult, requiring advanced techniques such as corporeal excavation.²⁵

Men with a subtype of ischemic priapism called “stuttering” priapism²⁶ suffer recurrent prolonged erections during sleep. The patient awakens with a painful erection that usually subsides, but sometimes only after several hours. Patients with this disorder suffer from sleep deprivation. Stuttering priapism may lead to full-blown ischemic priapism that does not resolve without intervention.

Nonischemic priapism

In nonischemic priapism, the corpora are engorged but not rigid. The condition results from unregulated arterial inflow and thus is not painful and does not result in damage to the corporeal smooth muscle.

Most cases of nonischemic priapism follow blunt perineal trauma or trauma associated with needle insertion into the corpora. This form of priapism is not associated with sickle cell disease. Because tissue damage does not occur, nonischemic or arterial priapism is not considered an emergency.

Treatment guidelines

Differentiating ischemic from nonischemic priapism is usually straightforward, based on the history, physical examination, corporeal blood gases, and duplex ultrasonography.²⁷

Ischemic priapism is an emergency. After needle aspiration of blood from the corpora cavernosa, phenylephrine is diluted with normal saline to a concentration of 100 to 500 µg/mL and is injected in 1-mL amounts repeatedly at 3- to 5-minute intervals until the erection subsides or until a 1-hour time limit is reached. Blood pressure and pulse are monitored during these injections. If aspiration and phenylephrine irrigation fail, surgical shunting is performed.²⁷

Measures to treat sickle cell disease (hydration, oxygen, exchange transfusions) may be employed simultaneously but should never delay aspiration and phenylephrine injections.²⁵

Early referral for predialysis nephrologic care is needed in sickle cell patients with chronic kidney disease

As nonischemic priapism is not considered an emergency, management begins with observation. Patients eventually become dissatisfied with their constant partial erection, and they then present for treatment. Most cases resolve after selective catheterization of the internal pudendal artery and embolization of the fistula with absorbable material. If this fails, surgical exploration with ligation of the vessels leading to the fistula is indicated.

Prevalence in sickle cell trait vs sickle cell disease

Ischemic priapism is uncommon in men with sickle cell trait, but prevalence rates in men with sickle cell disease are as high as 42%.²⁸ In a study of 130 men with sickle cell disease, 35% had a history of prolonged ischemic priapism, 72% had a history of stuttering priapism, and 75% of men with stuttering priapism had their first episode before age 20.²⁹

Rates of erectile dysfunction increase with the duration of ischemic episodes and range from 20% to 90%.^28,30 In childhood, sickle cell disease accounts for 63% of the cases of ischemic priapism, and in adults it accounts for 23% of cases.³¹

Take-home messages

• Sickle cell disease accounts for two-thirds of cases of ischemic priapism in children, and one-fourth of adult cases.
• Ischemic priapism is a medical emergency.
• Treatment with aspiration and phenylephrine injections should begin immediately and should not await treatment measures for sickle cell disease (hydration, oxygen, exchange transfusions).

OTHER UROLOGIC COMPLICATIONS OF SICKLE CELL DISEASE

Other urologic complications of sickle cell trait and sickle cell disease include microscopic hematuria, gross hematuria, and renal colic. A formal evaluation of any patient with persistent microscopic hematuria or gross hematuria should consist of urinalysis, computed tomography, and cystoscopy. This approach assesses the upper and lower genitourinary system for treatable causes. Renal ultrasonography can be used instead of computed tomography but tends to provide less information.

Special considerations

In patients with sickle cell trait and sickle cell disease, chronic hypoxia and subsequent sickling of erythrocytes in the renal medulla can lead to papillary hypertrophy and papillary necrosis. In papillary hypertrophy, friable blood vessels can rupture, resulting in microscopic and gross hematuria. In papillary necrosis, the papilla can slough off and become lodged in the ureter.

Nevertheless, hematuria and renal colic in patients with sickle cell disease or trait are most often attributable to common causes such as infection and stones. A finding of hydronephrosis in the absence of a stone, however, suggests obstruction due to a clot or a sloughed papilla. Ureteroscopy, fulguration, and ureteral stent placement can stop the bleeding and alleviate obstruction in these cases.

Renal medullary carcinoma

Another important reason to order imaging in patients with sickle cell disease or trait who present with urologic symptoms is to rule out renal medullary carcinoma, a rare but aggressive cancer that arises from the collecting duct epithelium. This cancer is twice as likely to occur in males than in females; it has been reported in patients ranging in age from 10 to 40, with a median age at presentation of 26.³²

When patients present with symptomatic renal medullary cancer, in most cases the cancer has already metastasized.

On computed tomography, the tumor tends to occupy a central location in the kidney and appears to infiltrate and replace adjacent kidney tissue. Retroperitoneal lymphadenopathy and metastasis are common.

Treatment typically entails radical nephrectomy, chemotherapy, and in some circumstances, radiotherapy. Case reports have shown promising tumor responses to carboplatin and paclitaxel regimens.^33,34 Also, a low threshold for imaging in patients with sickle cell disease and trait may increase the odds of early detection of this aggressive cancer.

Sickle cell disease is a common genetic disorder in the United States that disproportionately affects people of African ancestry. The characteristic sickling of red blood cells under conditions of reduced oxygen tension leads to intravascular hemolysis and vaso-occlusive events, which in turn cause tissue ischemia-reperfusion injury affecting multiple organs, including the genitourinary system.^1–3

In this paper, we review the genitourinary effects of sickle cell disease, focusing on sickle cell nephropathy, priapism, and renal medullary carcinoma.

THE WIDE-RANGING EFFECTS OF SICKLE CELL DISEASE

In the United States, sickle cell disease affects 1 of every 500 blacks and 1 of every 36,000 Hispanics.¹ The term describes hemoglobinopathies associated with sickling of red blood cells.

Sickling of red blood cells results from a single base-pair change in the beta-globin gene from glutamic acid to valine at position 6, causing abnormal hemoglobin (hemoglobin S), which polymerizes under conditions of reduced oxygen tension and alters the biconcave disk shape into a rigid, irregular, unstable cell. The sickle-shaped cells are prone to intravascular hemolysis,² causing intermittent vaso-occlusive events that result in tissue ischemia-reperfusion injury. Genitourinary problems include impaired ability to concentrate urine, hematuria, renal medullary carcinoma, and increased frequency of urinary tract infection.

SICKLE CELL NEPHROPATHY

Signs of kidney involvement may appear in early childhood

The kidney is one of the most frequently affected organs in sickle cell disease. Renal manifestations begin to appear in early childhood, with impaired medullary concentrating ability and ischemic damage to the tubular cells caused by sickling within the vasa recta renis precipitated by the acidic, hypoxic, and hypertonic environment in the renal medulla.

As in early diabetic nephropathy, renal blood flow is enhanced and the glomerular filtration rate (GFR) is increased. Increased cardiac output as a result of anemia, localized release of prostaglandins, and a hypoxia-induced increase in nitric oxide synthesis all play a role in the increase in GFR.^4,5

Oxidative stress, an increase in markers of inflammation, and local activation of the renin-angiotensin system contribute to renal damage in sickle cell disease.^5–7 The resulting hyperfiltration injury leads to microalbuminuria, which occurs in 20% to 40% of children with sickle cell anemia^8,9 and in as many as 60% of adults.

The glomerular lesions associated with sickle cell disease vary from glomerulopathy in the early stages to secondary focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis, and glomerular thrombotic microangiopathy.¹⁰

Clinical presentations and workup

Clinical presentations are not limited to glomerular disease but include hyperchloremic metabolic acidosis and hyperkalemia resulting from defects in potassium secretion and renal acidification.

Hyperphosphatemia—a result of increased reabsorption of phosphorus, increased secretion of uric acid, and increased creatinine clearance—is seen in patients with sickle cell disease.^11,12 About 10% of patients can develop an acute kidney injury as a result of volume depletion, rhabdomyolysis, renal vein thrombosis, papillary necrosis, and urinary tract obstruction secondary to blood clots.^11,13

Up to 30% of adult patients with sickle cell disease develop chronic kidney disease. Predictors include severe anemia, hypertension, proteinuria, nephrotic syndrome, and microscopic hematuria.¹⁴ From 4% to 12% of patients go on to develop end-stage renal disease, but with a 1-year mortality rate three times higher than in patients without sickle cell disease.¹⁵

In general, patients with sickle cell anemia have blood pressures below those of age- and sex-matched individuals, but elevated blood pressure and low GFR are not uncommon in affected children. In a cohort of 48 children ages 3 to 18, 8.3% had an estimated GFR less than 90 mL/min/1.73 m², and 16.7% had elevated blood pressure (prehypertension and hypertension).¹⁶

In patients with sickle cell disease, evaluation of proteinuria, hematuria, hypertension, and renal failure should take into consideration the unique renal physiologic and pathologic processes involved. Recent evidence^17,18 suggests that the Chronic Kidney Disease Epidemiology Collaboration equation provides a better estimate of GFR than the Modification of Diet in Renal Disease and Cockcroft-Gault equations, although all three creatinine-based methods overestimate GFR in patients with sickle cell disease when compared with GFR measured with technetium-99m-labeled diethylenetriamine penta-acetic acid renal scanning.

Treatment options

Treatment of sickle cell nephropathy includes adequate fluid intake (given the loss of concentrating ability), adequate blood pressure control, use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) in patients who have microalbuminuria or proteinuria (or both)^9,11,19 and hydroxyurea. Treatment with enalapril has been shown to decrease proteinuria in patients with sickle cell nephropathy.⁹ In a cohort of children with sickle cell disease, four of nine patients treated with an ACE inhibitor developed hyperkalemia, leading to discontinuation of the drug in three patients.⁹

ACE inhibitors and ARBs must be used cautiously in these patients because they have defects in potassium secretion. Hydroxyurea has also been shown to decrease hyperfiltration and microalbuminuria in recent studies,^20,21 and this could protect against the development of overt nephropathy.

Higher mortality rates have been reported in patients with sickle cell disease who developed end-stage renal disease than in patients with end-stage renal disease without sickle cell disease. Sickle cell disease also increases the risk of pulmonary hypertension and the vaso-occlusive complication known as acute chest syndrome, contributing to increased mortality rates. Of note, in a study that looked at the association between mortality rates and pre-end-stage care of renal disease using data from the Centers for Medicare and Medicaid Services, patients with sickle cell disease who had had predialysis nephrology care had lower mortality rates.¹⁵

Treatments for end-stage renal disease are also effective in patients with sickle cell disease and include hemodialysis, peritoneal dialysis, and transplantation

Treatments for end-stage renal disease are also effective in patients with sickle cell disease and include hemodialysis, peritoneal dialysis, and renal transplantation. Data from the Organ Procurement and Transplantation Network and the United Network for Organ Sharing show that from 2000 to 2011, African American kidney recipients with sickle cell disease had better survival rates than patients who had undergone transplantation from 1988 to 1999, although rates of long-term survival and graft survival were lower than in transplant recipients with other diagnoses.²²

It is important to note that complications as a result of vaso-occlusive events and thrombosis can lead to graft loss; therefore, sickle cell crisis after transplantation requires careful management.

Take-home messages

• Loss of urine-concentrating ability and hyperfiltration are the earliest pathologic changes in sickle cell disease.
• Microalbuminuria as seen in diabetic nephropathy is the earliest manifestation of sickle cell nephropathy, and the prevalence increases as these patients get older and live longer.
• ACE inhibitors or ARBs should be used with caution, given the heightened risk of hyperkalemia in sickle cell disease.
• Recent results with hydroxyurea in decreasing hyperfiltration and microalbuminuria are encouraging.
• Early referral for predialysis nephrologic care is needed in sickle cell patients with chronic kidney disease.

PRIAPISM IN SICKLE CELL DISEASE

Priapism was formerly defined as a full, painful erection lasting more than 4 hours and unrelated to sexual stimulation or orgasm. But priapism is now recognized as two separate disorders—ischemic (veno-occlusive, low-flow) priapism and nonischemic (arterial, high-flow) priapism. The new definition includes both disorders: ie, a full or partial erection lasting more than 4 hours and unrelated to sexual stimulation or orgasm.

Ischemic priapism

Hematologic disorders are major contributors to ischemic priapism and include sickle cell disease, multiple myeloma, fat emboli (hyperalimentation),²³ glucose-6-phosphate dehydrogenase deficiency, and hemoglobin Olmsted variant.²⁴

Ischemic priapism is often seen in sickle cell disease and is considered an emergency. It is characterized by an abnormally rigid erection not involving the glans penis. Entrapment of blood in the corpora cavernosa leads to hypoxia, hypercarbia, and acidosis, which in turn leads to a painful compartment syndrome that, if untreated, results in smooth muscle necrosis and subsequent fibrosis. The results are a smaller penis and erectile dysfunction that is unresponsive to any treatment other than implantation of a penile prosthesis. However, scarring of the corpora cavernosa can make this procedure exceedingly difficult, requiring advanced techniques such as corporeal excavation.²⁵

Men with a subtype of ischemic priapism called “stuttering” priapism²⁶ suffer recurrent prolonged erections during sleep. The patient awakens with a painful erection that usually subsides, but sometimes only after several hours. Patients with this disorder suffer from sleep deprivation. Stuttering priapism may lead to full-blown ischemic priapism that does not resolve without intervention.

Nonischemic priapism

In nonischemic priapism, the corpora are engorged but not rigid. The condition results from unregulated arterial inflow and thus is not painful and does not result in damage to the corporeal smooth muscle.

Most cases of nonischemic priapism follow blunt perineal trauma or trauma associated with needle insertion into the corpora. This form of priapism is not associated with sickle cell disease. Because tissue damage does not occur, nonischemic or arterial priapism is not considered an emergency.

Treatment guidelines

Differentiating ischemic from nonischemic priapism is usually straightforward, based on the history, physical examination, corporeal blood gases, and duplex ultrasonography.²⁷

Ischemic priapism is an emergency. After needle aspiration of blood from the corpora cavernosa, phenylephrine is diluted with normal saline to a concentration of 100 to 500 µg/mL and is injected in 1-mL amounts repeatedly at 3- to 5-minute intervals until the erection subsides or until a 1-hour time limit is reached. Blood pressure and pulse are monitored during these injections. If aspiration and phenylephrine irrigation fail, surgical shunting is performed.²⁷

Measures to treat sickle cell disease (hydration, oxygen, exchange transfusions) may be employed simultaneously but should never delay aspiration and phenylephrine injections.²⁵

Early referral for predialysis nephrologic care is needed in sickle cell patients with chronic kidney disease

As nonischemic priapism is not considered an emergency, management begins with observation. Patients eventually become dissatisfied with their constant partial erection, and they then present for treatment. Most cases resolve after selective catheterization of the internal pudendal artery and embolization of the fistula with absorbable material. If this fails, surgical exploration with ligation of the vessels leading to the fistula is indicated.

Prevalence in sickle cell trait vs sickle cell disease

Ischemic priapism is uncommon in men with sickle cell trait, but prevalence rates in men with sickle cell disease are as high as 42%.²⁸ In a study of 130 men with sickle cell disease, 35% had a history of prolonged ischemic priapism, 72% had a history of stuttering priapism, and 75% of men with stuttering priapism had their first episode before age 20.²⁹

Rates of erectile dysfunction increase with the duration of ischemic episodes and range from 20% to 90%.^28,30 In childhood, sickle cell disease accounts for 63% of the cases of ischemic priapism, and in adults it accounts for 23% of cases.³¹

Take-home messages

• Sickle cell disease accounts for two-thirds of cases of ischemic priapism in children, and one-fourth of adult cases.
• Ischemic priapism is a medical emergency.
• Treatment with aspiration and phenylephrine injections should begin immediately and should not await treatment measures for sickle cell disease (hydration, oxygen, exchange transfusions).

OTHER UROLOGIC COMPLICATIONS OF SICKLE CELL DISEASE

Other urologic complications of sickle cell trait and sickle cell disease include microscopic hematuria, gross hematuria, and renal colic. A formal evaluation of any patient with persistent microscopic hematuria or gross hematuria should consist of urinalysis, computed tomography, and cystoscopy. This approach assesses the upper and lower genitourinary system for treatable causes. Renal ultrasonography can be used instead of computed tomography but tends to provide less information.

Special considerations

In patients with sickle cell trait and sickle cell disease, chronic hypoxia and subsequent sickling of erythrocytes in the renal medulla can lead to papillary hypertrophy and papillary necrosis. In papillary hypertrophy, friable blood vessels can rupture, resulting in microscopic and gross hematuria. In papillary necrosis, the papilla can slough off and become lodged in the ureter.

Nevertheless, hematuria and renal colic in patients with sickle cell disease or trait are most often attributable to common causes such as infection and stones. A finding of hydronephrosis in the absence of a stone, however, suggests obstruction due to a clot or a sloughed papilla. Ureteroscopy, fulguration, and ureteral stent placement can stop the bleeding and alleviate obstruction in these cases.

Renal medullary carcinoma

Another important reason to order imaging in patients with sickle cell disease or trait who present with urologic symptoms is to rule out renal medullary carcinoma, a rare but aggressive cancer that arises from the collecting duct epithelium. This cancer is twice as likely to occur in males than in females; it has been reported in patients ranging in age from 10 to 40, with a median age at presentation of 26.³²

When patients present with symptomatic renal medullary cancer, in most cases the cancer has already metastasized.

On computed tomography, the tumor tends to occupy a central location in the kidney and appears to infiltrate and replace adjacent kidney tissue. Retroperitoneal lymphadenopathy and metastasis are common.

Treatment typically entails radical nephrectomy, chemotherapy, and in some circumstances, radiotherapy. Case reports have shown promising tumor responses to carboplatin and paclitaxel regimens.^33,34 Also, a low threshold for imaging in patients with sickle cell disease and trait may increase the odds of early detection of this aggressive cancer.

A 43-year-old man with no medical history presented with pain and swelling in his left arm for 2 weeks. He was a regular weight lifter, and his exercise routine included repetitive hyperextension and hyperabduction of his arms while lifting heavy weights.

He had no history of recent trauma or venous cannulation of the left arm. His family history was negative for thrombophilic disorders. Physical examination revealed a swollen and erythematous left arm and visible venous collaterals at the neck, shoulder, and chest. There was no evidence of arterial insufficiency.

Duplex ultrasonography confirmed thrombosis of the left brachial, axillary, and subclavian veins. Further evaluation with computed tomography showed no intrathoracic mass but revealed several subsegmental pulmonary thrombi in the right lung. A screen for thrombophilia was negative. Venography confirmed complete thrombotic occlusion of the subclavian, axillary, and brachial veins (Figure 1).

Catheter-directed thrombolysis with tissue plasminogen activator resulted in complete resolution of the thrombosis, but venography after 3 days of thrombolysis showed 50% residual stenosis of the left subclavian vein where it passes under the first rib (Figure 2). The redness and swelling had markedly improved 2 days after thrombolytic therapy. He was discharged home on rivaroxaban 20 mg daily.

Follow-up venography 2 months later (Figure 3), with the patient performing hyperabduction of the arms, showed a patent subclavian vein with no thrombosis, but dynamic compression and occlusion of the subclavian vein where it passes the first rib. Magnetic resonance imaging (MRI) of the neck showed no cervical (ie, extra) rib and no soft-tissue abnormalities of the scalene triangle.

Following this, the patient underwent resection of the left first rib for decompression of the venous thoracic outlet, which resulted in resolution of his symptoms. He remained asymptomatic at 6-month follow-up.

PAGET-SCHROETTER SYNDROME

Paget-Schroetter syndrome, also referred to as effort-induced or effort thrombosis, is thrombosis of the axillary or subclavian vein associated with strenuous and repetitive activity of the arms. Anatomic abnormalities at the thoracic outlet—cervical rib, congenital bands, hypertrophy of scalene tendons, abnormal insertion of the costoclavicular ligament—and repetitive trauma to the endothelium of the subclavian vein are key factors in its initiation and progression.

The condition is seen primarily in young people who participate in strenuous activities such as rowing, weight lifting, and baseball pitching. It is estimated to be the cause of 40% of cases of primary upper-extremity deep vein thrombosis in the absence of an obvious risk factor or trigger such as a central venous catheter, pacemaker, port, or occult malignancy.¹

A provocative test such as the Adson test or hyperabduction test during MRI or venography helps confirm thoracic outlet obstruction by demonstrating dynamic obstruction.²

TREATMENT CONSIDERATIONS

There are no universal guidelines for the treatment of Paget-Schroetter syndrome. However, the available data^3–5 suggest a multimodal approach that involves early catheter-directed thrombolysis and subsequent surgical decompression of the thoracic outlet. This can restore venous patency and reduce the risk of long-term complications such as rethrombosis and postthrombotic syndrome.^3–5

Surgical treatment includes resection of the first rib and division of the scalene muscles and the costoclavicular ligament. MRI with provocative testing helps guide the surgical approach. Anticoagulation therapy alone—ie, without thrombolysis and surgical decompression—is inadequate as it leads to recurrence of thrombosis and residual symptoms.⁶

Paget-Schroetter syndrome should not be managed the same as lower-extremity deep vein thrombosis because the cause and the exacerbating factors are different.

Unanswered questions

Because we have no data from randomized controlled trials, questions about management remain. What should be the duration of anticoagulation, especially in the absence of coexisting thrombophilia? Is thrombophilia screening useful? What is the optimal timing for starting thrombolytic therapy?

A careful history and heightened suspicion are required to make this diagnosis. If undiagnosed, it carries a risk of significant long-term morbidity and death. Dynamic obstruction during venography, in addition to MRI, can help identify an anatomic obstruction.

A 43-year-old man with no medical history presented with pain and swelling in his left arm for 2 weeks. He was a regular weight lifter, and his exercise routine included repetitive hyperextension and hyperabduction of his arms while lifting heavy weights.

He had no history of recent trauma or venous cannulation of the left arm. His family history was negative for thrombophilic disorders. Physical examination revealed a swollen and erythematous left arm and visible venous collaterals at the neck, shoulder, and chest. There was no evidence of arterial insufficiency.

Duplex ultrasonography confirmed thrombosis of the left brachial, axillary, and subclavian veins. Further evaluation with computed tomography showed no intrathoracic mass but revealed several subsegmental pulmonary thrombi in the right lung. A screen for thrombophilia was negative. Venography confirmed complete thrombotic occlusion of the subclavian, axillary, and brachial veins (Figure 1).

Catheter-directed thrombolysis with tissue plasminogen activator resulted in complete resolution of the thrombosis, but venography after 3 days of thrombolysis showed 50% residual stenosis of the left subclavian vein where it passes under the first rib (Figure 2). The redness and swelling had markedly improved 2 days after thrombolytic therapy. He was discharged home on rivaroxaban 20 mg daily.

Follow-up venography 2 months later (Figure 3), with the patient performing hyperabduction of the arms, showed a patent subclavian vein with no thrombosis, but dynamic compression and occlusion of the subclavian vein where it passes the first rib. Magnetic resonance imaging (MRI) of the neck showed no cervical (ie, extra) rib and no soft-tissue abnormalities of the scalene triangle.

Following this, the patient underwent resection of the left first rib for decompression of the venous thoracic outlet, which resulted in resolution of his symptoms. He remained asymptomatic at 6-month follow-up.

PAGET-SCHROETTER SYNDROME

Paget-Schroetter syndrome, also referred to as effort-induced or effort thrombosis, is thrombosis of the axillary or subclavian vein associated with strenuous and repetitive activity of the arms. Anatomic abnormalities at the thoracic outlet—cervical rib, congenital bands, hypertrophy of scalene tendons, abnormal insertion of the costoclavicular ligament—and repetitive trauma to the endothelium of the subclavian vein are key factors in its initiation and progression.

The condition is seen primarily in young people who participate in strenuous activities such as rowing, weight lifting, and baseball pitching. It is estimated to be the cause of 40% of cases of primary upper-extremity deep vein thrombosis in the absence of an obvious risk factor or trigger such as a central venous catheter, pacemaker, port, or occult malignancy.¹

A provocative test such as the Adson test or hyperabduction test during MRI or venography helps confirm thoracic outlet obstruction by demonstrating dynamic obstruction.²

TREATMENT CONSIDERATIONS

There are no universal guidelines for the treatment of Paget-Schroetter syndrome. However, the available data^3–5 suggest a multimodal approach that involves early catheter-directed thrombolysis and subsequent surgical decompression of the thoracic outlet. This can restore venous patency and reduce the risk of long-term complications such as rethrombosis and postthrombotic syndrome.^3–5

Surgical treatment includes resection of the first rib and division of the scalene muscles and the costoclavicular ligament. MRI with provocative testing helps guide the surgical approach. Anticoagulation therapy alone—ie, without thrombolysis and surgical decompression—is inadequate as it leads to recurrence of thrombosis and residual symptoms.⁶

Paget-Schroetter syndrome should not be managed the same as lower-extremity deep vein thrombosis because the cause and the exacerbating factors are different.

Unanswered questions

Because we have no data from randomized controlled trials, questions about management remain. What should be the duration of anticoagulation, especially in the absence of coexisting thrombophilia? Is thrombophilia screening useful? What is the optimal timing for starting thrombolytic therapy?

A careful history and heightened suspicion are required to make this diagnosis. If undiagnosed, it carries a risk of significant long-term morbidity and death. Dynamic obstruction during venography, in addition to MRI, can help identify an anatomic obstruction.

A 43-year-old man with no medical history presented with pain and swelling in his left arm for 2 weeks. He was a regular weight lifter, and his exercise routine included repetitive hyperextension and hyperabduction of his arms while lifting heavy weights.

He had no history of recent trauma or venous cannulation of the left arm. His family history was negative for thrombophilic disorders. Physical examination revealed a swollen and erythematous left arm and visible venous collaterals at the neck, shoulder, and chest. There was no evidence of arterial insufficiency.

Duplex ultrasonography confirmed thrombosis of the left brachial, axillary, and subclavian veins. Further evaluation with computed tomography showed no intrathoracic mass but revealed several subsegmental pulmonary thrombi in the right lung. A screen for thrombophilia was negative. Venography confirmed complete thrombotic occlusion of the subclavian, axillary, and brachial veins (Figure 1).

Catheter-directed thrombolysis with tissue plasminogen activator resulted in complete resolution of the thrombosis, but venography after 3 days of thrombolysis showed 50% residual stenosis of the left subclavian vein where it passes under the first rib (Figure 2). The redness and swelling had markedly improved 2 days after thrombolytic therapy. He was discharged home on rivaroxaban 20 mg daily.

Follow-up venography 2 months later (Figure 3), with the patient performing hyperabduction of the arms, showed a patent subclavian vein with no thrombosis, but dynamic compression and occlusion of the subclavian vein where it passes the first rib. Magnetic resonance imaging (MRI) of the neck showed no cervical (ie, extra) rib and no soft-tissue abnormalities of the scalene triangle.

Following this, the patient underwent resection of the left first rib for decompression of the venous thoracic outlet, which resulted in resolution of his symptoms. He remained asymptomatic at 6-month follow-up.

PAGET-SCHROETTER SYNDROME

Paget-Schroetter syndrome, also referred to as effort-induced or effort thrombosis, is thrombosis of the axillary or subclavian vein associated with strenuous and repetitive activity of the arms. Anatomic abnormalities at the thoracic outlet—cervical rib, congenital bands, hypertrophy of scalene tendons, abnormal insertion of the costoclavicular ligament—and repetitive trauma to the endothelium of the subclavian vein are key factors in its initiation and progression.

The condition is seen primarily in young people who participate in strenuous activities such as rowing, weight lifting, and baseball pitching. It is estimated to be the cause of 40% of cases of primary upper-extremity deep vein thrombosis in the absence of an obvious risk factor or trigger such as a central venous catheter, pacemaker, port, or occult malignancy.¹

A provocative test such as the Adson test or hyperabduction test during MRI or venography helps confirm thoracic outlet obstruction by demonstrating dynamic obstruction.²

TREATMENT CONSIDERATIONS

There are no universal guidelines for the treatment of Paget-Schroetter syndrome. However, the available data^3–5 suggest a multimodal approach that involves early catheter-directed thrombolysis and subsequent surgical decompression of the thoracic outlet. This can restore venous patency and reduce the risk of long-term complications such as rethrombosis and postthrombotic syndrome.^3–5

Surgical treatment includes resection of the first rib and division of the scalene muscles and the costoclavicular ligament. MRI with provocative testing helps guide the surgical approach. Anticoagulation therapy alone—ie, without thrombolysis and surgical decompression—is inadequate as it leads to recurrence of thrombosis and residual symptoms.⁶

Paget-Schroetter syndrome should not be managed the same as lower-extremity deep vein thrombosis because the cause and the exacerbating factors are different.

Unanswered questions

Because we have no data from randomized controlled trials, questions about management remain. What should be the duration of anticoagulation, especially in the absence of coexisting thrombophilia? Is thrombophilia screening useful? What is the optimal timing for starting thrombolytic therapy?

A careful history and heightened suspicion are required to make this diagnosis. If undiagnosed, it carries a risk of significant long-term morbidity and death. Dynamic obstruction during venography, in addition to MRI, can help identify an anatomic obstruction.

CHICAGO – Endovascular lower-extremity procedures were not associated with lower 30-day readmission rates compared with open surgery in a retrospective review of 7,089 patients.

All-cause, 30-day readmissions were actually higher with an endovascular approach at 12.3% vs. 9.6% for open procedures (Relative risk, 1.28; P = .0003).

Among all patients, an index diagnosis of gangrene was most predictive of readmission (RR, 1.89; P less than .0001), Dr. Todd R. Vogel said at the annual meeting of the Midwestern Vascular Surgical Society.

The data were compiled from 7,089 patients in the Cerner Health Facts database who were admitted for peripheral artery disease and elective lower extremity procedures (3,615 open; 3,474 endo) between September 2008 and March 2014. Their average age was 67.7 years, 44.7% were aged 70 years or older, 60% were men, and 21% were African American.

Frontline Medical News

Older patients and men were significantly more likely to receive endovascular procedures (P less than .0001), said Dr. Vogel, chief of vascular surgery, University of Missouri Health System in Columbia.

Overall, 767 patients (11%) were readmitted (344 open; 423 endo), with gangrene accounting for 21.7% of readmissions.

Other index diagnoses associated with higher 30-day readmissions for all lower extremity procedures were fluid and electrolyte disorders, chronic anemia, lower extremity infection, heart failure, chronic kidney disease, and chronic pulmonary disease.

When stratified by procedure type, the reasons for readmission were very different within the same population of patients based on procedure type, Dr. Vogel said.

Patients who underwent an open procedure were more likely to be readmitted if they had heart failure (RR, 1.78; P less than .0001) or posthemorrhagic anemia (RR, 1.54: P = .006).

Infections – be they lower extremity infection, other infection, postoperative infection, or sepsis – were not predictive of readmission when documented at the index admission for the open cohort.

In contrast, chronic conditions were the major predictors of readmission for patients undergoing endovascular procedures, he said. They included chronic anemia (RR, 1.58; P less than .0001), chronic airway obstruction (RR, 1.36; P = .0095), chronic heart disease (RR, 1.33; P = .0019), chronic kidney disease (RR, 1.37; P = .0013), diabetes (RR, 1.34; P = .0012), and hypertension (RR, 1.27; P = .023).

Fluid and electrolyte disorders (RR, 1.65, P less than .0001) and lower extremity infections (RR, 1.57, P = .0016) were also significant predictors of readmission in the endovascular group.

To ensure there were no disparities between index and readmission diagnoses, a final analysis was performed by procedure type in the 767 readmissions. It confirmed that for the endovascular procedures, chronic problems are bringing patients back to the hospital and not necessarily complications from the procedure, whereas infections, device complications, and hemorrhage are the reasons open surgery patients return, Dr. Vogel said.

“The question is are chronic conditions associated with readmissions the fault of the intervention? As physicians can we hope to curb this in patients who have chronic problems and are then readmitted?” he said.

Some audience members argued that no matter if the patient had a chronic condition or not preoperatively, the responsibility rests with the surgeon because he or she opted to put the patient through an elective endovascular procedure and now they’re returning with chronic heart failure, for example.

Dr. Vogel said this was the first pass at the data and trying to understand what drives readmissions and that it’s possible an endovascular procedure could exacerbate a chronic condition, but that surgeons should take steps to mitigate readmission risk in those with known chronic conditions.

Other attendees questioned how many of the readmissions were planned, hinting that the readmissions may not be directly related to the endovascular technique.

Dr. Vogel said it was difficult using only the ICD-9 codes in the database to determine exactly how many readmissions were planned, but noted that further analyses are intended.

“Reasons for readmission can be exacerbation of chronic patient issues, as seen in the endovascular group, or may be secondary to later complications of the procedure such as wound infections and device complications, as seen after open bypass procedures,” he said in an interview. “Identifying patients with increased risk for readmission after vascular procedures may lead to more effective and higher quality care during the index hospitalization. Our future studies will focus on a more detailed, granular evaluation of these high-risk diagnoses groups through use of the electronic medical record.”

Dr. Vogel reported having no financial disclosures.

[email protected]

On Twitter @pwendl

CHICAGO – Endovascular lower-extremity procedures were not associated with lower 30-day readmission rates compared with open surgery in a retrospective review of 7,089 patients.

All-cause, 30-day readmissions were actually higher with an endovascular approach at 12.3% vs. 9.6% for open procedures (Relative risk, 1.28; P = .0003).

Among all patients, an index diagnosis of gangrene was most predictive of readmission (RR, 1.89; P less than .0001), Dr. Todd R. Vogel said at the annual meeting of the Midwestern Vascular Surgical Society.

The data were compiled from 7,089 patients in the Cerner Health Facts database who were admitted for peripheral artery disease and elective lower extremity procedures (3,615 open; 3,474 endo) between September 2008 and March 2014. Their average age was 67.7 years, 44.7% were aged 70 years or older, 60% were men, and 21% were African American.

Frontline Medical News

Older patients and men were significantly more likely to receive endovascular procedures (P less than .0001), said Dr. Vogel, chief of vascular surgery, University of Missouri Health System in Columbia.

Overall, 767 patients (11%) were readmitted (344 open; 423 endo), with gangrene accounting for 21.7% of readmissions.

Other index diagnoses associated with higher 30-day readmissions for all lower extremity procedures were fluid and electrolyte disorders, chronic anemia, lower extremity infection, heart failure, chronic kidney disease, and chronic pulmonary disease.

When stratified by procedure type, the reasons for readmission were very different within the same population of patients based on procedure type, Dr. Vogel said.

Patients who underwent an open procedure were more likely to be readmitted if they had heart failure (RR, 1.78; P less than .0001) or posthemorrhagic anemia (RR, 1.54: P = .006).

Infections – be they lower extremity infection, other infection, postoperative infection, or sepsis – were not predictive of readmission when documented at the index admission for the open cohort.

In contrast, chronic conditions were the major predictors of readmission for patients undergoing endovascular procedures, he said. They included chronic anemia (RR, 1.58; P less than .0001), chronic airway obstruction (RR, 1.36; P = .0095), chronic heart disease (RR, 1.33; P = .0019), chronic kidney disease (RR, 1.37; P = .0013), diabetes (RR, 1.34; P = .0012), and hypertension (RR, 1.27; P = .023).

Fluid and electrolyte disorders (RR, 1.65, P less than .0001) and lower extremity infections (RR, 1.57, P = .0016) were also significant predictors of readmission in the endovascular group.

To ensure there were no disparities between index and readmission diagnoses, a final analysis was performed by procedure type in the 767 readmissions. It confirmed that for the endovascular procedures, chronic problems are bringing patients back to the hospital and not necessarily complications from the procedure, whereas infections, device complications, and hemorrhage are the reasons open surgery patients return, Dr. Vogel said.

“The question is are chronic conditions associated with readmissions the fault of the intervention? As physicians can we hope to curb this in patients who have chronic problems and are then readmitted?” he said.

Some audience members argued that no matter if the patient had a chronic condition or not preoperatively, the responsibility rests with the surgeon because he or she opted to put the patient through an elective endovascular procedure and now they’re returning with chronic heart failure, for example.

Dr. Vogel said this was the first pass at the data and trying to understand what drives readmissions and that it’s possible an endovascular procedure could exacerbate a chronic condition, but that surgeons should take steps to mitigate readmission risk in those with known chronic conditions.

Other attendees questioned how many of the readmissions were planned, hinting that the readmissions may not be directly related to the endovascular technique.

Dr. Vogel said it was difficult using only the ICD-9 codes in the database to determine exactly how many readmissions were planned, but noted that further analyses are intended.

“Reasons for readmission can be exacerbation of chronic patient issues, as seen in the endovascular group, or may be secondary to later complications of the procedure such as wound infections and device complications, as seen after open bypass procedures,” he said in an interview. “Identifying patients with increased risk for readmission after vascular procedures may lead to more effective and higher quality care during the index hospitalization. Our future studies will focus on a more detailed, granular evaluation of these high-risk diagnoses groups through use of the electronic medical record.”

Dr. Vogel reported having no financial disclosures.

[email protected]

On Twitter @pwendl

CHICAGO – Endovascular lower-extremity procedures were not associated with lower 30-day readmission rates compared with open surgery in a retrospective review of 7,089 patients.

All-cause, 30-day readmissions were actually higher with an endovascular approach at 12.3% vs. 9.6% for open procedures (Relative risk, 1.28; P = .0003).

Among all patients, an index diagnosis of gangrene was most predictive of readmission (RR, 1.89; P less than .0001), Dr. Todd R. Vogel said at the annual meeting of the Midwestern Vascular Surgical Society.

The data were compiled from 7,089 patients in the Cerner Health Facts database who were admitted for peripheral artery disease and elective lower extremity procedures (3,615 open; 3,474 endo) between September 2008 and March 2014. Their average age was 67.7 years, 44.7% were aged 70 years or older, 60% were men, and 21% were African American.

Frontline Medical News

Older patients and men were significantly more likely to receive endovascular procedures (P less than .0001), said Dr. Vogel, chief of vascular surgery, University of Missouri Health System in Columbia.

Overall, 767 patients (11%) were readmitted (344 open; 423 endo), with gangrene accounting for 21.7% of readmissions.

Other index diagnoses associated with higher 30-day readmissions for all lower extremity procedures were fluid and electrolyte disorders, chronic anemia, lower extremity infection, heart failure, chronic kidney disease, and chronic pulmonary disease.

When stratified by procedure type, the reasons for readmission were very different within the same population of patients based on procedure type, Dr. Vogel said.

Patients who underwent an open procedure were more likely to be readmitted if they had heart failure (RR, 1.78; P less than .0001) or posthemorrhagic anemia (RR, 1.54: P = .006).

Infections – be they lower extremity infection, other infection, postoperative infection, or sepsis – were not predictive of readmission when documented at the index admission for the open cohort.

In contrast, chronic conditions were the major predictors of readmission for patients undergoing endovascular procedures, he said. They included chronic anemia (RR, 1.58; P less than .0001), chronic airway obstruction (RR, 1.36; P = .0095), chronic heart disease (RR, 1.33; P = .0019), chronic kidney disease (RR, 1.37; P = .0013), diabetes (RR, 1.34; P = .0012), and hypertension (RR, 1.27; P = .023).

Fluid and electrolyte disorders (RR, 1.65, P less than .0001) and lower extremity infections (RR, 1.57, P = .0016) were also significant predictors of readmission in the endovascular group.

To ensure there were no disparities between index and readmission diagnoses, a final analysis was performed by procedure type in the 767 readmissions. It confirmed that for the endovascular procedures, chronic problems are bringing patients back to the hospital and not necessarily complications from the procedure, whereas infections, device complications, and hemorrhage are the reasons open surgery patients return, Dr. Vogel said.

“The question is are chronic conditions associated with readmissions the fault of the intervention? As physicians can we hope to curb this in patients who have chronic problems and are then readmitted?” he said.

Some audience members argued that no matter if the patient had a chronic condition or not preoperatively, the responsibility rests with the surgeon because he or she opted to put the patient through an elective endovascular procedure and now they’re returning with chronic heart failure, for example.

Dr. Vogel said this was the first pass at the data and trying to understand what drives readmissions and that it’s possible an endovascular procedure could exacerbate a chronic condition, but that surgeons should take steps to mitigate readmission risk in those with known chronic conditions.

Other attendees questioned how many of the readmissions were planned, hinting that the readmissions may not be directly related to the endovascular technique.

Dr. Vogel said it was difficult using only the ICD-9 codes in the database to determine exactly how many readmissions were planned, but noted that further analyses are intended.

“Reasons for readmission can be exacerbation of chronic patient issues, as seen in the endovascular group, or may be secondary to later complications of the procedure such as wound infections and device complications, as seen after open bypass procedures,” he said in an interview. “Identifying patients with increased risk for readmission after vascular procedures may lead to more effective and higher quality care during the index hospitalization. Our future studies will focus on a more detailed, granular evaluation of these high-risk diagnoses groups through use of the electronic medical record.”

Dr. Vogel reported having no financial disclosures.

[email protected]

On Twitter @pwendl

Novel anticoagulants will likely replace need for vitamin K antagonists

BY MADHUKAR S. PATEL, M.D., AND ELLIOT L. CHAIKOF, M.D.

The discovery of oral anticoagulants began in 1924, when Schofield linked the death of grazing cattle from internal hemorrhage to the consumption of spoiled sweet clover hay.¹ It was not until 1941, however, while trying to understand this observation, that Campbell & Link were able to identify the dicoumarol anticoagulant, which formed as a result of the spoiling process.² Ultimately, after noting that vitamin K led to reversal of the dicoumarol effect, synthesis of the first class of oral anticoagulants, known as vitamin K antagonists (VKAs), began.

Despite the numerous challenges associated with managing patients using this class of anticoagulants, VKAs have become the mainstay of oral anticoagulation therapy for the past 70 years. Over the past 5 years, however, new oral anticoagulants (NOACs) have emerged and are changing clinical practice.

Mechanistically, these medications are targeted therapies and work as either direct thrombin inhibitors (dabigatran etexilate) or direct factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban). Given their favorable pharmacologic design, NOACs have the potential to replace VKAs as they not only have an encouraging safety profile, but also are therapeutically equivalent or even superior to VKAs when used in certain patient populations.

Pharmacologic design

The targeted drug design of NOACs provides many pharmacologic advantages. Compared to VKAs, NOACs have a notably more predictable pharmacologic profile and relatively wide therapeutic window, which allows for fixed dosing, a rapid onset and offset, and fewer drug interactions.³ These characteristics eliminate the need for the routine dose monitoring and serial dose adjustments frequently associated with VKAs.

NOACs less commonly require bridging therapy with parenteral unfractionated heparin or low-molecular-weight heparins (LMWH) while awaiting therapeutic drug levels, as these levels are reached sooner and more predictably than with VKAs.⁴ As with any medication, however, appropriate consideration should to be given to specific patient populations such as those who are older or have significant comorbidities that may influence drug effect and clearance. Lastly, it should be mentioned that the pharmacologic benefits of NOACs apply not only from a patient perspective, but also from a health care systems standpoint, as their use may provide an opportunity to deliver more cost-effective care.

Specifically, economic models using available clinical trial data for stroke prevention in nonvalvular atrial fibrillation have shown that NOACs (apixaban, dabigatran, and rivaroxaban) are cost-effective alternatives when compared to warfarin.⁵ Although the results from such economic analyses are limited by the modeling assumptions they rely upon, these findings suggest that at least initially, cost should not be used as a prohibitive reason for adopting these new therapeutics.

Patient selection

The decision to institute oral anticoagulation therapy depends on each patient’s individualized bleeding risk to benefit of ischemia prevention ratio. A major determinant of this ratio is the clinical indication for which anticoagulation is begun. Numerous phase III clinical trials have been conducted comparing the use of NOACs to VKAs or placebos for the management of nonvalvular atrial fibrillation and venous thromboembolism, and as adjunctive therapy for patients with acute coronary syndrome.⁶

Meta-analyses of randomized trials have shown the most significant benefit to be in patients with nonvalvular atrial fibrillation, where NOACs yield significant reductions in stroke, intracranial hemorrhage, and all-cause mortality compared to warfarin, while displaying variable effects with regard to gastrointestinal bleeding.^6,7 In patients with VTE, NOACs have been found to have efficacy similar to that of VKAs with regard to the prevention of VTE or VTE-related death, and have been noted to have a better safety profile.⁶

Lastly, when studied as an adjunctive agent to dual antiplatelet therapy in patients with acute coronary syndrome, NOACs have been associated with an increased bleeding risk without a significant decrease in thrombosis risk.⁶ Taken together, these data suggest that the primary indication for instituting NOAC therapy should be considered strongly when deciding upon which class of anticoagulant to use.

Overcoming challenges

Since the introduction of NOACs, there has been concern over the lack of specific antidotes to therapy, especially when administered in patients with impaired clearance, a high likelihood of need for an urgent or emergent procedure, or those presenting with life threatening bleeding complications.

Most recently, however, interim analysis from clinical trial data has shown complete reversal of the direct thrombin inhibitor dabigatran with the humanized monoclonal antibody idarucizumab within minutes of administration in greater than 88% of patients studied.⁸ Similarly, agents such as a PER977 are currently under phase II clinical trials as they have been shown to form noncovalent hydrogen bonds and charge-charge interactions with oral factor Xa inhibitors as well as oral thrombin inhibitors leading to their reversal.⁹

Given these promising findings, it likely will not be long until reversal agents for NOACs become clinically available. Until that time, it is encouraging that the bleeding profile of these drugs has been found to be favorable compared to VKAs and their short half-life allows for a relatively expeditious natural reversal of their anticoagulant effect as the drug is eliminated.

Conclusion

Unlike the serendipitous path leading to the discovery of the first class of oral anticoagulants (VKAs), NOACs have been specifically designed to provide targeted anticoagulation and to address the shortcomings of VKAs. To this end, NOACs are becoming increasingly important in the management of patients with specific clinical conditions such as nonvalvular atrial fibrillation and venous thromboembolism, where they have been shown to provide a larger net clinical benefit relative to the available alternatives. Furthermore, with economic analyses providing evidence that NOACs are cost-effective for the healthcare system and clinical trial results suggesting progress in the development of antidotes for reversal, it is likely that with growing experience, these agents will replace VKAs as the mainstay for prophylactic and therapeutic oral anticoagulation in targeted patient populations.

Dr. Patel is a research fellow and Dr. Chaikof is surgeon-in-chief, both at the department of surgery, Beth Israel Deaconess Medical Center, Boston. They reported no conflicts of interest.

References

1. J Am Vet Med Assoc. 1924;64:553-75 (See Br J Haematol 2008 Mar 18;141[6]:757-63).

2. J Biol Chem. 1941;138:21-33 (See Nutr Rev. 1974 Aug;32[8]:244-6).

3. Am Soc Hematol Educ Program. 2013;2013:464-70.

4. Eur Heart J. 2013 Jul;34(27):2094-2106.

5. Stroke. 2013 Jun;44(6):1676-81.

6. Nat Rev Cardiol. 2014 Dec;11(12):693-703.

7. Lancet. 2014 Mar 15;383(9921):955-62.

8. N Engl J Med. 2015;373(6):511-20.

9. N Engl J Med. 2014;371(22):2141-2.

What the doctor didn’t order: unintended consequences and pitfalls of NOACs

BY THOMAS WAKEFIELD, M.D., ANDREA OBI, M.D., AND DAWN COLEMAN, M.D.

Recently, several new oral anticoagulants have gained FDA approval to replace warfarin, capturing the attention of popular media. These include dabigatran, rivaroxaban, apixaban, and edoxaban. Dabigatran targets activated factor II (factor IIa), while rivaroxaban, apixaban, and edoxaban target activated factor X (factor Xa). Easy to take with a once- or twice-daily pill, with no cumbersome monitoring, they represent a seemingly ideal treatment for the chronically anticoagulated patient. All agents are currently FDA approved in the United States for treatment of acute venous thromboembolism (VTE) and atrial fibrillation (AF).

Dabigatran and edoxaban

As with warfarin, dabigatran and edoxaban require the use of a low-molecular-weight heparin (LMWH) or unfractionated heparin “bridge” when therapy is beginning, while rivaroxaban and apixaban are instituted as monotherapy without such a bridge. Dabigatran etexilate (PradaxaR, Boehringer Ingelheim) has the longest half-life of all of the NOACs at 12-17 hours, and this half-life is prolonged with increasing age and decreasing renal function.¹ It is the only new agent that can be at least partially reversed with dialysis.² Edoxaban (SavaysaR, Daiichi Sankyo) carries a boxed warning stating that this agent is less effective in AF patients with a creatinine clearance greater than 95 mL/min, and that kidney function should be assessed prior to starting treatment: Such patients have a greater risk of stroke compared with similar patients treated with warfarin. Edoxaban is the only agent specifically tested at a lower dose in patients at significantly increased risk of bleeding complications (low body weight and/or decreased creatinine clearance).³

Rivaroxaban and apixaban

Rivaroxaban (XareltoR, Bayer and Janssen), and apixaban (EliquisR, Bristol Myers-Squibb), unique among the NOACs, have been tested for extended therapy of acute DVT after treatment of 6-12 months. They were found to result in a significant decrease in recurrent VTE without an increase in major bleeding compared to placebo.^4,5 Rivaroxaban has once-daily dosing and apixaban has twice-daily dosing; both are immediate monotherapy, making them quite convenient for patients. Apixaban is the only agent among the NOACs to have a slight decrease in gastrointestinal bleeding compared to warfarin.⁶

Consequences and pitfalls with NOACs

Problems with these new drugs, which may diminish our current level of enthusiasm for these agents to totally replace warfarin, include the inability to reliably follow their levels and to reverse their anticoagulant effects, the lack of data available on bridging when other procedures need to be performed, their short half-lives, and the lack of data on their anti-inflammatory effects.

With regard to monitoring of anticoagulation, the International Society of Thrombosis and Hemostasis (ISTH) has published a recommendation⁷ that lists these scenarios:

• When a patient is bleeding.

• Before surgery or an invasive procedure when the patient has taken the drug in the previous 24 hours, or longer if creatinine clearance (CrCl) is less than 50 mL/min.

• Identification of subtherapeutic or supratherapeutic levels in patients taking other drugs that are known to affect pharmacokinetics.

• Identification of subtherapeutic or supratherapeutic levels in patients at body weight extremes.

• Patients with deteriorating renal function.

• During perioperative management.

• During reversal of anticoagulation.

• When there is suspicion of overdose.

• Assessment of compliance in patients suffering thrombotic events while on treatment.

Currently, there exists no commercially available reversal agent for any of the NOACs and existing reversal agents for traditional anticoagulants are of limited, if any, use. Drugs under development include agents for the factor Xa inhibitors and for the thrombin inhibitor. Until the time that specific reversal agents exist, supportive care is the mainstay of therapy. In cases of trauma or severe or life-threatening bleeding, administration of concentrated clotting factors (prothrombin complex concentrate) or dialysis (dabigatran only) may be utilized. However, data from large clinical trials is lacking. A recent study of 90 patients receiving an antibody directed against dabigatran has revealed that the anticoagulant effects of dabigatran were reversed safely within minutes of administration; however, drug levels were not consistently suppressed at 24 hours in 20% of the cohort.⁸

There are no national guidelines nor large scale studies to guide bridging NOACs for procedures. The relatively short half-life for these agents makes it likely that traditional bridging as is practiced for warfarin is not necessary.⁹ However, this represents a double edged sword; withholding anticoagulation for two doses (such as if a patient becomes ill or a clinician is overly cautious around the time of a procedure) may leave the patient unprotected.

The final question with the new agents is their anti-inflammatory effects. We know that heparin and LMWH have significant pleiotropic effects that are not necessarily related to their anticoagulant effects. These effects are important to decrease the inflammatory nature of the thrombus and its effect on the vein wall. We do not know if the new oral agents have similar effects, as this has never fully been tested. In view of the fact that two of the agents are being used as monotherapy agents without any heparin/LMWH bridge, the anti-inflammatory properties of these new agents should be defined to make sure that such a bridge is not necessary.

Conclusion

So, in summary, although these agents have much to offer, there are many questions that remain to be addressed and answered before they totally replace traditional approaches to anticoagulation, in the realm of VTE. It must not be overlooked that for all the benefits, they each carry a risk of bleeding as they all target portions of the coagulation mechanism. We believe, that as with any “gift horse,” physicians should perhaps examine the data more closely and proceed with caution.

Dr. Wakefield is director of the Samuel and Jean Frankel Cardiovascular Center, Dr. Obi is a vascular surgery fellow, and Dr. Coleman is program director, section of vascular surgery, at the University of Michigan, Ann Arbor. They reported no conflicts of interest.

References

1. N Engl J Med. 2009;361:2342-52.

2. J Vasc Surg: Venous Lymphat Disord. 2013;1:418-26.

3. N Engl J Med. 2013;369:1406-15.

4. N Engl J Med. 2010;363:2499-2510.

5. N Engl J Med. 2013;368:699-708.

6. Arterioscler Thromb Vasc Biol. 2015;35:1056-65.

7. J Thromb Haemost. 2013;11:756-60.

8. N Engl J Med. 2015;373:511-20.

9. Curr Opin Anaesthesiol. 2014;27:409-19.

Novel anticoagulants will likely replace need for vitamin K antagonists

BY MADHUKAR S. PATEL, M.D., AND ELLIOT L. CHAIKOF, M.D.

The discovery of oral anticoagulants began in 1924, when Schofield linked the death of grazing cattle from internal hemorrhage to the consumption of spoiled sweet clover hay.¹ It was not until 1941, however, while trying to understand this observation, that Campbell & Link were able to identify the dicoumarol anticoagulant, which formed as a result of the spoiling process.² Ultimately, after noting that vitamin K led to reversal of the dicoumarol effect, synthesis of the first class of oral anticoagulants, known as vitamin K antagonists (VKAs), began.

Despite the numerous challenges associated with managing patients using this class of anticoagulants, VKAs have become the mainstay of oral anticoagulation therapy for the past 70 years. Over the past 5 years, however, new oral anticoagulants (NOACs) have emerged and are changing clinical practice.

Mechanistically, these medications are targeted therapies and work as either direct thrombin inhibitors (dabigatran etexilate) or direct factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban). Given their favorable pharmacologic design, NOACs have the potential to replace VKAs as they not only have an encouraging safety profile, but also are therapeutically equivalent or even superior to VKAs when used in certain patient populations.

Pharmacologic design

The targeted drug design of NOACs provides many pharmacologic advantages. Compared to VKAs, NOACs have a notably more predictable pharmacologic profile and relatively wide therapeutic window, which allows for fixed dosing, a rapid onset and offset, and fewer drug interactions.³ These characteristics eliminate the need for the routine dose monitoring and serial dose adjustments frequently associated with VKAs.

NOACs less commonly require bridging therapy with parenteral unfractionated heparin or low-molecular-weight heparins (LMWH) while awaiting therapeutic drug levels, as these levels are reached sooner and more predictably than with VKAs.⁴ As with any medication, however, appropriate consideration should to be given to specific patient populations such as those who are older or have significant comorbidities that may influence drug effect and clearance. Lastly, it should be mentioned that the pharmacologic benefits of NOACs apply not only from a patient perspective, but also from a health care systems standpoint, as their use may provide an opportunity to deliver more cost-effective care.

Specifically, economic models using available clinical trial data for stroke prevention in nonvalvular atrial fibrillation have shown that NOACs (apixaban, dabigatran, and rivaroxaban) are cost-effective alternatives when compared to warfarin.⁵ Although the results from such economic analyses are limited by the modeling assumptions they rely upon, these findings suggest that at least initially, cost should not be used as a prohibitive reason for adopting these new therapeutics.

Patient selection

The decision to institute oral anticoagulation therapy depends on each patient’s individualized bleeding risk to benefit of ischemia prevention ratio. A major determinant of this ratio is the clinical indication for which anticoagulation is begun. Numerous phase III clinical trials have been conducted comparing the use of NOACs to VKAs or placebos for the management of nonvalvular atrial fibrillation and venous thromboembolism, and as adjunctive therapy for patients with acute coronary syndrome.⁶

Meta-analyses of randomized trials have shown the most significant benefit to be in patients with nonvalvular atrial fibrillation, where NOACs yield significant reductions in stroke, intracranial hemorrhage, and all-cause mortality compared to warfarin, while displaying variable effects with regard to gastrointestinal bleeding.^6,7 In patients with VTE, NOACs have been found to have efficacy similar to that of VKAs with regard to the prevention of VTE or VTE-related death, and have been noted to have a better safety profile.⁶

Lastly, when studied as an adjunctive agent to dual antiplatelet therapy in patients with acute coronary syndrome, NOACs have been associated with an increased bleeding risk without a significant decrease in thrombosis risk.⁶ Taken together, these data suggest that the primary indication for instituting NOAC therapy should be considered strongly when deciding upon which class of anticoagulant to use.

Overcoming challenges

Since the introduction of NOACs, there has been concern over the lack of specific antidotes to therapy, especially when administered in patients with impaired clearance, a high likelihood of need for an urgent or emergent procedure, or those presenting with life threatening bleeding complications.

Most recently, however, interim analysis from clinical trial data has shown complete reversal of the direct thrombin inhibitor dabigatran with the humanized monoclonal antibody idarucizumab within minutes of administration in greater than 88% of patients studied.⁸ Similarly, agents such as a PER977 are currently under phase II clinical trials as they have been shown to form noncovalent hydrogen bonds and charge-charge interactions with oral factor Xa inhibitors as well as oral thrombin inhibitors leading to their reversal.⁹

Given these promising findings, it likely will not be long until reversal agents for NOACs become clinically available. Until that time, it is encouraging that the bleeding profile of these drugs has been found to be favorable compared to VKAs and their short half-life allows for a relatively expeditious natural reversal of their anticoagulant effect as the drug is eliminated.

Conclusion

Unlike the serendipitous path leading to the discovery of the first class of oral anticoagulants (VKAs), NOACs have been specifically designed to provide targeted anticoagulation and to address the shortcomings of VKAs. To this end, NOACs are becoming increasingly important in the management of patients with specific clinical conditions such as nonvalvular atrial fibrillation and venous thromboembolism, where they have been shown to provide a larger net clinical benefit relative to the available alternatives. Furthermore, with economic analyses providing evidence that NOACs are cost-effective for the healthcare system and clinical trial results suggesting progress in the development of antidotes for reversal, it is likely that with growing experience, these agents will replace VKAs as the mainstay for prophylactic and therapeutic oral anticoagulation in targeted patient populations.

Dr. Patel is a research fellow and Dr. Chaikof is surgeon-in-chief, both at the department of surgery, Beth Israel Deaconess Medical Center, Boston. They reported no conflicts of interest.

References

1. J Am Vet Med Assoc. 1924;64:553-75 (See Br J Haematol 2008 Mar 18;141[6]:757-63).

2. J Biol Chem. 1941;138:21-33 (See Nutr Rev. 1974 Aug;32[8]:244-6).

3. Am Soc Hematol Educ Program. 2013;2013:464-70.

4. Eur Heart J. 2013 Jul;34(27):2094-2106.

5. Stroke. 2013 Jun;44(6):1676-81.

6. Nat Rev Cardiol. 2014 Dec;11(12):693-703.

7. Lancet. 2014 Mar 15;383(9921):955-62.

8. N Engl J Med. 2015;373(6):511-20.

9. N Engl J Med. 2014;371(22):2141-2.

What the doctor didn’t order: unintended consequences and pitfalls of NOACs

BY THOMAS WAKEFIELD, M.D., ANDREA OBI, M.D., AND DAWN COLEMAN, M.D.

Recently, several new oral anticoagulants have gained FDA approval to replace warfarin, capturing the attention of popular media. These include dabigatran, rivaroxaban, apixaban, and edoxaban. Dabigatran targets activated factor II (factor IIa), while rivaroxaban, apixaban, and edoxaban target activated factor X (factor Xa). Easy to take with a once- or twice-daily pill, with no cumbersome monitoring, they represent a seemingly ideal treatment for the chronically anticoagulated patient. All agents are currently FDA approved in the United States for treatment of acute venous thromboembolism (VTE) and atrial fibrillation (AF).

Dabigatran and edoxaban

As with warfarin, dabigatran and edoxaban require the use of a low-molecular-weight heparin (LMWH) or unfractionated heparin “bridge” when therapy is beginning, while rivaroxaban and apixaban are instituted as monotherapy without such a bridge. Dabigatran etexilate (PradaxaR, Boehringer Ingelheim) has the longest half-life of all of the NOACs at 12-17 hours, and this half-life is prolonged with increasing age and decreasing renal function.¹ It is the only new agent that can be at least partially reversed with dialysis.² Edoxaban (SavaysaR, Daiichi Sankyo) carries a boxed warning stating that this agent is less effective in AF patients with a creatinine clearance greater than 95 mL/min, and that kidney function should be assessed prior to starting treatment: Such patients have a greater risk of stroke compared with similar patients treated with warfarin. Edoxaban is the only agent specifically tested at a lower dose in patients at significantly increased risk of bleeding complications (low body weight and/or decreased creatinine clearance).³

Rivaroxaban and apixaban

Rivaroxaban (XareltoR, Bayer and Janssen), and apixaban (EliquisR, Bristol Myers-Squibb), unique among the NOACs, have been tested for extended therapy of acute DVT after treatment of 6-12 months. They were found to result in a significant decrease in recurrent VTE without an increase in major bleeding compared to placebo.^4,5 Rivaroxaban has once-daily dosing and apixaban has twice-daily dosing; both are immediate monotherapy, making them quite convenient for patients. Apixaban is the only agent among the NOACs to have a slight decrease in gastrointestinal bleeding compared to warfarin.⁶

Consequences and pitfalls with NOACs

Problems with these new drugs, which may diminish our current level of enthusiasm for these agents to totally replace warfarin, include the inability to reliably follow their levels and to reverse their anticoagulant effects, the lack of data available on bridging when other procedures need to be performed, their short half-lives, and the lack of data on their anti-inflammatory effects.

With regard to monitoring of anticoagulation, the International Society of Thrombosis and Hemostasis (ISTH) has published a recommendation⁷ that lists these scenarios:

• When a patient is bleeding.

• Before surgery or an invasive procedure when the patient has taken the drug in the previous 24 hours, or longer if creatinine clearance (CrCl) is less than 50 mL/min.

• Identification of subtherapeutic or supratherapeutic levels in patients taking other drugs that are known to affect pharmacokinetics.

• Identification of subtherapeutic or supratherapeutic levels in patients at body weight extremes.

• Patients with deteriorating renal function.

• During perioperative management.

• During reversal of anticoagulation.

• When there is suspicion of overdose.

• Assessment of compliance in patients suffering thrombotic events while on treatment.

Currently, there exists no commercially available reversal agent for any of the NOACs and existing reversal agents for traditional anticoagulants are of limited, if any, use. Drugs under development include agents for the factor Xa inhibitors and for the thrombin inhibitor. Until the time that specific reversal agents exist, supportive care is the mainstay of therapy. In cases of trauma or severe or life-threatening bleeding, administration of concentrated clotting factors (prothrombin complex concentrate) or dialysis (dabigatran only) may be utilized. However, data from large clinical trials is lacking. A recent study of 90 patients receiving an antibody directed against dabigatran has revealed that the anticoagulant effects of dabigatran were reversed safely within minutes of administration; however, drug levels were not consistently suppressed at 24 hours in 20% of the cohort.⁸

There are no national guidelines nor large scale studies to guide bridging NOACs for procedures. The relatively short half-life for these agents makes it likely that traditional bridging as is practiced for warfarin is not necessary.⁹ However, this represents a double edged sword; withholding anticoagulation for two doses (such as if a patient becomes ill or a clinician is overly cautious around the time of a procedure) may leave the patient unprotected.

The final question with the new agents is their anti-inflammatory effects. We know that heparin and LMWH have significant pleiotropic effects that are not necessarily related to their anticoagulant effects. These effects are important to decrease the inflammatory nature of the thrombus and its effect on the vein wall. We do not know if the new oral agents have similar effects, as this has never fully been tested. In view of the fact that two of the agents are being used as monotherapy agents without any heparin/LMWH bridge, the anti-inflammatory properties of these new agents should be defined to make sure that such a bridge is not necessary.

Conclusion

So, in summary, although these agents have much to offer, there are many questions that remain to be addressed and answered before they totally replace traditional approaches to anticoagulation, in the realm of VTE. It must not be overlooked that for all the benefits, they each carry a risk of bleeding as they all target portions of the coagulation mechanism. We believe, that as with any “gift horse,” physicians should perhaps examine the data more closely and proceed with caution.

Dr. Wakefield is director of the Samuel and Jean Frankel Cardiovascular Center, Dr. Obi is a vascular surgery fellow, and Dr. Coleman is program director, section of vascular surgery, at the University of Michigan, Ann Arbor. They reported no conflicts of interest.

References

1. N Engl J Med. 2009;361:2342-52.

2. J Vasc Surg: Venous Lymphat Disord. 2013;1:418-26.

3. N Engl J Med. 2013;369:1406-15.

4. N Engl J Med. 2010;363:2499-2510.

5. N Engl J Med. 2013;368:699-708.

6. Arterioscler Thromb Vasc Biol. 2015;35:1056-65.

7. J Thromb Haemost. 2013;11:756-60.

8. N Engl J Med. 2015;373:511-20.

9. Curr Opin Anaesthesiol. 2014;27:409-19.

Novel anticoagulants will likely replace need for vitamin K antagonists

BY MADHUKAR S. PATEL, M.D., AND ELLIOT L. CHAIKOF, M.D.

The discovery of oral anticoagulants began in 1924, when Schofield linked the death of grazing cattle from internal hemorrhage to the consumption of spoiled sweet clover hay.¹ It was not until 1941, however, while trying to understand this observation, that Campbell & Link were able to identify the dicoumarol anticoagulant, which formed as a result of the spoiling process.² Ultimately, after noting that vitamin K led to reversal of the dicoumarol effect, synthesis of the first class of oral anticoagulants, known as vitamin K antagonists (VKAs), began.

Despite the numerous challenges associated with managing patients using this class of anticoagulants, VKAs have become the mainstay of oral anticoagulation therapy for the past 70 years. Over the past 5 years, however, new oral anticoagulants (NOACs) have emerged and are changing clinical practice.

Mechanistically, these medications are targeted therapies and work as either direct thrombin inhibitors (dabigatran etexilate) or direct factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban). Given their favorable pharmacologic design, NOACs have the potential to replace VKAs as they not only have an encouraging safety profile, but also are therapeutically equivalent or even superior to VKAs when used in certain patient populations.

Pharmacologic design

The targeted drug design of NOACs provides many pharmacologic advantages. Compared to VKAs, NOACs have a notably more predictable pharmacologic profile and relatively wide therapeutic window, which allows for fixed dosing, a rapid onset and offset, and fewer drug interactions.³ These characteristics eliminate the need for the routine dose monitoring and serial dose adjustments frequently associated with VKAs.

NOACs less commonly require bridging therapy with parenteral unfractionated heparin or low-molecular-weight heparins (LMWH) while awaiting therapeutic drug levels, as these levels are reached sooner and more predictably than with VKAs.⁴ As with any medication, however, appropriate consideration should to be given to specific patient populations such as those who are older or have significant comorbidities that may influence drug effect and clearance. Lastly, it should be mentioned that the pharmacologic benefits of NOACs apply not only from a patient perspective, but also from a health care systems standpoint, as their use may provide an opportunity to deliver more cost-effective care.

Specifically, economic models using available clinical trial data for stroke prevention in nonvalvular atrial fibrillation have shown that NOACs (apixaban, dabigatran, and rivaroxaban) are cost-effective alternatives when compared to warfarin.⁵ Although the results from such economic analyses are limited by the modeling assumptions they rely upon, these findings suggest that at least initially, cost should not be used as a prohibitive reason for adopting these new therapeutics.

Patient selection

The decision to institute oral anticoagulation therapy depends on each patient’s individualized bleeding risk to benefit of ischemia prevention ratio. A major determinant of this ratio is the clinical indication for which anticoagulation is begun. Numerous phase III clinical trials have been conducted comparing the use of NOACs to VKAs or placebos for the management of nonvalvular atrial fibrillation and venous thromboembolism, and as adjunctive therapy for patients with acute coronary syndrome.⁶

Meta-analyses of randomized trials have shown the most significant benefit to be in patients with nonvalvular atrial fibrillation, where NOACs yield significant reductions in stroke, intracranial hemorrhage, and all-cause mortality compared to warfarin, while displaying variable effects with regard to gastrointestinal bleeding.^6,7 In patients with VTE, NOACs have been found to have efficacy similar to that of VKAs with regard to the prevention of VTE or VTE-related death, and have been noted to have a better safety profile.⁶

Lastly, when studied as an adjunctive agent to dual antiplatelet therapy in patients with acute coronary syndrome, NOACs have been associated with an increased bleeding risk without a significant decrease in thrombosis risk.⁶ Taken together, these data suggest that the primary indication for instituting NOAC therapy should be considered strongly when deciding upon which class of anticoagulant to use.

Overcoming challenges

Since the introduction of NOACs, there has been concern over the lack of specific antidotes to therapy, especially when administered in patients with impaired clearance, a high likelihood of need for an urgent or emergent procedure, or those presenting with life threatening bleeding complications.

Most recently, however, interim analysis from clinical trial data has shown complete reversal of the direct thrombin inhibitor dabigatran with the humanized monoclonal antibody idarucizumab within minutes of administration in greater than 88% of patients studied.⁸ Similarly, agents such as a PER977 are currently under phase II clinical trials as they have been shown to form noncovalent hydrogen bonds and charge-charge interactions with oral factor Xa inhibitors as well as oral thrombin inhibitors leading to their reversal.⁹

Given these promising findings, it likely will not be long until reversal agents for NOACs become clinically available. Until that time, it is encouraging that the bleeding profile of these drugs has been found to be favorable compared to VKAs and their short half-life allows for a relatively expeditious natural reversal of their anticoagulant effect as the drug is eliminated.

Conclusion

Unlike the serendipitous path leading to the discovery of the first class of oral anticoagulants (VKAs), NOACs have been specifically designed to provide targeted anticoagulation and to address the shortcomings of VKAs. To this end, NOACs are becoming increasingly important in the management of patients with specific clinical conditions such as nonvalvular atrial fibrillation and venous thromboembolism, where they have been shown to provide a larger net clinical benefit relative to the available alternatives. Furthermore, with economic analyses providing evidence that NOACs are cost-effective for the healthcare system and clinical trial results suggesting progress in the development of antidotes for reversal, it is likely that with growing experience, these agents will replace VKAs as the mainstay for prophylactic and therapeutic oral anticoagulation in targeted patient populations.

Dr. Patel is a research fellow and Dr. Chaikof is surgeon-in-chief, both at the department of surgery, Beth Israel Deaconess Medical Center, Boston. They reported no conflicts of interest.

References

1. J Am Vet Med Assoc. 1924;64:553-75 (See Br J Haematol 2008 Mar 18;141[6]:757-63).

2. J Biol Chem. 1941;138:21-33 (See Nutr Rev. 1974 Aug;32[8]:244-6).

3. Am Soc Hematol Educ Program. 2013;2013:464-70.

4. Eur Heart J. 2013 Jul;34(27):2094-2106.

5. Stroke. 2013 Jun;44(6):1676-81.

6. Nat Rev Cardiol. 2014 Dec;11(12):693-703.

7. Lancet. 2014 Mar 15;383(9921):955-62.

8. N Engl J Med. 2015;373(6):511-20.

9. N Engl J Med. 2014;371(22):2141-2.

What the doctor didn’t order: unintended consequences and pitfalls of NOACs

BY THOMAS WAKEFIELD, M.D., ANDREA OBI, M.D., AND DAWN COLEMAN, M.D.

Recently, several new oral anticoagulants have gained FDA approval to replace warfarin, capturing the attention of popular media. These include dabigatran, rivaroxaban, apixaban, and edoxaban. Dabigatran targets activated factor II (factor IIa), while rivaroxaban, apixaban, and edoxaban target activated factor X (factor Xa). Easy to take with a once- or twice-daily pill, with no cumbersome monitoring, they represent a seemingly ideal treatment for the chronically anticoagulated patient. All agents are currently FDA approved in the United States for treatment of acute venous thromboembolism (VTE) and atrial fibrillation (AF).

Dabigatran and edoxaban

As with warfarin, dabigatran and edoxaban require the use of a low-molecular-weight heparin (LMWH) or unfractionated heparin “bridge” when therapy is beginning, while rivaroxaban and apixaban are instituted as monotherapy without such a bridge. Dabigatran etexilate (PradaxaR, Boehringer Ingelheim) has the longest half-life of all of the NOACs at 12-17 hours, and this half-life is prolonged with increasing age and decreasing renal function.¹ It is the only new agent that can be at least partially reversed with dialysis.² Edoxaban (SavaysaR, Daiichi Sankyo) carries a boxed warning stating that this agent is less effective in AF patients with a creatinine clearance greater than 95 mL/min, and that kidney function should be assessed prior to starting treatment: Such patients have a greater risk of stroke compared with similar patients treated with warfarin. Edoxaban is the only agent specifically tested at a lower dose in patients at significantly increased risk of bleeding complications (low body weight and/or decreased creatinine clearance).³

Rivaroxaban and apixaban

Rivaroxaban (XareltoR, Bayer and Janssen), and apixaban (EliquisR, Bristol Myers-Squibb), unique among the NOACs, have been tested for extended therapy of acute DVT after treatment of 6-12 months. They were found to result in a significant decrease in recurrent VTE without an increase in major bleeding compared to placebo.^4,5 Rivaroxaban has once-daily dosing and apixaban has twice-daily dosing; both are immediate monotherapy, making them quite convenient for patients. Apixaban is the only agent among the NOACs to have a slight decrease in gastrointestinal bleeding compared to warfarin.⁶

Consequences and pitfalls with NOACs

Problems with these new drugs, which may diminish our current level of enthusiasm for these agents to totally replace warfarin, include the inability to reliably follow their levels and to reverse their anticoagulant effects, the lack of data available on bridging when other procedures need to be performed, their short half-lives, and the lack of data on their anti-inflammatory effects.

With regard to monitoring of anticoagulation, the International Society of Thrombosis and Hemostasis (ISTH) has published a recommendation⁷ that lists these scenarios:

• When a patient is bleeding.

• Before surgery or an invasive procedure when the patient has taken the drug in the previous 24 hours, or longer if creatinine clearance (CrCl) is less than 50 mL/min.

• Identification of subtherapeutic or supratherapeutic levels in patients taking other drugs that are known to affect pharmacokinetics.

• Identification of subtherapeutic or supratherapeutic levels in patients at body weight extremes.

• Patients with deteriorating renal function.

• During perioperative management.

• During reversal of anticoagulation.

• When there is suspicion of overdose.

• Assessment of compliance in patients suffering thrombotic events while on treatment.

Currently, there exists no commercially available reversal agent for any of the NOACs and existing reversal agents for traditional anticoagulants are of limited, if any, use. Drugs under development include agents for the factor Xa inhibitors and for the thrombin inhibitor. Until the time that specific reversal agents exist, supportive care is the mainstay of therapy. In cases of trauma or severe or life-threatening bleeding, administration of concentrated clotting factors (prothrombin complex concentrate) or dialysis (dabigatran only) may be utilized. However, data from large clinical trials is lacking. A recent study of 90 patients receiving an antibody directed against dabigatran has revealed that the anticoagulant effects of dabigatran were reversed safely within minutes of administration; however, drug levels were not consistently suppressed at 24 hours in 20% of the cohort.⁸

There are no national guidelines nor large scale studies to guide bridging NOACs for procedures. The relatively short half-life for these agents makes it likely that traditional bridging as is practiced for warfarin is not necessary.⁹ However, this represents a double edged sword; withholding anticoagulation for two doses (such as if a patient becomes ill or a clinician is overly cautious around the time of a procedure) may leave the patient unprotected.

The final question with the new agents is their anti-inflammatory effects. We know that heparin and LMWH have significant pleiotropic effects that are not necessarily related to their anticoagulant effects. These effects are important to decrease the inflammatory nature of the thrombus and its effect on the vein wall. We do not know if the new oral agents have similar effects, as this has never fully been tested. In view of the fact that two of the agents are being used as monotherapy agents without any heparin/LMWH bridge, the anti-inflammatory properties of these new agents should be defined to make sure that such a bridge is not necessary.

Conclusion

So, in summary, although these agents have much to offer, there are many questions that remain to be addressed and answered before they totally replace traditional approaches to anticoagulation, in the realm of VTE. It must not be overlooked that for all the benefits, they each carry a risk of bleeding as they all target portions of the coagulation mechanism. We believe, that as with any “gift horse,” physicians should perhaps examine the data more closely and proceed with caution.

Dr. Wakefield is director of the Samuel and Jean Frankel Cardiovascular Center, Dr. Obi is a vascular surgery fellow, and Dr. Coleman is program director, section of vascular surgery, at the University of Michigan, Ann Arbor. They reported no conflicts of interest.

References

1. N Engl J Med. 2009;361:2342-52.

2. J Vasc Surg: Venous Lymphat Disord. 2013;1:418-26.

3. N Engl J Med. 2013;369:1406-15.

4. N Engl J Med. 2010;363:2499-2510.

5. N Engl J Med. 2013;368:699-708.

6. Arterioscler Thromb Vasc Biol. 2015;35:1056-65.

7. J Thromb Haemost. 2013;11:756-60.

8. N Engl J Med. 2015;373:511-20.

9. Curr Opin Anaesthesiol. 2014;27:409-19.

Adding a mechanical suction technique to local thrombolysis to break up and remove blood clots reduced postthrombotic syndrome (PTS) after deep vein thrombosis (DVT) without causing increased complications, according to a small retrospective study.

Dr. Chun-Yang Huang of the National Yang Ming University (Taipei, Taiwan) and colleagues examined patients diagnosed with acute proximal lower limb DVT. Patients received either thrombolysis alone via a catheter-directed thrombolysis (CDT), or percutaneous mechanical thrombectomy (PMT) by a combination of pharmacologic thrombolysis and suction; both techniques were accompanied by systemic anticoagulation. Though both treatment groups fared well during treatment and for the 12-month follow-up period, the PMT group had a significantly lower incidence of PTS 1 year after treatment (Ann. Vascular Surg. 2015. doi: 10.1016/j.avsg.2015.01.014).

For those with DVT, parenteral anticoagulation prevents propagation of the clot and minimizes risk of pulmonary embolism (PE); however, anticoagulation does not accelerate dissolution of the existing clot. According to study authors, 30%-40% of those with proximal leg DVTs will go on to develop PTS, with the prolonged distal venous stasis from an undisturbed clot causing loss of valvular competence and resultant chronic venous insufficiency. PTS can involve leg swelling, discomfort, skin changes, and ulceration, with significant impact on quality of life and health care costs.

Techniques such as CDT and PMT can increase the rate of clot dissolution, thus restoring patency sooner and minimizing risk for PTS. However, these methods also can carry increased risk of bleeding and infection, considerations that must be balanced against potential benefit.

Investigators reviewed records for 39 patients who were diagnosed with ultrasound- or CT-confirmed acute proximal lower limb DVT and received either CDT or PMT during the period from November 2010 to November 2013. Patients were not randomized to treatment arms but were assigned using clinical judgment and patient preference. During the 12-month follow-up, three participants died of malignancy and two were lost to follow-up. Analysis was completed for the remaining 34 patients.

Overall, patient characteristics did not differ significantly between groups, with mean ages of 62.75 for the PMT group (n = 16) and 64.17 for the CDT group (n = 18). In all, 13/34 participants were female. Patients in both treatment groups fared well, with no 30-day mortality, and no episodes of major bleeding, PE, or renal failure. Ten patients in the PMT group and six in the CDT group required stenting of the common iliac vein to maintain patency, a nonsignificant difference. Just one participant in the CDE group experienced a minor bleeding event.

Turning to outcomes, study authors assessed postprocedure patency, finding improved patency for both procedures (P less than .001 for both, compared with preoperation patency scores), with no significant difference between the two groups post procedure. Thrombus scores were also significantly better for both treatment arms post procedure (P less than .001). Clot burden tended to improve more rapidly over the 12-month follow-up period for the PMT group, though the difference between groups was just short of statistically significant.

At 12 months, though the amount of venous reflux did not differ significantly between groups, those who had received PMT had significantly fewer signs and symptoms of PTS. This assessment used the Villalta scale, a standardized assessment and scoring system for PTS, where higher numbers indicate worse PTS. The PMT group’s Villalta score was 2.06 +/–2.95, compared with 5.06 +/–4.07 for the CDT group (P = .030).

Study limitations included the small study size, retrospective study design, and lack of randomization. Acknowledging these limitations, Dr. Huang and coauthors called for larger, multicenter, randomized controlled studies of PMT. The personal and economic costs of PTS, they argue, warrant exploring whether PMT may help minimize total thrombolysis dose, reduce hospital stays, and decrease costs while minimizing the risks of chronic venous insufficiency post DVT.

Dr. Huang and coauthors reported no conflicts of interest.

Adding a mechanical suction technique to local thrombolysis to break up and remove blood clots reduced postthrombotic syndrome (PTS) after deep vein thrombosis (DVT) without causing increased complications, according to a small retrospective study.

Dr. Chun-Yang Huang of the National Yang Ming University (Taipei, Taiwan) and colleagues examined patients diagnosed with acute proximal lower limb DVT. Patients received either thrombolysis alone via a catheter-directed thrombolysis (CDT), or percutaneous mechanical thrombectomy (PMT) by a combination of pharmacologic thrombolysis and suction; both techniques were accompanied by systemic anticoagulation. Though both treatment groups fared well during treatment and for the 12-month follow-up period, the PMT group had a significantly lower incidence of PTS 1 year after treatment (Ann. Vascular Surg. 2015. doi: 10.1016/j.avsg.2015.01.014).

For those with DVT, parenteral anticoagulation prevents propagation of the clot and minimizes risk of pulmonary embolism (PE); however, anticoagulation does not accelerate dissolution of the existing clot. According to study authors, 30%-40% of those with proximal leg DVTs will go on to develop PTS, with the prolonged distal venous stasis from an undisturbed clot causing loss of valvular competence and resultant chronic venous insufficiency. PTS can involve leg swelling, discomfort, skin changes, and ulceration, with significant impact on quality of life and health care costs.

Techniques such as CDT and PMT can increase the rate of clot dissolution, thus restoring patency sooner and minimizing risk for PTS. However, these methods also can carry increased risk of bleeding and infection, considerations that must be balanced against potential benefit.

Investigators reviewed records for 39 patients who were diagnosed with ultrasound- or CT-confirmed acute proximal lower limb DVT and received either CDT or PMT during the period from November 2010 to November 2013. Patients were not randomized to treatment arms but were assigned using clinical judgment and patient preference. During the 12-month follow-up, three participants died of malignancy and two were lost to follow-up. Analysis was completed for the remaining 34 patients.

Overall, patient characteristics did not differ significantly between groups, with mean ages of 62.75 for the PMT group (n = 16) and 64.17 for the CDT group (n = 18). In all, 13/34 participants were female. Patients in both treatment groups fared well, with no 30-day mortality, and no episodes of major bleeding, PE, or renal failure. Ten patients in the PMT group and six in the CDT group required stenting of the common iliac vein to maintain patency, a nonsignificant difference. Just one participant in the CDE group experienced a minor bleeding event.

Turning to outcomes, study authors assessed postprocedure patency, finding improved patency for both procedures (P less than .001 for both, compared with preoperation patency scores), with no significant difference between the two groups post procedure. Thrombus scores were also significantly better for both treatment arms post procedure (P less than .001). Clot burden tended to improve more rapidly over the 12-month follow-up period for the PMT group, though the difference between groups was just short of statistically significant.

At 12 months, though the amount of venous reflux did not differ significantly between groups, those who had received PMT had significantly fewer signs and symptoms of PTS. This assessment used the Villalta scale, a standardized assessment and scoring system for PTS, where higher numbers indicate worse PTS. The PMT group’s Villalta score was 2.06 +/–2.95, compared with 5.06 +/–4.07 for the CDT group (P = .030).

Study limitations included the small study size, retrospective study design, and lack of randomization. Acknowledging these limitations, Dr. Huang and coauthors called for larger, multicenter, randomized controlled studies of PMT. The personal and economic costs of PTS, they argue, warrant exploring whether PMT may help minimize total thrombolysis dose, reduce hospital stays, and decrease costs while minimizing the risks of chronic venous insufficiency post DVT.

Dr. Huang and coauthors reported no conflicts of interest.

Adding a mechanical suction technique to local thrombolysis to break up and remove blood clots reduced postthrombotic syndrome (PTS) after deep vein thrombosis (DVT) without causing increased complications, according to a small retrospective study.

Dr. Chun-Yang Huang of the National Yang Ming University (Taipei, Taiwan) and colleagues examined patients diagnosed with acute proximal lower limb DVT. Patients received either thrombolysis alone via a catheter-directed thrombolysis (CDT), or percutaneous mechanical thrombectomy (PMT) by a combination of pharmacologic thrombolysis and suction; both techniques were accompanied by systemic anticoagulation. Though both treatment groups fared well during treatment and for the 12-month follow-up period, the PMT group had a significantly lower incidence of PTS 1 year after treatment (Ann. Vascular Surg. 2015. doi: 10.1016/j.avsg.2015.01.014).

For those with DVT, parenteral anticoagulation prevents propagation of the clot and minimizes risk of pulmonary embolism (PE); however, anticoagulation does not accelerate dissolution of the existing clot. According to study authors, 30%-40% of those with proximal leg DVTs will go on to develop PTS, with the prolonged distal venous stasis from an undisturbed clot causing loss of valvular competence and resultant chronic venous insufficiency. PTS can involve leg swelling, discomfort, skin changes, and ulceration, with significant impact on quality of life and health care costs.

Techniques such as CDT and PMT can increase the rate of clot dissolution, thus restoring patency sooner and minimizing risk for PTS. However, these methods also can carry increased risk of bleeding and infection, considerations that must be balanced against potential benefit.

Investigators reviewed records for 39 patients who were diagnosed with ultrasound- or CT-confirmed acute proximal lower limb DVT and received either CDT or PMT during the period from November 2010 to November 2013. Patients were not randomized to treatment arms but were assigned using clinical judgment and patient preference. During the 12-month follow-up, three participants died of malignancy and two were lost to follow-up. Analysis was completed for the remaining 34 patients.

Overall, patient characteristics did not differ significantly between groups, with mean ages of 62.75 for the PMT group (n = 16) and 64.17 for the CDT group (n = 18). In all, 13/34 participants were female. Patients in both treatment groups fared well, with no 30-day mortality, and no episodes of major bleeding, PE, or renal failure. Ten patients in the PMT group and six in the CDT group required stenting of the common iliac vein to maintain patency, a nonsignificant difference. Just one participant in the CDE group experienced a minor bleeding event.

Turning to outcomes, study authors assessed postprocedure patency, finding improved patency for both procedures (P less than .001 for both, compared with preoperation patency scores), with no significant difference between the two groups post procedure. Thrombus scores were also significantly better for both treatment arms post procedure (P less than .001). Clot burden tended to improve more rapidly over the 12-month follow-up period for the PMT group, though the difference between groups was just short of statistically significant.

At 12 months, though the amount of venous reflux did not differ significantly between groups, those who had received PMT had significantly fewer signs and symptoms of PTS. This assessment used the Villalta scale, a standardized assessment and scoring system for PTS, where higher numbers indicate worse PTS. The PMT group’s Villalta score was 2.06 +/–2.95, compared with 5.06 +/–4.07 for the CDT group (P = .030).

Study limitations included the small study size, retrospective study design, and lack of randomization. Acknowledging these limitations, Dr. Huang and coauthors called for larger, multicenter, randomized controlled studies of PMT. The personal and economic costs of PTS, they argue, warrant exploring whether PMT may help minimize total thrombolysis dose, reduce hospital stays, and decrease costs while minimizing the risks of chronic venous insufficiency post DVT.

Dr. Huang and coauthors reported no conflicts of interest.

Endovascular stenting is a safe and effective way to treat iliofemoral obstructions in patients with postthrombotic syndrome, according to Dr. M. Yin of Shanghai (China) JiaoTong University, and associates.

The stenting process was achieved without major complications in 95% of cases. Cumulative primary, assisted primary, and secondary patency rates after 3 years were 69%, 79%, and 92%, respectively. Patients with severe postthrombotic syndrome (PTS) saw a significant drop in their Villalta score, compared with patients treated with elastic compression stockings (ECS) therapy, though scores were similar in patients with moderate PTS in both groups. The 24-month recurrence-free ulcer healing rate was significantly higher in the stenting group (87% vs. 71%).

“ECS therapy shows equal clinical effects with stent placement in patients with moderate PTS,” but the stented patients did not have to wear stockings after the procedure, the researchers wrote.

Find the full study in the European Journal of Vascular & Endovascular Surgery (doi: 10.1016/j.ejvs.2015.03.029).

Endovascular stenting is a safe and effective way to treat iliofemoral obstructions in patients with postthrombotic syndrome, according to Dr. M. Yin of Shanghai (China) JiaoTong University, and associates.

The stenting process was achieved without major complications in 95% of cases. Cumulative primary, assisted primary, and secondary patency rates after 3 years were 69%, 79%, and 92%, respectively. Patients with severe postthrombotic syndrome (PTS) saw a significant drop in their Villalta score, compared with patients treated with elastic compression stockings (ECS) therapy, though scores were similar in patients with moderate PTS in both groups. The 24-month recurrence-free ulcer healing rate was significantly higher in the stenting group (87% vs. 71%).

“ECS therapy shows equal clinical effects with stent placement in patients with moderate PTS,” but the stented patients did not have to wear stockings after the procedure, the researchers wrote.

Find the full study in the European Journal of Vascular & Endovascular Surgery (doi: 10.1016/j.ejvs.2015.03.029).

Endovascular stenting is a safe and effective way to treat iliofemoral obstructions in patients with postthrombotic syndrome, according to Dr. M. Yin of Shanghai (China) JiaoTong University, and associates.

The stenting process was achieved without major complications in 95% of cases. Cumulative primary, assisted primary, and secondary patency rates after 3 years were 69%, 79%, and 92%, respectively. Patients with severe postthrombotic syndrome (PTS) saw a significant drop in their Villalta score, compared with patients treated with elastic compression stockings (ECS) therapy, though scores were similar in patients with moderate PTS in both groups. The 24-month recurrence-free ulcer healing rate was significantly higher in the stenting group (87% vs. 71%).

“ECS therapy shows equal clinical effects with stent placement in patients with moderate PTS,” but the stented patients did not have to wear stockings after the procedure, the researchers wrote.

Find the full study in the European Journal of Vascular & Endovascular Surgery (doi: 10.1016/j.ejvs.2015.03.029).

CHICAGO – For some patients, surveillance of low-risk abdominal aortic aneurysms is so stressful that early repair might be a better option.

Until now, though, it’s been hard to know who those patients are. There hasn’t been a way to quantify the impact of abdominal aortic aneurysm (AAA) surveillance on quality of life.

Dr. Bjoern Suckow, a vascular surgeon at Dartmouth-Hitchcock Medical Center in Lebanon, N.H., and his colleagues at the University of Massachusetts and elsewhere are working to fix that problem. “I do believe that there is a certain subset of patients who we know are” at low risk for rupture “who are so consumed by fear and anxiety during surveillance that the impact on quality of life might make us want to repair them slightly sooner. I hope this will help us weed out who that subgroup might be,” Dr. Suckow said at a meeting hosted by the Society for Vascular Surgery.

Alexander Otto/Frontline Medical News

With the help of patient and physician focus groups and interviews, the team developed AAA-specific quality of life (QOL) surveys and administered them to 351 patients under surveillance for aneurysms below about 5.5 cm, and 657 who had undergone mostly endovascular AAA repair at six United States institutions.

The surveys included nine questions to assess concerns about rupture, surgery, costs, and death. The responses were averaged to give an emotional impact score (EIS) ranging from 0 to 100, with higher scores indicating worse emotional QOL. The survey also included 10 questions to assess changes in heavy lifting, strenuous activity, travel habits, and other behaviors. Those results were averaged to give a behavioral change score (BCS) that also ranged from 0 to 100, with higher scores indicating greater negative impact.

A significant portion of the surveillance patients thought it was “very likely” their aneurysm would rupture within a year; their EIS was 45 and BCS 30; patients who thought rupture was unlikely had an EIS of 12 and BCS of 13 (P less than .001). Overall, patients under surveillance had worse emotional impact sores than did those who had undergone repair.

“We routinely counsel patients with small aneurysms that the rupture risk is low” – less than 5% – “and outweighed by the higher risk of repair. We were surprised that even though we feel we do a great job counseling and educating our patients, some of them do not understand or retain what we mean.” Eventually, surveys could be used in the clinic to identify patients with “less understanding, so [we can] spend more time with them,” Dr. Suckow said.

In general, “the range of impact on QOL by AAA surveillance is broad. For most patients, the impact is minimal, but for some, especially those with a greater perceived rupture risk, it is severe. Overall, surveillance has a persistent negative impact on QOL, particularly emotional QOL. This impact appears to diminish following either open or endovascular repair,” he said.

The respondents were about 76 years old, on average. Most were white men, and about half were high school graduates.

Dr. Suckow has no relevant financial conflicts. The work was funded by the National Institutes of Health and career development awards from the Society for Vascular Surgery and the American College of Surgeons.

[email protected]

CHICAGO – For some patients, surveillance of low-risk abdominal aortic aneurysms is so stressful that early repair might be a better option.

Until now, though, it’s been hard to know who those patients are. There hasn’t been a way to quantify the impact of abdominal aortic aneurysm (AAA) surveillance on quality of life.

Dr. Bjoern Suckow, a vascular surgeon at Dartmouth-Hitchcock Medical Center in Lebanon, N.H., and his colleagues at the University of Massachusetts and elsewhere are working to fix that problem. “I do believe that there is a certain subset of patients who we know are” at low risk for rupture “who are so consumed by fear and anxiety during surveillance that the impact on quality of life might make us want to repair them slightly sooner. I hope this will help us weed out who that subgroup might be,” Dr. Suckow said at a meeting hosted by the Society for Vascular Surgery.

Alexander Otto/Frontline Medical News

With the help of patient and physician focus groups and interviews, the team developed AAA-specific quality of life (QOL) surveys and administered them to 351 patients under surveillance for aneurysms below about 5.5 cm, and 657 who had undergone mostly endovascular AAA repair at six United States institutions.

The surveys included nine questions to assess concerns about rupture, surgery, costs, and death. The responses were averaged to give an emotional impact score (EIS) ranging from 0 to 100, with higher scores indicating worse emotional QOL. The survey also included 10 questions to assess changes in heavy lifting, strenuous activity, travel habits, and other behaviors. Those results were averaged to give a behavioral change score (BCS) that also ranged from 0 to 100, with higher scores indicating greater negative impact.

A significant portion of the surveillance patients thought it was “very likely” their aneurysm would rupture within a year; their EIS was 45 and BCS 30; patients who thought rupture was unlikely had an EIS of 12 and BCS of 13 (P less than .001). Overall, patients under surveillance had worse emotional impact sores than did those who had undergone repair.

“We routinely counsel patients with small aneurysms that the rupture risk is low” – less than 5% – “and outweighed by the higher risk of repair. We were surprised that even though we feel we do a great job counseling and educating our patients, some of them do not understand or retain what we mean.” Eventually, surveys could be used in the clinic to identify patients with “less understanding, so [we can] spend more time with them,” Dr. Suckow said.

In general, “the range of impact on QOL by AAA surveillance is broad. For most patients, the impact is minimal, but for some, especially those with a greater perceived rupture risk, it is severe. Overall, surveillance has a persistent negative impact on QOL, particularly emotional QOL. This impact appears to diminish following either open or endovascular repair,” he said.

The respondents were about 76 years old, on average. Most were white men, and about half were high school graduates.

Dr. Suckow has no relevant financial conflicts. The work was funded by the National Institutes of Health and career development awards from the Society for Vascular Surgery and the American College of Surgeons.

[email protected]

CHICAGO – For some patients, surveillance of low-risk abdominal aortic aneurysms is so stressful that early repair might be a better option.

Until now, though, it’s been hard to know who those patients are. There hasn’t been a way to quantify the impact of abdominal aortic aneurysm (AAA) surveillance on quality of life.

Dr. Bjoern Suckow, a vascular surgeon at Dartmouth-Hitchcock Medical Center in Lebanon, N.H., and his colleagues at the University of Massachusetts and elsewhere are working to fix that problem. “I do believe that there is a certain subset of patients who we know are” at low risk for rupture “who are so consumed by fear and anxiety during surveillance that the impact on quality of life might make us want to repair them slightly sooner. I hope this will help us weed out who that subgroup might be,” Dr. Suckow said at a meeting hosted by the Society for Vascular Surgery.

Alexander Otto/Frontline Medical News

With the help of patient and physician focus groups and interviews, the team developed AAA-specific quality of life (QOL) surveys and administered them to 351 patients under surveillance for aneurysms below about 5.5 cm, and 657 who had undergone mostly endovascular AAA repair at six United States institutions.

The surveys included nine questions to assess concerns about rupture, surgery, costs, and death. The responses were averaged to give an emotional impact score (EIS) ranging from 0 to 100, with higher scores indicating worse emotional QOL. The survey also included 10 questions to assess changes in heavy lifting, strenuous activity, travel habits, and other behaviors. Those results were averaged to give a behavioral change score (BCS) that also ranged from 0 to 100, with higher scores indicating greater negative impact.

A significant portion of the surveillance patients thought it was “very likely” their aneurysm would rupture within a year; their EIS was 45 and BCS 30; patients who thought rupture was unlikely had an EIS of 12 and BCS of 13 (P less than .001). Overall, patients under surveillance had worse emotional impact sores than did those who had undergone repair.

“We routinely counsel patients with small aneurysms that the rupture risk is low” – less than 5% – “and outweighed by the higher risk of repair. We were surprised that even though we feel we do a great job counseling and educating our patients, some of them do not understand or retain what we mean.” Eventually, surveys could be used in the clinic to identify patients with “less understanding, so [we can] spend more time with them,” Dr. Suckow said.

In general, “the range of impact on QOL by AAA surveillance is broad. For most patients, the impact is minimal, but for some, especially those with a greater perceived rupture risk, it is severe. Overall, surveillance has a persistent negative impact on QOL, particularly emotional QOL. This impact appears to diminish following either open or endovascular repair,” he said.

The respondents were about 76 years old, on average. Most were white men, and about half were high school graduates.

Dr. Suckow has no relevant financial conflicts. The work was funded by the National Institutes of Health and career development awards from the Society for Vascular Surgery and the American College of Surgeons.

[email protected]

No. In patients with severe atherosclerotic renal artery stenosis and hypertension or chronic kidney disease, renal artery stenting offers no additional benefit when added to comprehensive medical therapy.

See related editorial

In these patients, renal artery stenting in addition to antihypertensive drug therapy can improve blood pressure control modestly but has no significant effect on outcomes such as adverse cardiovascular events and death. And because renal artery stenting carries a risk of complications, medical management should continue to be the first-line therapy.

RENAL ARTERY STENOSIS

Renal artery stenosis is a common form of peripheral artery disease. Atherosclerosis is the most common cause, but it can also be caused by fibromuscular dysplasia or vasculitis (eg, Takayasu arteritis). It is most often unilateral, but bilateral disease has also been reported.

The prevalence of atherosclerotic renal vascular disease in the US Medicare population is 0.5%, and 5.5% in those with chronic kidney disease.¹ Furthermore, renal artery stenosis is found in 6.8% of adults over age 65.² The prevalence increases with age and is higher in patients with hyperlipidemia, peripheral arterial disease, and hypertension. The prevalence of renal artery stenosis in patients with atherosclerotic disease and renal dysfunction is as high as 50%.³

Patients with peripheral artery disease may be five times more likely to develop renal artery stenosis than people without peripheral artery disease.⁴ Significant stenosis can result in resistant arterial hypertension, renal insufficiency, left ventricular hypertrophy, and congestive heart failure.⁵

Renal artery stenting added to drug therapy can modestly improve blood pressure control, but has no significant effect on outcomes

Nephropathy due to renal artery stenosis is complex and is caused by hypoperfusion and chronic microatheroembolism. Renal artery stenosis leads to oxidative stress, inflammation, fibrosis in the stenotic kidney, and, over time, loss of kidney function. Hypoperfusion also leads to activation of the renin-angiotensin-aldosterone system, which plays a role in development of left ventricular hypertrophy.^5,6

Adequate blood pressure control, goal-directed lipid-lowering therapy, smoking cessation, and other preventive measures are the foundation of management.

RENAL ARTERY STENOSIS AND HYPERTENSION

Renal artery stenosis is a cause of secondary hypertension. The stenosis decreases renal perfusion pressure, activating the release of renin and the production of angiotensin II, which in turn raises the blood pressure by two mechanisms (Figure 1): directly, by causing generalized vasoconstriction, and indirectly, by stimulating the release of aldosterone, which in turn increases the reabsorption of sodium and causes hypervolemia. These two mechanisms play a major role in renal vascular hypertension when renal artery stenosis is bilateral. In unilateral renal artery stenosis, pressure diuresis in the unaffected kidney compensates for the reabsorption of sodium in the affected kidney, keeping the blood pressure down. However, with time, the unaffected kidney will develop hypertensive nephropathy, and pressure diuresis will be lost.^7,8 In addition, the activation of the renin-angiotensin-aldosterone system results in structural heart disease, such as left ventricular hypertrophy,⁵ and may shorten survival.

STENTING PLUS ANTIHYPERTENSIVE DRUG THERAPY

Because observational studies showed improvement in blood pressure control after endovascular stenting of atherosclerotic renal artery stenosis,^9,10 this approach became a treatment option for uncontrolled hypertension in these patients. The 2005 joint guidelines of the American College of Cardiology and the American Heart Association¹¹ considered percutaneous revascularization a reasonable option (level of evidence B) for patients who meet one of the following criteria:

• Hemodynamically significant stenosis and accelerated, resistant, or malignant hypertension, hypertension with an unexplained unilateral small kidney, or hypertension with intolerance to medication
• Renal artery stenosis and progressive chronic kidney disease with bilateral stenosis or stenosis in a solitary functioning kidney
• Hemodynamically significant stenosis and recurrent, unexplained congestive heart failure or sudden, unexplained pulmonary edema or unstable angina.¹¹

However, no randomized study has shown a direct benefit of renal artery stenting on rates of cardiovascular events or renal function compared with drug therapy alone.

TRIALS OF STENTING VS MEDICAL THERAPY ALONE

Technical improvements have led to more widespread use of diagnostic and interventional endovascular tools for renal artery revascularization. Studies over the past 10 years examined the impact of stenting in patients with uncontrolled hypertension.

The STAR trial

In the Stent Placement and Blood Pressure and Lipid-lowering for the Prevention of Progression of Renal Dysfunction Caused by Atherosclerotic Ostial Stenosis of the Renal Artery (STAR) trial,⁹ patients with creatinine clearance less than 80 mL/min/1.73 m², renal artery stenosis greater than 50%, and well-controlled blood pressure were randomized to either renal artery stenting plus medical therapy or medical therapy alone. The authors concluded that stenting had no effect on the progression of renal dysfunction but led to a small number of significant, procedure-related complications. The study was criticized for including patients with mild stenosis (< 50% stenosis) and for being underpowered for the primary end point.

The ASTRAL study

The Angioplasty and Stenting for Renal Artery Lesions (ASTRAL) study¹⁰ was a similar comparison with similar results, showing no benefit from stenting with respect to renal function, systolic blood pressure control, cardiovascular events, or death.

HERCULES

The Herculink Elite Cobalt Chromium Renal Stent Trial to Demonstrate Efficacy and Safety (HERCULES)¹² was a prospective multicenter study of the effects of renal artery stenting in 202 patients with significant renal artery stenosis and uncontrolled hypertension. It showed a reduction in systolic blood pressure from baseline (P < .0001). However, follow-up was only 9 months, which was insufficient to show a significant effect on long-term cardiovascular and cerebrovascular outcomes.

The CORAL trial

The Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) trial¹³ used more stringent definitions and longer follow-up. It randomized 947 patients to either stenting plus medical therapy or medical therapy alone. Patients had atherosclerotic renal artery stenosis, defined as stenosis of at least 80% or stenosis of 60% to 80% with a gradient of at least 20 mm Hg in the systolic pressure), and either systolic hypertension while taking two or more antihypertensive drugs or stage 3 or higher chronic kidney disease (glomerular filtration rate < 60 mL/min/1.73 m² as calculated by the Modification of Diet in Renal Disease formula).

Complications of renal artery stenting are a limiting factor compared with drug therapy alone

Participants were followed for 43 months to detect the occurrence of adverse cardiovascular and renal events. There was no significant difference in primary outcome between stenting plus drug therapy and drug therapy alone (35.1% and 35.8%, respectively; P = .58). However, stenting plus drug therapy was associated with modestly lower systolic pressures compared with drug therapy alone (−2.3 mm Hg, 95% confidence interval −4.4 to −0.2 mm Hg, P = .03).¹³ This study provided strong evidence that renal artery stenting offers no significant benefit to patients with moderately severe atherosclerotic renal artery stenosis, and that stenting may actually pose an unnecessary risk.

COMPLICATIONS OF RENAL ARTERY STENTING

Complications of renal artery stenting are a limiting factor compared with drug therapy alone, especially since the procedure offers no significant benefit in outcome. Procedural complication rates of 10% to 15% have been reported.^9,10,12 The CORAL trial reported arterial dissection in 2.2%, branch-vessel occlusion in 1.2%, and distal embolization in 1.2% of patients undergoing stenting.¹³ Other reported complications have included stent misplacement requiring an additional stent, access-vessel damage, stent embolization, renal artery thrombosis or occlusion, and death.^10,12

No. In patients with severe atherosclerotic renal artery stenosis and hypertension or chronic kidney disease, renal artery stenting offers no additional benefit when added to comprehensive medical therapy.

See related editorial

In these patients, renal artery stenting in addition to antihypertensive drug therapy can improve blood pressure control modestly but has no significant effect on outcomes such as adverse cardiovascular events and death. And because renal artery stenting carries a risk of complications, medical management should continue to be the first-line therapy.

RENAL ARTERY STENOSIS

Renal artery stenosis is a common form of peripheral artery disease. Atherosclerosis is the most common cause, but it can also be caused by fibromuscular dysplasia or vasculitis (eg, Takayasu arteritis). It is most often unilateral, but bilateral disease has also been reported.

The prevalence of atherosclerotic renal vascular disease in the US Medicare population is 0.5%, and 5.5% in those with chronic kidney disease.¹ Furthermore, renal artery stenosis is found in 6.8% of adults over age 65.² The prevalence increases with age and is higher in patients with hyperlipidemia, peripheral arterial disease, and hypertension. The prevalence of renal artery stenosis in patients with atherosclerotic disease and renal dysfunction is as high as 50%.³

Patients with peripheral artery disease may be five times more likely to develop renal artery stenosis than people without peripheral artery disease.⁴ Significant stenosis can result in resistant arterial hypertension, renal insufficiency, left ventricular hypertrophy, and congestive heart failure.⁵

Renal artery stenting added to drug therapy can modestly improve blood pressure control, but has no significant effect on outcomes

Nephropathy due to renal artery stenosis is complex and is caused by hypoperfusion and chronic microatheroembolism. Renal artery stenosis leads to oxidative stress, inflammation, fibrosis in the stenotic kidney, and, over time, loss of kidney function. Hypoperfusion also leads to activation of the renin-angiotensin-aldosterone system, which plays a role in development of left ventricular hypertrophy.^5,6

Adequate blood pressure control, goal-directed lipid-lowering therapy, smoking cessation, and other preventive measures are the foundation of management.

RENAL ARTERY STENOSIS AND HYPERTENSION

Renal artery stenosis is a cause of secondary hypertension. The stenosis decreases renal perfusion pressure, activating the release of renin and the production of angiotensin II, which in turn raises the blood pressure by two mechanisms (Figure 1): directly, by causing generalized vasoconstriction, and indirectly, by stimulating the release of aldosterone, which in turn increases the reabsorption of sodium and causes hypervolemia. These two mechanisms play a major role in renal vascular hypertension when renal artery stenosis is bilateral. In unilateral renal artery stenosis, pressure diuresis in the unaffected kidney compensates for the reabsorption of sodium in the affected kidney, keeping the blood pressure down. However, with time, the unaffected kidney will develop hypertensive nephropathy, and pressure diuresis will be lost.^7,8 In addition, the activation of the renin-angiotensin-aldosterone system results in structural heart disease, such as left ventricular hypertrophy,⁵ and may shorten survival.

STENTING PLUS ANTIHYPERTENSIVE DRUG THERAPY

Because observational studies showed improvement in blood pressure control after endovascular stenting of atherosclerotic renal artery stenosis,^9,10 this approach became a treatment option for uncontrolled hypertension in these patients. The 2005 joint guidelines of the American College of Cardiology and the American Heart Association¹¹ considered percutaneous revascularization a reasonable option (level of evidence B) for patients who meet one of the following criteria:

• Hemodynamically significant stenosis and accelerated, resistant, or malignant hypertension, hypertension with an unexplained unilateral small kidney, or hypertension with intolerance to medication
• Renal artery stenosis and progressive chronic kidney disease with bilateral stenosis or stenosis in a solitary functioning kidney
• Hemodynamically significant stenosis and recurrent, unexplained congestive heart failure or sudden, unexplained pulmonary edema or unstable angina.¹¹

However, no randomized study has shown a direct benefit of renal artery stenting on rates of cardiovascular events or renal function compared with drug therapy alone.

TRIALS OF STENTING VS MEDICAL THERAPY ALONE

Technical improvements have led to more widespread use of diagnostic and interventional endovascular tools for renal artery revascularization. Studies over the past 10 years examined the impact of stenting in patients with uncontrolled hypertension.

The STAR trial

In the Stent Placement and Blood Pressure and Lipid-lowering for the Prevention of Progression of Renal Dysfunction Caused by Atherosclerotic Ostial Stenosis of the Renal Artery (STAR) trial,⁹ patients with creatinine clearance less than 80 mL/min/1.73 m², renal artery stenosis greater than 50%, and well-controlled blood pressure were randomized to either renal artery stenting plus medical therapy or medical therapy alone. The authors concluded that stenting had no effect on the progression of renal dysfunction but led to a small number of significant, procedure-related complications. The study was criticized for including patients with mild stenosis (< 50% stenosis) and for being underpowered for the primary end point.

The ASTRAL study

The Angioplasty and Stenting for Renal Artery Lesions (ASTRAL) study¹⁰ was a similar comparison with similar results, showing no benefit from stenting with respect to renal function, systolic blood pressure control, cardiovascular events, or death.

HERCULES

The Herculink Elite Cobalt Chromium Renal Stent Trial to Demonstrate Efficacy and Safety (HERCULES)¹² was a prospective multicenter study of the effects of renal artery stenting in 202 patients with significant renal artery stenosis and uncontrolled hypertension. It showed a reduction in systolic blood pressure from baseline (P < .0001). However, follow-up was only 9 months, which was insufficient to show a significant effect on long-term cardiovascular and cerebrovascular outcomes.

The CORAL trial

The Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) trial¹³ used more stringent definitions and longer follow-up. It randomized 947 patients to either stenting plus medical therapy or medical therapy alone. Patients had atherosclerotic renal artery stenosis, defined as stenosis of at least 80% or stenosis of 60% to 80% with a gradient of at least 20 mm Hg in the systolic pressure), and either systolic hypertension while taking two or more antihypertensive drugs or stage 3 or higher chronic kidney disease (glomerular filtration rate < 60 mL/min/1.73 m² as calculated by the Modification of Diet in Renal Disease formula).

Complications of renal artery stenting are a limiting factor compared with drug therapy alone

Participants were followed for 43 months to detect the occurrence of adverse cardiovascular and renal events. There was no significant difference in primary outcome between stenting plus drug therapy and drug therapy alone (35.1% and 35.8%, respectively; P = .58). However, stenting plus drug therapy was associated with modestly lower systolic pressures compared with drug therapy alone (−2.3 mm Hg, 95% confidence interval −4.4 to −0.2 mm Hg, P = .03).¹³ This study provided strong evidence that renal artery stenting offers no significant benefit to patients with moderately severe atherosclerotic renal artery stenosis, and that stenting may actually pose an unnecessary risk.

COMPLICATIONS OF RENAL ARTERY STENTING

Complications of renal artery stenting are a limiting factor compared with drug therapy alone, especially since the procedure offers no significant benefit in outcome. Procedural complication rates of 10% to 15% have been reported.^9,10,12 The CORAL trial reported arterial dissection in 2.2%, branch-vessel occlusion in 1.2%, and distal embolization in 1.2% of patients undergoing stenting.¹³ Other reported complications have included stent misplacement requiring an additional stent, access-vessel damage, stent embolization, renal artery thrombosis or occlusion, and death.^10,12

No. In patients with severe atherosclerotic renal artery stenosis and hypertension or chronic kidney disease, renal artery stenting offers no additional benefit when added to comprehensive medical therapy.

See related editorial

In these patients, renal artery stenting in addition to antihypertensive drug therapy can improve blood pressure control modestly but has no significant effect on outcomes such as adverse cardiovascular events and death. And because renal artery stenting carries a risk of complications, medical management should continue to be the first-line therapy.

RENAL ARTERY STENOSIS

Renal artery stenosis is a common form of peripheral artery disease. Atherosclerosis is the most common cause, but it can also be caused by fibromuscular dysplasia or vasculitis (eg, Takayasu arteritis). It is most often unilateral, but bilateral disease has also been reported.

The prevalence of atherosclerotic renal vascular disease in the US Medicare population is 0.5%, and 5.5% in those with chronic kidney disease.¹ Furthermore, renal artery stenosis is found in 6.8% of adults over age 65.² The prevalence increases with age and is higher in patients with hyperlipidemia, peripheral arterial disease, and hypertension. The prevalence of renal artery stenosis in patients with atherosclerotic disease and renal dysfunction is as high as 50%.³

Patients with peripheral artery disease may be five times more likely to develop renal artery stenosis than people without peripheral artery disease.⁴ Significant stenosis can result in resistant arterial hypertension, renal insufficiency, left ventricular hypertrophy, and congestive heart failure.⁵

Renal artery stenting added to drug therapy can modestly improve blood pressure control, but has no significant effect on outcomes

Nephropathy due to renal artery stenosis is complex and is caused by hypoperfusion and chronic microatheroembolism. Renal artery stenosis leads to oxidative stress, inflammation, fibrosis in the stenotic kidney, and, over time, loss of kidney function. Hypoperfusion also leads to activation of the renin-angiotensin-aldosterone system, which plays a role in development of left ventricular hypertrophy.^5,6

Adequate blood pressure control, goal-directed lipid-lowering therapy, smoking cessation, and other preventive measures are the foundation of management.

RENAL ARTERY STENOSIS AND HYPERTENSION

Renal artery stenosis is a cause of secondary hypertension. The stenosis decreases renal perfusion pressure, activating the release of renin and the production of angiotensin II, which in turn raises the blood pressure by two mechanisms (Figure 1): directly, by causing generalized vasoconstriction, and indirectly, by stimulating the release of aldosterone, which in turn increases the reabsorption of sodium and causes hypervolemia. These two mechanisms play a major role in renal vascular hypertension when renal artery stenosis is bilateral. In unilateral renal artery stenosis, pressure diuresis in the unaffected kidney compensates for the reabsorption of sodium in the affected kidney, keeping the blood pressure down. However, with time, the unaffected kidney will develop hypertensive nephropathy, and pressure diuresis will be lost.^7,8 In addition, the activation of the renin-angiotensin-aldosterone system results in structural heart disease, such as left ventricular hypertrophy,⁵ and may shorten survival.

STENTING PLUS ANTIHYPERTENSIVE DRUG THERAPY

Because observational studies showed improvement in blood pressure control after endovascular stenting of atherosclerotic renal artery stenosis,^9,10 this approach became a treatment option for uncontrolled hypertension in these patients. The 2005 joint guidelines of the American College of Cardiology and the American Heart Association¹¹ considered percutaneous revascularization a reasonable option (level of evidence B) for patients who meet one of the following criteria:

• Hemodynamically significant stenosis and accelerated, resistant, or malignant hypertension, hypertension with an unexplained unilateral small kidney, or hypertension with intolerance to medication
• Renal artery stenosis and progressive chronic kidney disease with bilateral stenosis or stenosis in a solitary functioning kidney
• Hemodynamically significant stenosis and recurrent, unexplained congestive heart failure or sudden, unexplained pulmonary edema or unstable angina.¹¹

However, no randomized study has shown a direct benefit of renal artery stenting on rates of cardiovascular events or renal function compared with drug therapy alone.

TRIALS OF STENTING VS MEDICAL THERAPY ALONE

Technical improvements have led to more widespread use of diagnostic and interventional endovascular tools for renal artery revascularization. Studies over the past 10 years examined the impact of stenting in patients with uncontrolled hypertension.

The STAR trial

In the Stent Placement and Blood Pressure and Lipid-lowering for the Prevention of Progression of Renal Dysfunction Caused by Atherosclerotic Ostial Stenosis of the Renal Artery (STAR) trial,⁹ patients with creatinine clearance less than 80 mL/min/1.73 m², renal artery stenosis greater than 50%, and well-controlled blood pressure were randomized to either renal artery stenting plus medical therapy or medical therapy alone. The authors concluded that stenting had no effect on the progression of renal dysfunction but led to a small number of significant, procedure-related complications. The study was criticized for including patients with mild stenosis (< 50% stenosis) and for being underpowered for the primary end point.

The ASTRAL study

The Angioplasty and Stenting for Renal Artery Lesions (ASTRAL) study¹⁰ was a similar comparison with similar results, showing no benefit from stenting with respect to renal function, systolic blood pressure control, cardiovascular events, or death.

HERCULES

The Herculink Elite Cobalt Chromium Renal Stent Trial to Demonstrate Efficacy and Safety (HERCULES)¹² was a prospective multicenter study of the effects of renal artery stenting in 202 patients with significant renal artery stenosis and uncontrolled hypertension. It showed a reduction in systolic blood pressure from baseline (P < .0001). However, follow-up was only 9 months, which was insufficient to show a significant effect on long-term cardiovascular and cerebrovascular outcomes.

The CORAL trial

The Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) trial¹³ used more stringent definitions and longer follow-up. It randomized 947 patients to either stenting plus medical therapy or medical therapy alone. Patients had atherosclerotic renal artery stenosis, defined as stenosis of at least 80% or stenosis of 60% to 80% with a gradient of at least 20 mm Hg in the systolic pressure), and either systolic hypertension while taking two or more antihypertensive drugs or stage 3 or higher chronic kidney disease (glomerular filtration rate < 60 mL/min/1.73 m² as calculated by the Modification of Diet in Renal Disease formula).

Complications of renal artery stenting are a limiting factor compared with drug therapy alone

Participants were followed for 43 months to detect the occurrence of adverse cardiovascular and renal events. There was no significant difference in primary outcome between stenting plus drug therapy and drug therapy alone (35.1% and 35.8%, respectively; P = .58). However, stenting plus drug therapy was associated with modestly lower systolic pressures compared with drug therapy alone (−2.3 mm Hg, 95% confidence interval −4.4 to −0.2 mm Hg, P = .03).¹³ This study provided strong evidence that renal artery stenting offers no significant benefit to patients with moderately severe atherosclerotic renal artery stenosis, and that stenting may actually pose an unnecessary risk.

COMPLICATIONS OF RENAL ARTERY STENTING

Complications of renal artery stenting are a limiting factor compared with drug therapy alone, especially since the procedure offers no significant benefit in outcome. Procedural complication rates of 10% to 15% have been reported.^9,10,12 The CORAL trial reported arterial dissection in 2.2%, branch-vessel occlusion in 1.2%, and distal embolization in 1.2% of patients undergoing stenting.¹³ Other reported complications have included stent misplacement requiring an additional stent, access-vessel damage, stent embolization, renal artery thrombosis or occlusion, and death.^10,12