A 53-year-old Native American woman with a history of liver cirrhosis secondary to alcohol abuse presents to the emergency department after 2 days of diffuse abdominal pain and weakness. The pain was sudden in onset and has progressed relentlessly over the last day, reaching 9 on a scale of 10 in severity. Family members say that her oral intake has been decreased for the last 2 days, but she has had no fever, vomiting, change in bowel habit, blood in stool, or black stool. She has never undergone surgery, and has had one uncomplicated pregnancy.

Physical examination

Vital signs:

• Blood pressure 82/57 mm Hg
• Heart rate 96 beats per minute
• Temperature 37.3°C (99.1°F)
• Respiratory rate 16 per minute
• Oxygen saturation 92% while receiving oxygen at 2 L/minute.

The patient is somnolent and has scleral icterus. Her cardiopulmonary examination is normal. Her abdomen is tense, distended, and diffusely tender. She has bilateral +2 pitting edema in her lower extremities. She is oriented to person only and is noted to have asterixis. Her baseline Model for End-stage Liver Disease score is 18 points on a scale of 6 (less ill) to 40 (gravely ill).

Laboratory studies:

• Hemoglobin 9.8 g/dL (reference range 11.5–15.5)
• Platelet count 100 × 10⁹/L (150–400)
• White blood cell count 9.9 × 10⁹/L (3.7–11.0)
• Serum creatinine 1.06 mg/dL (0.58–0.96)
• Bilirubin 6.3 mg/dL (0.2–1.3)
• International normalized ratio of the prothrombin time 2.15 (0.8–1.2)
• Blood urea nitrogen 13 mg/dL (7–21)
• Serum albumin 2.7 g/dL (3.9–4.9).

Intravenous fluid resuscitation is initiated but the patient remains hypotensive, and on repeat laboratory testing 4 hours later her hemoglobin level has dropped to 7.3 mg/dL.

DIFFERENTIAL DIAGNOSIS

1. Which of the following are likely causes of this patient’s presentation?

• Splenic arterial aneurysm rupture
• Spontaneous bacterial peritonitis
• Variceal hemorrhage
• Portal vein thrombosis
• Abdominal aortic aneurysm rupture

Ruptured splenic artery aneurysm

Splenic artery aneurysms are the third most common intra-abdominal aneurysm, after those of the abdominal aorta and iliac artery.¹ They are often asymptomatic and are being detected more frequently because of increased use of computed tomography (CT).² Symptomatic splenic artery aneurysms may present with abdominal pain and have the potential to rupture, which can be life-threatening.^3,4

This patient may have a ruptured splenic artery aneurysm, given her hemodynamic shock.

Spontaneous bacterial peritonitis

Ten percent to 20% of hospitalized patients with cirrhosis and ascites develop spontaneous bacterial peritonitis. Patients may present with ascites and abdominal pain, tenderness to palpation, fever, encephalopathy, or worsening liver and renal function.

Diagnostic paracentesis is paramount to delineate the cause of ascites; one should calculate the serum-ascites albumin gradient and obtain a cell count and culture of the ascitic fluid. The diagnosis of spontaneous bacterial peritonitis can be made if the ascitic fluid polymorphonuclear cell count is 0.25 × 10⁹/L or higher, even if the ascitic fluid culture is negative.^5,6 Simultaneous blood cultures should also be collected, as 50% of cases are associated with bacteremia.

The in-hospital mortality rate of an episode of spontaneous bacterial peritonitis has been reduced to 10% to 20% thanks to prompt diagnosis and empiric treatment with third-generation cephalosporins.⁷

Five percent of cases of infected ascites fluid are due to secondary bacterial peritonitis from a perforated viscus or a loculated abscess, which cannot be differentiated clinically from spontaneous bacterial peritonitis but can be diagnosed with CT.⁸

This patient may be presenting with septic shock secondary to either of these causes.

Variceal hemorrhage

Half of patients with cirrhosis have gastroesophageal varices due to portal hypertension. Endoscopic surveillance is warranted, as the risk of hemorrhage is 12% to 15% per year, and the mortality rate approaches 15% to 20% with each episode. Prompt resuscitation, diagnosis, and control of bleeding is paramount.

Esophagogastroduodenoscopy is used for both diagnosis and intervention. Short-term prophylactic use of antibiotics improves survival by preventing infections in the event bleeding recurs.^9–11

Our patient may be presenting with hemodynamic shock from bleeding esophageal varices.

 

 

Portal vein thrombosis

Portal vein thrombosis is a common complication of cirrhosis, occurring in 5% to 28% of patients. The risk increases with the severity of liver disease and in association with hepatocellular carcinoma.¹² Forty-three percent of cases are discovered incidentally in asymptomatic patients during ultrasonography, 39% present with upper gastrointestinal bleeding, and 18% present with abdominal pain.^13,14

Portal vein thrombosis is the complete or partial obstruction of blood flow due to a thrombus in the lumen of the portal vein. Contrast ultrasonography and CT can be used to establish the diagnosis.¹⁵

Anticoagulation is recommended in cases of complete thrombosis in candidates for living-donor liver transplant and for those at risk of mesenteric ischemia because of the thrombus extending into the mesenteric veins. In symptomatic patients, the decision to initiate anticoagulation should be made on a case-by-case basis after appropriate screening and management of varices.^16–18

Our patient’s thrombocytopenia reflects the severity of portal hypertension and increases her risk of portal vein thrombosis, but this is unlikely to be the sole cause of the hemodynamic compromise in this patient.

Ruptured abdominal aortic aneurysm

Rupture of an abdominal aortic aneurysm is a medical emergency, with a mortality rate approaching 90%. Risk factors for abdominal aortic aneurysms are smoking, male sex, age over 65, history of cardiovascular disease, hypertension, and a family history of abdominal aortic aneurysm, especially if a first-degree relative is affected.¹⁹ Endovascular repair is associated with lower rates of death and complications compared with open repair.²⁰

The patient does not have any of those risk factors, making this diagnosis less likely.

CASE CONTINUED: RUPTURED SPLENIC ARTERY ANEURYSM

Emergency CT of the abdomen and pelvis with contrast enhancement shows a large left intraperitoneal hematoma with active extravasation from a ruptured splenic artery aneurysm (Figure 1). The patient receives packed red blood cells and fresh-frozen plasma before being transferred to our hospital.

2. Which of the following is false regarding splenic artery aneurysms?

• They are the most common type of splanchnic arterial aneurysm
• True aneurysms are more common than pseudoaneurysms
• Asymptomatic aneurysms are discovered incidentally during assessment for other radiographic indications
• Splenic artery aneurysm in portal hypertension is the result of athero-sclerotic changes to the vascular intima

Splenic artery aneurysm in portal hypertension is not the result of atherosclerotic change to the vascular intima.

Splenic artery aneurysms are the most common type of splanchnic artery aneurysm.¹ True aneurysms involve all 3 layers of the arterial wall, ie, intima, media, and adventitia. Cirrhosis and portal hypertension are associated with true aneurysm formation. The proposed mechanism of aneurysm formation is increased splenic blood flow in response to portal congestion with resultant hemodynamic stress that disrupts arterial wall structure, leading to aneurysmal dilation.²¹

In earlier reports, the incidence of true splenic artery aneurysm in portal hypertension varied from 2.9% to 50%, the latter representing autopsy findings of small aneurysms that were found in the splenic hilum of patients with cirrhosis.^22–25 The incidence of clinically significant aneurysms in cirrhosis is unknown but incidental asymptomatic aneurysm is being detected more frequently on imaging studies pursued for screening purposes.²⁶

The risk of rupture is low, only 2% to 10% in older studies and likely even lower now due to increased incidental detection in asymptomatic patients.²⁷ However, emergent management of rupture at a tertiary care facility is paramount, as the mortality rate of ruptured splenic artery aneurysm is 29% to 36%.^1,26,28

Splenic artery pseudoaneurysm is rarer and has a different pathophysiologic process than true aneurysm. It usually arises in the setting of trauma, pancreatitis, or postsurgery.^29,30 Pseudoaneurysm is more likely to rupture, owing to compromise in the vascular wall integrity.^4,21,28 As a result, treatment is indicated for every pseudoaneurysm regardless of size.

RISK FACTORS FOR SPLENIC ARTERY ANEURYSM

3. Which of the following is true regarding our patient’s risk of splenic artery aneurysm?

• Liver cirrhosis and portal hypertension are her greatest risk factors for it
• Female sex and prior pregnancy are her greatest risk factors for it
• Being Native American makes it more likely that the patient has splenic artery aneurysm secondary to collagen vascular disease
• Her risk of rupture would diminish after receiving a liver transplant

Liver cirrhosis and portal hypertension are her greatest risk factors for splenic artery aneurysm.

Risk factors for true aneurysm include hypertension, atherosclerosis, portal hypertension with or without liver cirrhosis, liver transplant, third trimester of pregnancy, and multiparity.^1,4,26,28,31 Splenic artery aneurysm is  usually diagnosed in the sixth decade. It may be 4 times as common in women, given a hormonal influence.³² Cirrhosis is also associated with massive splenic artery aneurysm (≥ 5 cm). Although rare, massive splenic artery aneurysm is more frequent in men (the male-to-female ratio is 1.78:1) and has a heightened risk of rupture.²⁸ The incidence of rupture increases to around 3% to 4% after liver transplant.³³ Rare causes of true aneurysm include fibrodysplasia, collagen vascular disease (eg, Loeys-Dietz and type IV Ehler-Danlos syndromes), vasculitis (eg, polyarteritis nodosa due to amphetamine abuse), and mycotic aneurysms.^24,25,28,29

This patient’s age, sex, and history of cirrhosis puts her at increased risk of splenic artery aneurysm. The risk of rupture is highest in the peripartum period and in patients with cirrhosis who become pregnant. Although being Native American portends an increased risk for collagen vascular disease, the latter is unlikely to be a contributing factor.

 

 

TREATMENT OF SPLENIC ARTERY ANEURYSM

4. Which of the following is false regarding treatment of splenic artery aneurysms?

• Aneurysms larger than 2 cm and those that are expanding require repair
• Treatment should be offered if the patient has symptoms attributable to the aneurysm
• Asymptomatic aneurysms in pregnant women can be followed with watchful waiting
• Minimally invasive therapies such as percutaneous embolization may be a good option in poor operative candidates

Asymptomatic aneurysms in pregnant women should not be followed with watchful waiting—they should be repaired, as rupture carries a maternal mortality rate of 75% and a fetal mortality rate of 95%.³⁴

Complications of splenic artery aneurysm depend on the type of aneurysm and its predisposing factors. Indications for treatment of true aneurysms include:

• Symptoms attributable to the aneurysm (hence, the second answer choice above is true)
• Diameter 2  cm or greater or enlarging diameter (hence, the first answer choice is true)
• Women of childbearing age in anticipation of pregnancy
• Need for surgical intervention such as portocaval shunt and liver transplant.

Conservative management is associated with a late mortality risk of 4.9%.² Interventional options include percutaneous embolization or stenting; or laparotomy with splenic artery ligation or excision with or without splenectomy.^1,28,35–37

Endovascular and open surgical repair have both been used to treat splenic artery aneurysms. The method used depends on the patient’s surgical history and aneurysm anatomy such as splenic artery tortuosity hindering passage of a catheter. Open surgery is associated with longer intraoperative time and length of hospital stay and higher rates of 30-day mortality and perioperative morbidity.^38–41 With endovascular repair, the complication of persistent or recurrent flow occurs in 3% to 5% of cases by 30 days; hence, postprocedural surveillance is recommended.^42–44 Endovascular repair has a higher reintervention rate but may still be more cost-effective than open surgical repair.

Because patients with cirrhosis have a higher risk of surgical complications,⁴⁵ elective endovascular treatment may be an option for patients with aneurysms at high risk of rupturing. Endovascular treatment of visceral aneurysms is associated with complications such as postembolization syndrome (fever, abdominal pain, pleural effusion, and pancreatitis), access site hematoma, splenic infarction, and persistent abdominal pain.⁴²

Patients with cirrhosis as the cause of splenic artery aneurysm tend to need longer hospitalization after endovascular treatment, but there is insufficient evidence to suggest that they are at higher risk of other complications.³⁷

CASE CONTINUED: SPLENIC ARTERY EMBOLIZATION

The patient undergoes emergency splenic artery embolization, performed by an interventional radiology team (Figure 2 and Figure 3). Over the next few days, her mental status improves and her abdominal pain resolves. Her hemoglobin level remains stable after the procedure.

The surgical and interventional radiology teams discuss the risk of repeat intervention with the patient and her family, who prefer a nonoperative approach. She is managed supportively in the intensive care unit and is finally discharged home in stable condition and is scheduled for outpatient follow-up.

SUSPECT THIS FATAL CONDITION

The low prevalence of ruptured splenic artery aneurysm may lead physicians to attribute septic shock to spontaneous bacterial peritonitis or hemorrhagic shock from gastroesophageal varices in patients with cirrhosis, but a high index of suspicion and early recognition of this rare disease can lead to timely diagnosis and treatment of this highly fatal complication.

KEY POINTS

• Splenic artery aneurysm is a common complication of cirrhosis, often diagnosed incidentally.
• Elective embolization should be considered for asymptomatic splenic artery aneurysms larger than 2 cm in diameter, clinically symptomatic aneurysms, women of childbearing age, and patients who are candidates for liver transplant.
• Although splenic artery aneurysm rupture is rare, it has a high mortality rate and warrants a high index of suspicion to institute prompt specialized intervention.
• We recommend that physicians consider splenic artery aneurysm rupture in their differential diagnoses in patients with liver cirrhosis presenting with abdominal pain, altered mental status, and hemodynamic shock.

A 53-year-old Native American woman with a history of liver cirrhosis secondary to alcohol abuse presents to the emergency department after 2 days of diffuse abdominal pain and weakness. The pain was sudden in onset and has progressed relentlessly over the last day, reaching 9 on a scale of 10 in severity. Family members say that her oral intake has been decreased for the last 2 days, but she has had no fever, vomiting, change in bowel habit, blood in stool, or black stool. She has never undergone surgery, and has had one uncomplicated pregnancy.

Physical examination

Vital signs:

• Blood pressure 82/57 mm Hg
• Heart rate 96 beats per minute
• Temperature 37.3°C (99.1°F)
• Respiratory rate 16 per minute
• Oxygen saturation 92% while receiving oxygen at 2 L/minute.

The patient is somnolent and has scleral icterus. Her cardiopulmonary examination is normal. Her abdomen is tense, distended, and diffusely tender. She has bilateral +2 pitting edema in her lower extremities. She is oriented to person only and is noted to have asterixis. Her baseline Model for End-stage Liver Disease score is 18 points on a scale of 6 (less ill) to 40 (gravely ill).

Laboratory studies:

• Hemoglobin 9.8 g/dL (reference range 11.5–15.5)
• Platelet count 100 × 10⁹/L (150–400)
• White blood cell count 9.9 × 10⁹/L (3.7–11.0)
• Serum creatinine 1.06 mg/dL (0.58–0.96)
• Bilirubin 6.3 mg/dL (0.2–1.3)
• International normalized ratio of the prothrombin time 2.15 (0.8–1.2)
• Blood urea nitrogen 13 mg/dL (7–21)
• Serum albumin 2.7 g/dL (3.9–4.9).

Intravenous fluid resuscitation is initiated but the patient remains hypotensive, and on repeat laboratory testing 4 hours later her hemoglobin level has dropped to 7.3 mg/dL.

DIFFERENTIAL DIAGNOSIS

1. Which of the following are likely causes of this patient’s presentation?

• Splenic arterial aneurysm rupture
• Spontaneous bacterial peritonitis
• Variceal hemorrhage
• Portal vein thrombosis
• Abdominal aortic aneurysm rupture

Ruptured splenic artery aneurysm

Splenic artery aneurysms are the third most common intra-abdominal aneurysm, after those of the abdominal aorta and iliac artery.¹ They are often asymptomatic and are being detected more frequently because of increased use of computed tomography (CT).² Symptomatic splenic artery aneurysms may present with abdominal pain and have the potential to rupture, which can be life-threatening.^3,4

This patient may have a ruptured splenic artery aneurysm, given her hemodynamic shock.

Spontaneous bacterial peritonitis

Ten percent to 20% of hospitalized patients with cirrhosis and ascites develop spontaneous bacterial peritonitis. Patients may present with ascites and abdominal pain, tenderness to palpation, fever, encephalopathy, or worsening liver and renal function.

Diagnostic paracentesis is paramount to delineate the cause of ascites; one should calculate the serum-ascites albumin gradient and obtain a cell count and culture of the ascitic fluid. The diagnosis of spontaneous bacterial peritonitis can be made if the ascitic fluid polymorphonuclear cell count is 0.25 × 10⁹/L or higher, even if the ascitic fluid culture is negative.^5,6 Simultaneous blood cultures should also be collected, as 50% of cases are associated with bacteremia.

The in-hospital mortality rate of an episode of spontaneous bacterial peritonitis has been reduced to 10% to 20% thanks to prompt diagnosis and empiric treatment with third-generation cephalosporins.⁷

Five percent of cases of infected ascites fluid are due to secondary bacterial peritonitis from a perforated viscus or a loculated abscess, which cannot be differentiated clinically from spontaneous bacterial peritonitis but can be diagnosed with CT.⁸

This patient may be presenting with septic shock secondary to either of these causes.

Variceal hemorrhage

Half of patients with cirrhosis have gastroesophageal varices due to portal hypertension. Endoscopic surveillance is warranted, as the risk of hemorrhage is 12% to 15% per year, and the mortality rate approaches 15% to 20% with each episode. Prompt resuscitation, diagnosis, and control of bleeding is paramount.

Esophagogastroduodenoscopy is used for both diagnosis and intervention. Short-term prophylactic use of antibiotics improves survival by preventing infections in the event bleeding recurs.^9–11

Our patient may be presenting with hemodynamic shock from bleeding esophageal varices.

 

 

Portal vein thrombosis

Portal vein thrombosis is a common complication of cirrhosis, occurring in 5% to 28% of patients. The risk increases with the severity of liver disease and in association with hepatocellular carcinoma.¹² Forty-three percent of cases are discovered incidentally in asymptomatic patients during ultrasonography, 39% present with upper gastrointestinal bleeding, and 18% present with abdominal pain.^13,14

Portal vein thrombosis is the complete or partial obstruction of blood flow due to a thrombus in the lumen of the portal vein. Contrast ultrasonography and CT can be used to establish the diagnosis.¹⁵

Anticoagulation is recommended in cases of complete thrombosis in candidates for living-donor liver transplant and for those at risk of mesenteric ischemia because of the thrombus extending into the mesenteric veins. In symptomatic patients, the decision to initiate anticoagulation should be made on a case-by-case basis after appropriate screening and management of varices.^16–18

Our patient’s thrombocytopenia reflects the severity of portal hypertension and increases her risk of portal vein thrombosis, but this is unlikely to be the sole cause of the hemodynamic compromise in this patient.

Ruptured abdominal aortic aneurysm

Rupture of an abdominal aortic aneurysm is a medical emergency, with a mortality rate approaching 90%. Risk factors for abdominal aortic aneurysms are smoking, male sex, age over 65, history of cardiovascular disease, hypertension, and a family history of abdominal aortic aneurysm, especially if a first-degree relative is affected.¹⁹ Endovascular repair is associated with lower rates of death and complications compared with open repair.²⁰

The patient does not have any of those risk factors, making this diagnosis less likely.

CASE CONTINUED: RUPTURED SPLENIC ARTERY ANEURYSM

Emergency CT of the abdomen and pelvis with contrast enhancement shows a large left intraperitoneal hematoma with active extravasation from a ruptured splenic artery aneurysm (Figure 1). The patient receives packed red blood cells and fresh-frozen plasma before being transferred to our hospital.

2. Which of the following is false regarding splenic artery aneurysms?

• They are the most common type of splanchnic arterial aneurysm
• True aneurysms are more common than pseudoaneurysms
• Asymptomatic aneurysms are discovered incidentally during assessment for other radiographic indications
• Splenic artery aneurysm in portal hypertension is the result of athero-sclerotic changes to the vascular intima

Splenic artery aneurysm in portal hypertension is not the result of atherosclerotic change to the vascular intima.

Splenic artery aneurysms are the most common type of splanchnic artery aneurysm.¹ True aneurysms involve all 3 layers of the arterial wall, ie, intima, media, and adventitia. Cirrhosis and portal hypertension are associated with true aneurysm formation. The proposed mechanism of aneurysm formation is increased splenic blood flow in response to portal congestion with resultant hemodynamic stress that disrupts arterial wall structure, leading to aneurysmal dilation.²¹

In earlier reports, the incidence of true splenic artery aneurysm in portal hypertension varied from 2.9% to 50%, the latter representing autopsy findings of small aneurysms that were found in the splenic hilum of patients with cirrhosis.^22–25 The incidence of clinically significant aneurysms in cirrhosis is unknown but incidental asymptomatic aneurysm is being detected more frequently on imaging studies pursued for screening purposes.²⁶

The risk of rupture is low, only 2% to 10% in older studies and likely even lower now due to increased incidental detection in asymptomatic patients.²⁷ However, emergent management of rupture at a tertiary care facility is paramount, as the mortality rate of ruptured splenic artery aneurysm is 29% to 36%.^1,26,28

Splenic artery pseudoaneurysm is rarer and has a different pathophysiologic process than true aneurysm. It usually arises in the setting of trauma, pancreatitis, or postsurgery.^29,30 Pseudoaneurysm is more likely to rupture, owing to compromise in the vascular wall integrity.^4,21,28 As a result, treatment is indicated for every pseudoaneurysm regardless of size.

RISK FACTORS FOR SPLENIC ARTERY ANEURYSM

3. Which of the following is true regarding our patient’s risk of splenic artery aneurysm?

• Liver cirrhosis and portal hypertension are her greatest risk factors for it
• Female sex and prior pregnancy are her greatest risk factors for it
• Being Native American makes it more likely that the patient has splenic artery aneurysm secondary to collagen vascular disease
• Her risk of rupture would diminish after receiving a liver transplant

Liver cirrhosis and portal hypertension are her greatest risk factors for splenic artery aneurysm.

Risk factors for true aneurysm include hypertension, atherosclerosis, portal hypertension with or without liver cirrhosis, liver transplant, third trimester of pregnancy, and multiparity.^1,4,26,28,31 Splenic artery aneurysm is  usually diagnosed in the sixth decade. It may be 4 times as common in women, given a hormonal influence.³² Cirrhosis is also associated with massive splenic artery aneurysm (≥ 5 cm). Although rare, massive splenic artery aneurysm is more frequent in men (the male-to-female ratio is 1.78:1) and has a heightened risk of rupture.²⁸ The incidence of rupture increases to around 3% to 4% after liver transplant.³³ Rare causes of true aneurysm include fibrodysplasia, collagen vascular disease (eg, Loeys-Dietz and type IV Ehler-Danlos syndromes), vasculitis (eg, polyarteritis nodosa due to amphetamine abuse), and mycotic aneurysms.^24,25,28,29

This patient’s age, sex, and history of cirrhosis puts her at increased risk of splenic artery aneurysm. The risk of rupture is highest in the peripartum period and in patients with cirrhosis who become pregnant. Although being Native American portends an increased risk for collagen vascular disease, the latter is unlikely to be a contributing factor.

 

 

TREATMENT OF SPLENIC ARTERY ANEURYSM

4. Which of the following is false regarding treatment of splenic artery aneurysms?

• Aneurysms larger than 2 cm and those that are expanding require repair
• Treatment should be offered if the patient has symptoms attributable to the aneurysm
• Asymptomatic aneurysms in pregnant women can be followed with watchful waiting
• Minimally invasive therapies such as percutaneous embolization may be a good option in poor operative candidates

Asymptomatic aneurysms in pregnant women should not be followed with watchful waiting—they should be repaired, as rupture carries a maternal mortality rate of 75% and a fetal mortality rate of 95%.³⁴

Complications of splenic artery aneurysm depend on the type of aneurysm and its predisposing factors. Indications for treatment of true aneurysms include:

• Symptoms attributable to the aneurysm (hence, the second answer choice above is true)
• Diameter 2  cm or greater or enlarging diameter (hence, the first answer choice is true)
• Women of childbearing age in anticipation of pregnancy
• Need for surgical intervention such as portocaval shunt and liver transplant.

Conservative management is associated with a late mortality risk of 4.9%.² Interventional options include percutaneous embolization or stenting; or laparotomy with splenic artery ligation or excision with or without splenectomy.^1,28,35–37

Endovascular and open surgical repair have both been used to treat splenic artery aneurysms. The method used depends on the patient’s surgical history and aneurysm anatomy such as splenic artery tortuosity hindering passage of a catheter. Open surgery is associated with longer intraoperative time and length of hospital stay and higher rates of 30-day mortality and perioperative morbidity.^38–41 With endovascular repair, the complication of persistent or recurrent flow occurs in 3% to 5% of cases by 30 days; hence, postprocedural surveillance is recommended.^42–44 Endovascular repair has a higher reintervention rate but may still be more cost-effective than open surgical repair.

Because patients with cirrhosis have a higher risk of surgical complications,⁴⁵ elective endovascular treatment may be an option for patients with aneurysms at high risk of rupturing. Endovascular treatment of visceral aneurysms is associated with complications such as postembolization syndrome (fever, abdominal pain, pleural effusion, and pancreatitis), access site hematoma, splenic infarction, and persistent abdominal pain.⁴²

Patients with cirrhosis as the cause of splenic artery aneurysm tend to need longer hospitalization after endovascular treatment, but there is insufficient evidence to suggest that they are at higher risk of other complications.³⁷

CASE CONTINUED: SPLENIC ARTERY EMBOLIZATION

The patient undergoes emergency splenic artery embolization, performed by an interventional radiology team (Figure 2 and Figure 3). Over the next few days, her mental status improves and her abdominal pain resolves. Her hemoglobin level remains stable after the procedure.

The surgical and interventional radiology teams discuss the risk of repeat intervention with the patient and her family, who prefer a nonoperative approach. She is managed supportively in the intensive care unit and is finally discharged home in stable condition and is scheduled for outpatient follow-up.

SUSPECT THIS FATAL CONDITION

The low prevalence of ruptured splenic artery aneurysm may lead physicians to attribute septic shock to spontaneous bacterial peritonitis or hemorrhagic shock from gastroesophageal varices in patients with cirrhosis, but a high index of suspicion and early recognition of this rare disease can lead to timely diagnosis and treatment of this highly fatal complication.

KEY POINTS

• Splenic artery aneurysm is a common complication of cirrhosis, often diagnosed incidentally.
• Elective embolization should be considered for asymptomatic splenic artery aneurysms larger than 2 cm in diameter, clinically symptomatic aneurysms, women of childbearing age, and patients who are candidates for liver transplant.
• Although splenic artery aneurysm rupture is rare, it has a high mortality rate and warrants a high index of suspicion to institute prompt specialized intervention.
• We recommend that physicians consider splenic artery aneurysm rupture in their differential diagnoses in patients with liver cirrhosis presenting with abdominal pain, altered mental status, and hemodynamic shock.

A 53-year-old Native American woman with a history of liver cirrhosis secondary to alcohol abuse presents to the emergency department after 2 days of diffuse abdominal pain and weakness. The pain was sudden in onset and has progressed relentlessly over the last day, reaching 9 on a scale of 10 in severity. Family members say that her oral intake has been decreased for the last 2 days, but she has had no fever, vomiting, change in bowel habit, blood in stool, or black stool. She has never undergone surgery, and has had one uncomplicated pregnancy.

Physical examination

Vital signs:

• Blood pressure 82/57 mm Hg
• Heart rate 96 beats per minute
• Temperature 37.3°C (99.1°F)
• Respiratory rate 16 per minute
• Oxygen saturation 92% while receiving oxygen at 2 L/minute.

The patient is somnolent and has scleral icterus. Her cardiopulmonary examination is normal. Her abdomen is tense, distended, and diffusely tender. She has bilateral +2 pitting edema in her lower extremities. She is oriented to person only and is noted to have asterixis. Her baseline Model for End-stage Liver Disease score is 18 points on a scale of 6 (less ill) to 40 (gravely ill).

Laboratory studies:

• Hemoglobin 9.8 g/dL (reference range 11.5–15.5)
• Platelet count 100 × 10⁹/L (150–400)
• White blood cell count 9.9 × 10⁹/L (3.7–11.0)
• Serum creatinine 1.06 mg/dL (0.58–0.96)
• Bilirubin 6.3 mg/dL (0.2–1.3)
• International normalized ratio of the prothrombin time 2.15 (0.8–1.2)
• Blood urea nitrogen 13 mg/dL (7–21)
• Serum albumin 2.7 g/dL (3.9–4.9).

Intravenous fluid resuscitation is initiated but the patient remains hypotensive, and on repeat laboratory testing 4 hours later her hemoglobin level has dropped to 7.3 mg/dL.

DIFFERENTIAL DIAGNOSIS

1. Which of the following are likely causes of this patient’s presentation?

• Splenic arterial aneurysm rupture
• Spontaneous bacterial peritonitis
• Variceal hemorrhage
• Portal vein thrombosis
• Abdominal aortic aneurysm rupture

Ruptured splenic artery aneurysm

Splenic artery aneurysms are the third most common intra-abdominal aneurysm, after those of the abdominal aorta and iliac artery.¹ They are often asymptomatic and are being detected more frequently because of increased use of computed tomography (CT).² Symptomatic splenic artery aneurysms may present with abdominal pain and have the potential to rupture, which can be life-threatening.^3,4

This patient may have a ruptured splenic artery aneurysm, given her hemodynamic shock.

Spontaneous bacterial peritonitis

Ten percent to 20% of hospitalized patients with cirrhosis and ascites develop spontaneous bacterial peritonitis. Patients may present with ascites and abdominal pain, tenderness to palpation, fever, encephalopathy, or worsening liver and renal function.

Diagnostic paracentesis is paramount to delineate the cause of ascites; one should calculate the serum-ascites albumin gradient and obtain a cell count and culture of the ascitic fluid. The diagnosis of spontaneous bacterial peritonitis can be made if the ascitic fluid polymorphonuclear cell count is 0.25 × 10⁹/L or higher, even if the ascitic fluid culture is negative.^5,6 Simultaneous blood cultures should also be collected, as 50% of cases are associated with bacteremia.

The in-hospital mortality rate of an episode of spontaneous bacterial peritonitis has been reduced to 10% to 20% thanks to prompt diagnosis and empiric treatment with third-generation cephalosporins.⁷

Five percent of cases of infected ascites fluid are due to secondary bacterial peritonitis from a perforated viscus or a loculated abscess, which cannot be differentiated clinically from spontaneous bacterial peritonitis but can be diagnosed with CT.⁸

This patient may be presenting with septic shock secondary to either of these causes.

Variceal hemorrhage

Half of patients with cirrhosis have gastroesophageal varices due to portal hypertension. Endoscopic surveillance is warranted, as the risk of hemorrhage is 12% to 15% per year, and the mortality rate approaches 15% to 20% with each episode. Prompt resuscitation, diagnosis, and control of bleeding is paramount.

Esophagogastroduodenoscopy is used for both diagnosis and intervention. Short-term prophylactic use of antibiotics improves survival by preventing infections in the event bleeding recurs.^9–11

Our patient may be presenting with hemodynamic shock from bleeding esophageal varices.

 

 

Portal vein thrombosis

Portal vein thrombosis is a common complication of cirrhosis, occurring in 5% to 28% of patients. The risk increases with the severity of liver disease and in association with hepatocellular carcinoma.¹² Forty-three percent of cases are discovered incidentally in asymptomatic patients during ultrasonography, 39% present with upper gastrointestinal bleeding, and 18% present with abdominal pain.^13,14

Portal vein thrombosis is the complete or partial obstruction of blood flow due to a thrombus in the lumen of the portal vein. Contrast ultrasonography and CT can be used to establish the diagnosis.¹⁵

Anticoagulation is recommended in cases of complete thrombosis in candidates for living-donor liver transplant and for those at risk of mesenteric ischemia because of the thrombus extending into the mesenteric veins. In symptomatic patients, the decision to initiate anticoagulation should be made on a case-by-case basis after appropriate screening and management of varices.^16–18

Our patient’s thrombocytopenia reflects the severity of portal hypertension and increases her risk of portal vein thrombosis, but this is unlikely to be the sole cause of the hemodynamic compromise in this patient.

Ruptured abdominal aortic aneurysm

Rupture of an abdominal aortic aneurysm is a medical emergency, with a mortality rate approaching 90%. Risk factors for abdominal aortic aneurysms are smoking, male sex, age over 65, history of cardiovascular disease, hypertension, and a family history of abdominal aortic aneurysm, especially if a first-degree relative is affected.¹⁹ Endovascular repair is associated with lower rates of death and complications compared with open repair.²⁰

The patient does not have any of those risk factors, making this diagnosis less likely.

CASE CONTINUED: RUPTURED SPLENIC ARTERY ANEURYSM

Emergency CT of the abdomen and pelvis with contrast enhancement shows a large left intraperitoneal hematoma with active extravasation from a ruptured splenic artery aneurysm (Figure 1). The patient receives packed red blood cells and fresh-frozen plasma before being transferred to our hospital.

2. Which of the following is false regarding splenic artery aneurysms?

• They are the most common type of splanchnic arterial aneurysm
• True aneurysms are more common than pseudoaneurysms
• Asymptomatic aneurysms are discovered incidentally during assessment for other radiographic indications
• Splenic artery aneurysm in portal hypertension is the result of athero-sclerotic changes to the vascular intima

Splenic artery aneurysm in portal hypertension is not the result of atherosclerotic change to the vascular intima.

Splenic artery aneurysms are the most common type of splanchnic artery aneurysm.¹ True aneurysms involve all 3 layers of the arterial wall, ie, intima, media, and adventitia. Cirrhosis and portal hypertension are associated with true aneurysm formation. The proposed mechanism of aneurysm formation is increased splenic blood flow in response to portal congestion with resultant hemodynamic stress that disrupts arterial wall structure, leading to aneurysmal dilation.²¹

In earlier reports, the incidence of true splenic artery aneurysm in portal hypertension varied from 2.9% to 50%, the latter representing autopsy findings of small aneurysms that were found in the splenic hilum of patients with cirrhosis.^22–25 The incidence of clinically significant aneurysms in cirrhosis is unknown but incidental asymptomatic aneurysm is being detected more frequently on imaging studies pursued for screening purposes.²⁶

The risk of rupture is low, only 2% to 10% in older studies and likely even lower now due to increased incidental detection in asymptomatic patients.²⁷ However, emergent management of rupture at a tertiary care facility is paramount, as the mortality rate of ruptured splenic artery aneurysm is 29% to 36%.^1,26,28

Splenic artery pseudoaneurysm is rarer and has a different pathophysiologic process than true aneurysm. It usually arises in the setting of trauma, pancreatitis, or postsurgery.^29,30 Pseudoaneurysm is more likely to rupture, owing to compromise in the vascular wall integrity.^4,21,28 As a result, treatment is indicated for every pseudoaneurysm regardless of size.

RISK FACTORS FOR SPLENIC ARTERY ANEURYSM

3. Which of the following is true regarding our patient’s risk of splenic artery aneurysm?

• Liver cirrhosis and portal hypertension are her greatest risk factors for it
• Female sex and prior pregnancy are her greatest risk factors for it
• Being Native American makes it more likely that the patient has splenic artery aneurysm secondary to collagen vascular disease
• Her risk of rupture would diminish after receiving a liver transplant

Liver cirrhosis and portal hypertension are her greatest risk factors for splenic artery aneurysm.

Risk factors for true aneurysm include hypertension, atherosclerosis, portal hypertension with or without liver cirrhosis, liver transplant, third trimester of pregnancy, and multiparity.^1,4,26,28,31 Splenic artery aneurysm is  usually diagnosed in the sixth decade. It may be 4 times as common in women, given a hormonal influence.³² Cirrhosis is also associated with massive splenic artery aneurysm (≥ 5 cm). Although rare, massive splenic artery aneurysm is more frequent in men (the male-to-female ratio is 1.78:1) and has a heightened risk of rupture.²⁸ The incidence of rupture increases to around 3% to 4% after liver transplant.³³ Rare causes of true aneurysm include fibrodysplasia, collagen vascular disease (eg, Loeys-Dietz and type IV Ehler-Danlos syndromes), vasculitis (eg, polyarteritis nodosa due to amphetamine abuse), and mycotic aneurysms.^24,25,28,29

This patient’s age, sex, and history of cirrhosis puts her at increased risk of splenic artery aneurysm. The risk of rupture is highest in the peripartum period and in patients with cirrhosis who become pregnant. Although being Native American portends an increased risk for collagen vascular disease, the latter is unlikely to be a contributing factor.

 

 

TREATMENT OF SPLENIC ARTERY ANEURYSM

4. Which of the following is false regarding treatment of splenic artery aneurysms?

• Aneurysms larger than 2 cm and those that are expanding require repair
• Treatment should be offered if the patient has symptoms attributable to the aneurysm
• Asymptomatic aneurysms in pregnant women can be followed with watchful waiting
• Minimally invasive therapies such as percutaneous embolization may be a good option in poor operative candidates

Asymptomatic aneurysms in pregnant women should not be followed with watchful waiting—they should be repaired, as rupture carries a maternal mortality rate of 75% and a fetal mortality rate of 95%.³⁴

Complications of splenic artery aneurysm depend on the type of aneurysm and its predisposing factors. Indications for treatment of true aneurysms include:

• Symptoms attributable to the aneurysm (hence, the second answer choice above is true)
• Diameter 2  cm or greater or enlarging diameter (hence, the first answer choice is true)
• Women of childbearing age in anticipation of pregnancy
• Need for surgical intervention such as portocaval shunt and liver transplant.

Conservative management is associated with a late mortality risk of 4.9%.² Interventional options include percutaneous embolization or stenting; or laparotomy with splenic artery ligation or excision with or without splenectomy.^1,28,35–37

Endovascular and open surgical repair have both been used to treat splenic artery aneurysms. The method used depends on the patient’s surgical history and aneurysm anatomy such as splenic artery tortuosity hindering passage of a catheter. Open surgery is associated with longer intraoperative time and length of hospital stay and higher rates of 30-day mortality and perioperative morbidity.^38–41 With endovascular repair, the complication of persistent or recurrent flow occurs in 3% to 5% of cases by 30 days; hence, postprocedural surveillance is recommended.^42–44 Endovascular repair has a higher reintervention rate but may still be more cost-effective than open surgical repair.

Because patients with cirrhosis have a higher risk of surgical complications,⁴⁵ elective endovascular treatment may be an option for patients with aneurysms at high risk of rupturing. Endovascular treatment of visceral aneurysms is associated with complications such as postembolization syndrome (fever, abdominal pain, pleural effusion, and pancreatitis), access site hematoma, splenic infarction, and persistent abdominal pain.⁴²

Patients with cirrhosis as the cause of splenic artery aneurysm tend to need longer hospitalization after endovascular treatment, but there is insufficient evidence to suggest that they are at higher risk of other complications.³⁷

CASE CONTINUED: SPLENIC ARTERY EMBOLIZATION

The patient undergoes emergency splenic artery embolization, performed by an interventional radiology team (Figure 2 and Figure 3). Over the next few days, her mental status improves and her abdominal pain resolves. Her hemoglobin level remains stable after the procedure.

The surgical and interventional radiology teams discuss the risk of repeat intervention with the patient and her family, who prefer a nonoperative approach. She is managed supportively in the intensive care unit and is finally discharged home in stable condition and is scheduled for outpatient follow-up.

SUSPECT THIS FATAL CONDITION

The low prevalence of ruptured splenic artery aneurysm may lead physicians to attribute septic shock to spontaneous bacterial peritonitis or hemorrhagic shock from gastroesophageal varices in patients with cirrhosis, but a high index of suspicion and early recognition of this rare disease can lead to timely diagnosis and treatment of this highly fatal complication.

KEY POINTS

• Splenic artery aneurysm is a common complication of cirrhosis, often diagnosed incidentally.
• Elective embolization should be considered for asymptomatic splenic artery aneurysms larger than 2 cm in diameter, clinically symptomatic aneurysms, women of childbearing age, and patients who are candidates for liver transplant.
• Although splenic artery aneurysm rupture is rare, it has a high mortality rate and warrants a high index of suspicion to institute prompt specialized intervention.
• We recommend that physicians consider splenic artery aneurysm rupture in their differential diagnoses in patients with liver cirrhosis presenting with abdominal pain, altered mental status, and hemodynamic shock.

A 64-year-old man with end-stage renal disease was evaluated in the pulmonary clinic for persistent abnormalities on axial computed tomography (CT) of the chest. He was a lifelong nonsmoker and had no history of exposure to occupational dust or fumes. His oxygen saturation was 100% on room air, and he denied any respiratory symptoms.

WHEN TO CONSIDER METASTATIC PULMONARY CALCIFICATION

The differential diagnosis for chronic upper-lobe-predominant ground-glass nodules is broad and includes atypical infections, recurrent alveolar hemorrhage, hypersensitivity pneumonitis, vasculitis, sarcoidosis, chronic eosinophilic pneumonia, occupational lung disease, and pulmonary alveolar microlithiasis. However, several aspects of our patient’s case suggested an often overlooked diagnosis, metastatic pulmonary calcification.

Metastatic pulmonary calcification is caused by deposition of calcium salts in lung tissue and is most commonly seen in patients on dialysis,^1,2 and our patient had been dependent on dialysis for many years. The chronically elevated calcium-phosphorus product and secondary hyperparathyroidism often seen with end-stage renal disease may explain this association.

Our patient’s lack of symptoms is also an important diagnostic clue. Unlike many other causes of chronic upper-lobe-predominant ground-glass nodules, metastatic pulmonary calcification does not usually cause symptoms and is often identified only at autopsy.³ Results of pulmonary function testing are often normal.⁴

Metastatic pulmonary calcification can appear as diffusely calcified nodules or high-attenuation areas of consolidation on CT. However, as in our patient’s case, CT may demonstrate fluffy, centrilobular ground-glass nodules due to the microscopic size of the deposited calcium crystals.¹ Identifying calcified vessels on imaging supports the diagnosis.⁴

Treatment of metastatic pulmonary calcification in a patient with end-stage renal disease is focused on correcting underlying metabolic abnormalities with phosphate binders, vitamin D supplementation, and dialysis.

A 64-year-old man with end-stage renal disease was evaluated in the pulmonary clinic for persistent abnormalities on axial computed tomography (CT) of the chest. He was a lifelong nonsmoker and had no history of exposure to occupational dust or fumes. His oxygen saturation was 100% on room air, and he denied any respiratory symptoms.

WHEN TO CONSIDER METASTATIC PULMONARY CALCIFICATION

The differential diagnosis for chronic upper-lobe-predominant ground-glass nodules is broad and includes atypical infections, recurrent alveolar hemorrhage, hypersensitivity pneumonitis, vasculitis, sarcoidosis, chronic eosinophilic pneumonia, occupational lung disease, and pulmonary alveolar microlithiasis. However, several aspects of our patient’s case suggested an often overlooked diagnosis, metastatic pulmonary calcification.

Metastatic pulmonary calcification is caused by deposition of calcium salts in lung tissue and is most commonly seen in patients on dialysis,^1,2 and our patient had been dependent on dialysis for many years. The chronically elevated calcium-phosphorus product and secondary hyperparathyroidism often seen with end-stage renal disease may explain this association.

Our patient’s lack of symptoms is also an important diagnostic clue. Unlike many other causes of chronic upper-lobe-predominant ground-glass nodules, metastatic pulmonary calcification does not usually cause symptoms and is often identified only at autopsy.³ Results of pulmonary function testing are often normal.⁴

Metastatic pulmonary calcification can appear as diffusely calcified nodules or high-attenuation areas of consolidation on CT. However, as in our patient’s case, CT may demonstrate fluffy, centrilobular ground-glass nodules due to the microscopic size of the deposited calcium crystals.¹ Identifying calcified vessels on imaging supports the diagnosis.⁴

Treatment of metastatic pulmonary calcification in a patient with end-stage renal disease is focused on correcting underlying metabolic abnormalities with phosphate binders, vitamin D supplementation, and dialysis.

A 64-year-old man with end-stage renal disease was evaluated in the pulmonary clinic for persistent abnormalities on axial computed tomography (CT) of the chest. He was a lifelong nonsmoker and had no history of exposure to occupational dust or fumes. His oxygen saturation was 100% on room air, and he denied any respiratory symptoms.

WHEN TO CONSIDER METASTATIC PULMONARY CALCIFICATION

The differential diagnosis for chronic upper-lobe-predominant ground-glass nodules is broad and includes atypical infections, recurrent alveolar hemorrhage, hypersensitivity pneumonitis, vasculitis, sarcoidosis, chronic eosinophilic pneumonia, occupational lung disease, and pulmonary alveolar microlithiasis. However, several aspects of our patient’s case suggested an often overlooked diagnosis, metastatic pulmonary calcification.

Metastatic pulmonary calcification is caused by deposition of calcium salts in lung tissue and is most commonly seen in patients on dialysis,^1,2 and our patient had been dependent on dialysis for many years. The chronically elevated calcium-phosphorus product and secondary hyperparathyroidism often seen with end-stage renal disease may explain this association.

Our patient’s lack of symptoms is also an important diagnostic clue. Unlike many other causes of chronic upper-lobe-predominant ground-glass nodules, metastatic pulmonary calcification does not usually cause symptoms and is often identified only at autopsy.³ Results of pulmonary function testing are often normal.⁴

Metastatic pulmonary calcification can appear as diffusely calcified nodules or high-attenuation areas of consolidation on CT. However, as in our patient’s case, CT may demonstrate fluffy, centrilobular ground-glass nodules due to the microscopic size of the deposited calcium crystals.¹ Identifying calcified vessels on imaging supports the diagnosis.⁴

Treatment of metastatic pulmonary calcification in a patient with end-stage renal disease is focused on correcting underlying metabolic abnormalities with phosphate binders, vitamin D supplementation, and dialysis.

To the Editor: We read with great interest the article by Patnaik et al¹ about a patient who had a cardiac metastasis of ovarian cancer, and we would like to raise a few points.

It is important to clarify that metastatic cardiac tumors are not necessary malignant. Intravenous leiomyomatosis is a benign small-muscle tumor that can spread to the heart, causing various cardiac symptoms.² Even with extensive disease, patients with intravenous leiomyomatosis may remain asymptomatic until cardiac involvement occurs. The most common cardiac symptoms are dyspnea, syncope, and lower-extremity edema.

Cardiac involvement in intravenous leiomyomatosis may occur via direct invasion or hematogenous or lymphatic spread of the tumor. In leiomyoma and leiomyosarcoma, cardiac invasion usually occurs via direct spread through the inferior vena cava into the right atrium and ventricle. Thus, cardiac involvement with these tumors (except for nephroma) was reported to exclusively involve the right side of the heart.

In 2014, we reported a unique case of intravenous leiomyomatosis that extended from the right side into the left side of the heart and the aorta via an atrial septal defect.² Intracardiac extension of intravenous leiomyomatosis may result in pulmonary embolism, systemic embolization if involving the left side, and, rarely, sudden death.²

In patients with malignancy, differentiating between thrombosis and tumor is critical. These patients have a hypercoagulable state and a fourfold increase in thrombosis risk, and chemotherapy increases this risk even more.³ Although tissue pathology examination is important for differentiating thrombosis from tumor, visualization of the direct extension of the mass from the primary source into the heart through the inferior vena cava by ultrasonography, computed tomography, or magnetic resonance imaging may help in making this distinction.²

To the Editor: We read with great interest the article by Patnaik et al¹ about a patient who had a cardiac metastasis of ovarian cancer, and we would like to raise a few points.

It is important to clarify that metastatic cardiac tumors are not necessary malignant. Intravenous leiomyomatosis is a benign small-muscle tumor that can spread to the heart, causing various cardiac symptoms.² Even with extensive disease, patients with intravenous leiomyomatosis may remain asymptomatic until cardiac involvement occurs. The most common cardiac symptoms are dyspnea, syncope, and lower-extremity edema.

Cardiac involvement in intravenous leiomyomatosis may occur via direct invasion or hematogenous or lymphatic spread of the tumor. In leiomyoma and leiomyosarcoma, cardiac invasion usually occurs via direct spread through the inferior vena cava into the right atrium and ventricle. Thus, cardiac involvement with these tumors (except for nephroma) was reported to exclusively involve the right side of the heart.

In 2014, we reported a unique case of intravenous leiomyomatosis that extended from the right side into the left side of the heart and the aorta via an atrial septal defect.² Intracardiac extension of intravenous leiomyomatosis may result in pulmonary embolism, systemic embolization if involving the left side, and, rarely, sudden death.²

In patients with malignancy, differentiating between thrombosis and tumor is critical. These patients have a hypercoagulable state and a fourfold increase in thrombosis risk, and chemotherapy increases this risk even more.³ Although tissue pathology examination is important for differentiating thrombosis from tumor, visualization of the direct extension of the mass from the primary source into the heart through the inferior vena cava by ultrasonography, computed tomography, or magnetic resonance imaging may help in making this distinction.²

To the Editor: We read with great interest the article by Patnaik et al¹ about a patient who had a cardiac metastasis of ovarian cancer, and we would like to raise a few points.

It is important to clarify that metastatic cardiac tumors are not necessary malignant. Intravenous leiomyomatosis is a benign small-muscle tumor that can spread to the heart, causing various cardiac symptoms.² Even with extensive disease, patients with intravenous leiomyomatosis may remain asymptomatic until cardiac involvement occurs. The most common cardiac symptoms are dyspnea, syncope, and lower-extremity edema.

Cardiac involvement in intravenous leiomyomatosis may occur via direct invasion or hematogenous or lymphatic spread of the tumor. In leiomyoma and leiomyosarcoma, cardiac invasion usually occurs via direct spread through the inferior vena cava into the right atrium and ventricle. Thus, cardiac involvement with these tumors (except for nephroma) was reported to exclusively involve the right side of the heart.

In 2014, we reported a unique case of intravenous leiomyomatosis that extended from the right side into the left side of the heart and the aorta via an atrial septal defect.² Intracardiac extension of intravenous leiomyomatosis may result in pulmonary embolism, systemic embolization if involving the left side, and, rarely, sudden death.²

In patients with malignancy, differentiating between thrombosis and tumor is critical. These patients have a hypercoagulable state and a fourfold increase in thrombosis risk, and chemotherapy increases this risk even more.³ Although tissue pathology examination is important for differentiating thrombosis from tumor, visualization of the direct extension of the mass from the primary source into the heart through the inferior vena cava by ultrasonography, computed tomography, or magnetic resonance imaging may help in making this distinction.²

To the Editor: As a geriatric medicine fellow, I eagerly read Hagerty and Rich’s review “Fall risk and anticoagulation for atrial fibrillation in the elderly: A delicate balance”¹ and Suh’s editorial, “Whether to anticoagulate: Toward a more reasoned approach”² in the January 2017 issue. Both pieces were helpful and informative.

I appreciate that Dr. Suh encourages shared decision-making between physicians and patients that balances patient preferences and risk stratification to inform whether to anticoagulate. He states, “Unfortunately, there is no similar screening tool to predict bleeding risk from anticoagulation with greater precision in the middle to lower part of the risk spectrum...The patient’s life expectancy and personal preferences are important independent factors that affect the decision of whether to anticoagulate or not.” 

Dr. Mark Eckman’s Atrial Fibrillation Decision Support Tool (AFDST) incorporates patients’ CHA₂DS₂-VASc and HAS-BLED scores to determine their quality-adjusted life expectancy on or off anticoagulation. The tool helps guide physicians and patients to make shared decisions about anticoagulation.^3–5 The AFDST informs clinicians if a patient is undertreated or being treated unnecessarily. Eckman and his colleagues have demonstrated the AFDST’s effective application in clinical practice, including for older adults. I invite readers to learn more about Eckman’s work!

To the Editor: As a geriatric medicine fellow, I eagerly read Hagerty and Rich’s review “Fall risk and anticoagulation for atrial fibrillation in the elderly: A delicate balance”¹ and Suh’s editorial, “Whether to anticoagulate: Toward a more reasoned approach”² in the January 2017 issue. Both pieces were helpful and informative.

I appreciate that Dr. Suh encourages shared decision-making between physicians and patients that balances patient preferences and risk stratification to inform whether to anticoagulate. He states, “Unfortunately, there is no similar screening tool to predict bleeding risk from anticoagulation with greater precision in the middle to lower part of the risk spectrum...The patient’s life expectancy and personal preferences are important independent factors that affect the decision of whether to anticoagulate or not.” 

Dr. Mark Eckman’s Atrial Fibrillation Decision Support Tool (AFDST) incorporates patients’ CHA₂DS₂-VASc and HAS-BLED scores to determine their quality-adjusted life expectancy on or off anticoagulation. The tool helps guide physicians and patients to make shared decisions about anticoagulation.^3–5 The AFDST informs clinicians if a patient is undertreated or being treated unnecessarily. Eckman and his colleagues have demonstrated the AFDST’s effective application in clinical practice, including for older adults. I invite readers to learn more about Eckman’s work!

To the Editor: As a geriatric medicine fellow, I eagerly read Hagerty and Rich’s review “Fall risk and anticoagulation for atrial fibrillation in the elderly: A delicate balance”¹ and Suh’s editorial, “Whether to anticoagulate: Toward a more reasoned approach”² in the January 2017 issue. Both pieces were helpful and informative.

I appreciate that Dr. Suh encourages shared decision-making between physicians and patients that balances patient preferences and risk stratification to inform whether to anticoagulate. He states, “Unfortunately, there is no similar screening tool to predict bleeding risk from anticoagulation with greater precision in the middle to lower part of the risk spectrum...The patient’s life expectancy and personal preferences are important independent factors that affect the decision of whether to anticoagulate or not.” 

Dr. Mark Eckman’s Atrial Fibrillation Decision Support Tool (AFDST) incorporates patients’ CHA₂DS₂-VASc and HAS-BLED scores to determine their quality-adjusted life expectancy on or off anticoagulation. The tool helps guide physicians and patients to make shared decisions about anticoagulation.^3–5 The AFDST informs clinicians if a patient is undertreated or being treated unnecessarily. Eckman and his colleagues have demonstrated the AFDST’s effective application in clinical practice, including for older adults. I invite readers to learn more about Eckman’s work!

In Reply: I appreciate Dr. Henning’s letter in response to my editorial.¹ Indeed, Dr. Eckman’s Atrial Fibrillation Decision Support Tool (AFDST) is useful for determining quality-adjusted life expectancy on or off anticoagulation, and could possibly help with shared decision-making in regard to anticoagulation.^2–4 

However, the AFDST does not incorporate personal preferences regarding anticoagulant or medication use in general. Many older adults are on too many medications (ie, polypharmacy) and wish to reduce their overall pill count.

A number of potential barriers to shared decision-making regarding medication use have been identified, including poor physician communication skills, the growing number of available medications, multiple prescribers for the same patient, lack of trust in the prescribing physician, and patients feeling that their preferences are not valued or important.⁵ Until communication and acceptance between prescribers and patients regarding possible medication choices improves, shared decision-making for medication use in general and anticoagulant use in particular will be an unfulfilled ideal.

In Reply: I appreciate Dr. Henning’s letter in response to my editorial.¹ Indeed, Dr. Eckman’s Atrial Fibrillation Decision Support Tool (AFDST) is useful for determining quality-adjusted life expectancy on or off anticoagulation, and could possibly help with shared decision-making in regard to anticoagulation.^2–4 

However, the AFDST does not incorporate personal preferences regarding anticoagulant or medication use in general. Many older adults are on too many medications (ie, polypharmacy) and wish to reduce their overall pill count.

A number of potential barriers to shared decision-making regarding medication use have been identified, including poor physician communication skills, the growing number of available medications, multiple prescribers for the same patient, lack of trust in the prescribing physician, and patients feeling that their preferences are not valued or important.⁵ Until communication and acceptance between prescribers and patients regarding possible medication choices improves, shared decision-making for medication use in general and anticoagulant use in particular will be an unfulfilled ideal.

In Reply: I appreciate Dr. Henning’s letter in response to my editorial.¹ Indeed, Dr. Eckman’s Atrial Fibrillation Decision Support Tool (AFDST) is useful for determining quality-adjusted life expectancy on or off anticoagulation, and could possibly help with shared decision-making in regard to anticoagulation.^2–4 

However, the AFDST does not incorporate personal preferences regarding anticoagulant or medication use in general. Many older adults are on too many medications (ie, polypharmacy) and wish to reduce their overall pill count.

A number of potential barriers to shared decision-making regarding medication use have been identified, including poor physician communication skills, the growing number of available medications, multiple prescribers for the same patient, lack of trust in the prescribing physician, and patients feeling that their preferences are not valued or important.⁵ Until communication and acceptance between prescribers and patients regarding possible medication choices improves, shared decision-making for medication use in general and anticoagulant use in particular will be an unfulfilled ideal.

Many patients, clinicians, and researchers had hoped that renal denervation would help control resistant hypertension. However, in the SYMPLICITY HTN-3 trial,¹ named for the catheter-based system used in the study (Symplicity RDN, Medtronic, Dublin, Ireland), this endovascular procedure failed to meet its primary and secondary efficacy end points, although it was found to be safe. These results were surprising, especially given the results of an earlier randomized trial (SYMPLICITY HTN-2),² which showed larger reductions in blood pressures 6 months after denervation than in the current trial.

See related editorial

Here, we discuss the results of the SYMPLICITY HTN-3 trial and offer possible explanations for its negative outcomes.

LEAD-UP TO SYMPLICITY HTN-3

Renal denervation consists of passing a catheter through the femoral artery into the renal arteries and ablating their sympathetic nerves using radiofrequency energy. In theory, this should interrupt efferent sympathetic communication between the brain and renal arteries, reducing muscular contraction of these arteries, increasing renal blood flow, reducing activation of the renin-angiotensin-adosterone system, thus reducing sodium retention, reducing afferent sympathetic communication between the kidneys and brain, and in turn reducing further sympathetic activity elsewhere in the body, such as in the heart. Blood pressure should fall.³

The results of the SYMPLICITY HTN-1 and 2 trials were discussed in an earlier article in this Journal,³ and the Medtronic-Ardian renal denervation system has been available in Europe and Australia for clinical use for over 2 years.⁴ Indeed, after the SYMPLICITY HTN-2 results were published in 2010, Boston Scientific’s Vessix, St. Jude Medical’s EnligHTN, and Covidien’s OneShot radiofrequency renal denervation devices—albeit each with some modifications—received a Conformité Européene (CE) mark and became available in Europe and Australia for clinical use. These devices are not available for clinical use or research in the United States.^3,5

Therefore, SYMPLICITY HTN-3, sponsored by Medtronic, was designed to obtain US Food and Drug Administration approval in the United States.⁶

SYMPLICITY HTN-3 DESIGN

Inclusion criteria were similar to those in the earlier SYMPLICITY trials. Patients had to have resistant hypertension, defined as a systolic blood pressure ≥ 160 mm Hg despite taking at least 3 blood pressure medications at maximum tolerated doses. Patients were excluded if they had a glomerular filtration rate of less than 45 mL/min/1.73 m², renal artery stenosis, or known secondary hypertension.

A total of 1,441 patients were enrolled, of whom 364 were eventually randomized to undergo renal denervation, and 171 were randomized to undergo a sham procedure. The mean systolic blood pressure at baseline was 188 mm Hg in each group. Most patients were taking maximum doses of blood pressure medications, and almost one-fourth were taking an aldosterone antagonist. Patients in both groups were taking an average of 5 medications.

The 2 groups were well matched for important covariates, including obstructive sleep apnea, diabetes mellitus, and renal insufficiency. Most of the patients were white; 25% of the renal denervation group and 29% of the sham procedure group were black.

The physicians conducting the follow-up appointments did not know which procedure the patients underwent, and neither did the patients. Medications were closely monitored, and patients had close follow-up. The catheter (Symplicity RDS, Medtronic) was of the same design that was used in the earlier SYMPLICITY trials and in clinical practice in countries where renal denervation was available.

Researchers expected that the systolic blood pressure, as measured in the office, would fall in both groups, but they hoped it would fall farther in the denervation group—at least 5 mm Hg farther, the primary end point of the trial. The secondary effectiveness end point was a 2-mm Hg greater reduction in 24-hour ambulatory systolic blood pressure.

 

 

SYMPLICITY HTN-3 RESULTS

No statistically significant difference in safety was observed between the denervation and control groups. However, the procedure was associated with 1 embolic event and 1 case of renal artery stenosis.

Blood pressure fell in both groups. However, at 6 months, office systolic pressure had fallen by a mean of 14.13 mm Hg in the denervation group and 11.74 mm Hg in the sham procedure group, a difference of only 2.39 mm Hg. The mean ambulatory systolic blood pressure had fallen by 6.75 vs 4.79 mm Hg, a difference of only 1.96 mm Hg. Neither difference was statistically significant.

A number of prespecified subgroup analyses were conducted, but the benefit of the procedure was statistically significant in only 3 subgroups: patients who were not black (P = .01), patients who were less than 65 years old (P = .04), and patients who had an estimated glomerular filtration rate of 60 mL/min/1.73 m² or higher (P = .05).

WHAT WENT WRONG?

The results of SYMPLICITY HTN-3 were disappointing and led companies that were developing renal denervation devices to discontinue or reevaluate their programs.

Although the results were surprising, many observers (including our group) raised concerns about the initial enthusiasm surrounding renal denervation.^3–7 Indeed, in 2010, we had concerns about the discrepancy between office-based blood pressure measurements (the primary end point of all renal denervation trials) and ambulatory blood pressure measurements in SYMPLICITY HTN-2.⁷

The enthusiasm surrounding this procedure led to the publication of 2 consensus documents on this novel therapy based on only 1 small randomized controlled study (SYMPLICITY HTN-2).^8,9 Renal denervation was even reported to be useful in other conditions involving the sympathorenal axis, including diabetes mellitus, metabolic syndrome, and obstructive sleep apnea, and also as a potential treatment adjunct in atrial fibrillation and other arrhythmias.⁵

What went wrong?

Shortcomings in trial design?

The trial was well designed. Both patients and operators were blinded to the procedure, and 24-hour ambulatory blood pressure monitoring was used. We presume that appropriate patients with resistant hypertension were enrolled—the mean baseline systolic blood pressure was 188 mm Hg, and patients in each group were taking an average of 5 medications.

On the other hand, true medication adherence is difficult to ascertain. Further, the term maximal “tolerated” doses of medications is vague, and we cannot rule out the possibility that some patients were enrolled who did not truly have resistant hypertension—they simply did not want to take medications.

Patients were required to be on a stable medication regimen before enrollment and, ideally, to not have any medication changes during the course of the study, but at least 40% of patients did require medication changes during the study. Additionally, it is unclear whether all patients underwent specific testing to rule out secondary hypertension, as this was done at the discretion of the treating physician.

First-generation catheters?

The same type of catheter was used as in the earlier SYMPLICITY trials, and it had been used in many patients in clinical practice in countries where the catheter is routinely available. It is unknown, however, whether newer multisite denervation devices would yield better results than the first-generation devices used in SYMPLICITY HTN-3. But even this would not explain the discrepancies in data between earlier trials and this trial.

Operator inexperience?

It has been suggested that operator inexperience may have played a role, but an analysis of operator volume did not find any association between this variable and the outcomes. Each procedure was supervised by at least 1 and in most cases 2 certified Medtronic representatives, who made certain that meticulous attention was paid to procedure details and that no shortcuts were taken during the procedure.

Inadequate ablation?

While we can assume that the correct technique was followed in most cases, renal denervation is still a “blind” procedure, and there is no nerve mapping to ascertain the degree of ablation achieved. Notably, patients who had the most ablations reportedly had a greater average drop in systolic ambulatory blood pressure than those who received fewer ablations. Sympathetic nervous system activity is a potential marker of adequacy of ablation, but it was not routinely assessed in the SYMPLICITY HTN-3 trial. Techniques to assess sympathetic nerve activity such as norepinephrine spillover and muscle sympathetic nerve activity are highly specialized and available only at a few research centers, and are not available for routine clinical use.

While these points may explain the negative findings of this trial, they fail to account for the discrepant results between this study and previous trials that used exactly the same definitions and techniques.

 

 

Patient demographics?

Is it possible that renal denervation has a differential effect according to race? All previous renal denervation studies were conducted in Europe or Australia; therefore, few data are available on the efficacy of the procedure in other racial groups, such as black Americans. Most of the patients in this trial were white, but approximately 25% were black—a good representation. There was a statistically significant benefit favoring renal denervation in nonblack (mostly white) patients, but not in black patients. This may be related to racial differences in the pathophysiology of hypertension or possibly due to chance alone.

A Hawthorne effect?

A Hawthorne effect (patients being more compliant because physicians are paying more attention to them) is unlikely, since the renal denervation arm did not have any reduction in blood pressure medications. At 6 months, both the sham group and the procedure group were still on an average of 5 medications.

Additionally, while the blood pressure reduction in both treatment groups was significant, the systolic blood pressure at 6 months was still 166 mm Hg in the denervation group and 168 mm Hg in the sham group. If denervation was effective, one would have expected a greater reduction in blood pressure or at least a decrease in the number of medications needed, eg, 1 to 2 fewer medications in the denervation group compared with the sham procedure group.

Regression to the mean?

It is unknown whether the results represent a statistical error such as regression to the mean. But given the run-in period and the confirmatory data from 24-hour ambulatory blood pressure, this would be unlikely.

WHAT NOW?

Is renal denervation dead? SYMPLICITY HTN-3 is only a single trial with multiple shortcomings and lessons to learn from. Since its publication, there have been updates from 2 prospective, randomized, open-label trials concerning the efficacy of catheter-based renal denervation in lowering blood pressure.^10,11

DENERHTN (Renal Denervation for Hypertension)¹⁰ studied patients with ambulatory systolic blood pressure higher than 135 mm Hg, diastolic blood pressure higher than 80 mm Hg, or both (after excluding secondary etiologies), despite 4 weeks of standardized triple-drug treatment including a diuretic. Patients were randomized to standardized stepped-care antihypertensive treatment alone (control group) or standard care plus renal denervation. The latter resulted in a significant further reduction in ambulatory blood pressure at 6 months.

The Prague-15 trial¹¹ studied patients with resistant hypertension. Secondary etiologies were excluded and adherence to therapy was confirmed by measuring plasma medication levels. It showed that renal denervation along with optimal antihypertensive medical therapy (unchanged after randomization) resulted in a significant reduction in ambulatory blood pressure that was comparable to the effect of intensified antihypertensive medical therapy including spironolactone. (Studies have shown that spironolactone is effective when added on as a fourth-line medication in resistant hypertension.¹²) At 6 months, patients in the intensive medical therapy group were using an average of 0.3 more antihypertensive medications than those in the procedure group.

These two trials addressed some of the drawbacks of the SYMPLICITY HTN-3 trial. However, both have many limitations including and not limited to being open-label and nonblinded, lacking a sham procedure, using a lower blood pressure threshold than SYMPLICITY HTN-3 did to define resistant hypertension, and using the same catheter as in the SYMPLICITY trials.

 

 

Better technology is coming

Advanced renal denervation catheters are needed that are multielectrode, smaller, easier to manipulate, and capable of providing simultaneous, circumferential, more-intense, and deeper ablations. The ongoing Investigator-Steered Project on Intravascular Renal Denervation for Management of Drug-Resistant Hypertension (INSPIRED)¹⁶ and Renal Denervation Using the Vessix Renal Denervation System for the Treatment of Hypertension (REDUCE-HTN: REINFORCE)¹⁷ trials are using contemporary innovative ablation catheters to address the limitations of the first-generation Symplicity catheter.

Further, Fischell et al¹⁸ reported encouraging results of renal denervation performed by injecting ethanol into the adventitial space of the renal arteries. This is still an invasive procedure; however, ethanol can spread out in all directions and reach all targeted nerves, potentially resulting in a more complete renal artery sympathetic ablation.

As technology advances, the WAVE IV trial¹⁹ is examining renal denervation performed from the outside through the skin using high-intensity focused ultrasound, which eliminates the need for femoral arterial catheterization, a promising noninvasive approach.

Proposals for future trials

The European Clinical Consensus Conference for Renal Denervation²⁰ proposed that future trials of renal denervation include patients with moderate rather than resistant hypertension, reflecting the pathogenic importance of sympathetic activity in earlier stages of hypertension. The conference also proposed excluding patients with stiff large arteries, a cause of isolated systolic hypertension. Other proposals included standardizing concomitant antihypertensive therapy, preferably treating all patients with the combination of a renin-angiotensin system blocker, calcium channel blocker, and diuretic in the run-in period; monitoring drug adherence through the use of pill counts, electronic pill dispensers, and drug blood tests; and using change in ambulatory blood pressure as the primary efficacy end point and change in office blood pressure as a secondary end point.

Trials ongoing

To possibly address the limitations posed by the SYMPLICITY HTN-3 trial and to answer other important questions, several sham-controlled clinical trials of renal denervation are currently being conducted:

• INSPiRED¹⁶
• REDUCE-HTN: REINFORCE¹⁷
• Spyral HTN-Off Med²¹
• Spyral HTN-On Med²¹
• Study of the ReCor Medical Paradise System in Clinical Hypertension (RADIANCE-HTN).²²

We hope these new studies can more clearly identify subsets of patients who would benefit from this technology, determine predictors of blood pressure reduction in such patients, and lead to newer devices that may provide more complete ablation.

Obviously, we also need better ways to identify the exact location of these sympathetic nerves within the renal artery and have a clearer sense of procedural success.

Until then, our colleagues in Europe and Australia continue to treat patients with this technology as we appropriately and patiently wait for level 1 clinical evidence of its efficacy.

Acknowledgments: We thank Kathryn Brock, BA, Editorial Services Manager, Heart and Vascular Institute, Cleveland Clinic, for her assistance in the preparation of this paper.

Many patients, clinicians, and researchers had hoped that renal denervation would help control resistant hypertension. However, in the SYMPLICITY HTN-3 trial,¹ named for the catheter-based system used in the study (Symplicity RDN, Medtronic, Dublin, Ireland), this endovascular procedure failed to meet its primary and secondary efficacy end points, although it was found to be safe. These results were surprising, especially given the results of an earlier randomized trial (SYMPLICITY HTN-2),² which showed larger reductions in blood pressures 6 months after denervation than in the current trial.

See related editorial

Here, we discuss the results of the SYMPLICITY HTN-3 trial and offer possible explanations for its negative outcomes.

LEAD-UP TO SYMPLICITY HTN-3

Renal denervation consists of passing a catheter through the femoral artery into the renal arteries and ablating their sympathetic nerves using radiofrequency energy. In theory, this should interrupt efferent sympathetic communication between the brain and renal arteries, reducing muscular contraction of these arteries, increasing renal blood flow, reducing activation of the renin-angiotensin-adosterone system, thus reducing sodium retention, reducing afferent sympathetic communication between the kidneys and brain, and in turn reducing further sympathetic activity elsewhere in the body, such as in the heart. Blood pressure should fall.³

The results of the SYMPLICITY HTN-1 and 2 trials were discussed in an earlier article in this Journal,³ and the Medtronic-Ardian renal denervation system has been available in Europe and Australia for clinical use for over 2 years.⁴ Indeed, after the SYMPLICITY HTN-2 results were published in 2010, Boston Scientific’s Vessix, St. Jude Medical’s EnligHTN, and Covidien’s OneShot radiofrequency renal denervation devices—albeit each with some modifications—received a Conformité Européene (CE) mark and became available in Europe and Australia for clinical use. These devices are not available for clinical use or research in the United States.^3,5

Therefore, SYMPLICITY HTN-3, sponsored by Medtronic, was designed to obtain US Food and Drug Administration approval in the United States.⁶

SYMPLICITY HTN-3 DESIGN

Inclusion criteria were similar to those in the earlier SYMPLICITY trials. Patients had to have resistant hypertension, defined as a systolic blood pressure ≥ 160 mm Hg despite taking at least 3 blood pressure medications at maximum tolerated doses. Patients were excluded if they had a glomerular filtration rate of less than 45 mL/min/1.73 m², renal artery stenosis, or known secondary hypertension.

A total of 1,441 patients were enrolled, of whom 364 were eventually randomized to undergo renal denervation, and 171 were randomized to undergo a sham procedure. The mean systolic blood pressure at baseline was 188 mm Hg in each group. Most patients were taking maximum doses of blood pressure medications, and almost one-fourth were taking an aldosterone antagonist. Patients in both groups were taking an average of 5 medications.

The 2 groups were well matched for important covariates, including obstructive sleep apnea, diabetes mellitus, and renal insufficiency. Most of the patients were white; 25% of the renal denervation group and 29% of the sham procedure group were black.

The physicians conducting the follow-up appointments did not know which procedure the patients underwent, and neither did the patients. Medications were closely monitored, and patients had close follow-up. The catheter (Symplicity RDS, Medtronic) was of the same design that was used in the earlier SYMPLICITY trials and in clinical practice in countries where renal denervation was available.

Researchers expected that the systolic blood pressure, as measured in the office, would fall in both groups, but they hoped it would fall farther in the denervation group—at least 5 mm Hg farther, the primary end point of the trial. The secondary effectiveness end point was a 2-mm Hg greater reduction in 24-hour ambulatory systolic blood pressure.

 

 

SYMPLICITY HTN-3 RESULTS

No statistically significant difference in safety was observed between the denervation and control groups. However, the procedure was associated with 1 embolic event and 1 case of renal artery stenosis.

Blood pressure fell in both groups. However, at 6 months, office systolic pressure had fallen by a mean of 14.13 mm Hg in the denervation group and 11.74 mm Hg in the sham procedure group, a difference of only 2.39 mm Hg. The mean ambulatory systolic blood pressure had fallen by 6.75 vs 4.79 mm Hg, a difference of only 1.96 mm Hg. Neither difference was statistically significant.

A number of prespecified subgroup analyses were conducted, but the benefit of the procedure was statistically significant in only 3 subgroups: patients who were not black (P = .01), patients who were less than 65 years old (P = .04), and patients who had an estimated glomerular filtration rate of 60 mL/min/1.73 m² or higher (P = .05).

WHAT WENT WRONG?

The results of SYMPLICITY HTN-3 were disappointing and led companies that were developing renal denervation devices to discontinue or reevaluate their programs.

Although the results were surprising, many observers (including our group) raised concerns about the initial enthusiasm surrounding renal denervation.^3–7 Indeed, in 2010, we had concerns about the discrepancy between office-based blood pressure measurements (the primary end point of all renal denervation trials) and ambulatory blood pressure measurements in SYMPLICITY HTN-2.⁷

The enthusiasm surrounding this procedure led to the publication of 2 consensus documents on this novel therapy based on only 1 small randomized controlled study (SYMPLICITY HTN-2).^8,9 Renal denervation was even reported to be useful in other conditions involving the sympathorenal axis, including diabetes mellitus, metabolic syndrome, and obstructive sleep apnea, and also as a potential treatment adjunct in atrial fibrillation and other arrhythmias.⁵

What went wrong?

Shortcomings in trial design?

The trial was well designed. Both patients and operators were blinded to the procedure, and 24-hour ambulatory blood pressure monitoring was used. We presume that appropriate patients with resistant hypertension were enrolled—the mean baseline systolic blood pressure was 188 mm Hg, and patients in each group were taking an average of 5 medications.

On the other hand, true medication adherence is difficult to ascertain. Further, the term maximal “tolerated” doses of medications is vague, and we cannot rule out the possibility that some patients were enrolled who did not truly have resistant hypertension—they simply did not want to take medications.

Patients were required to be on a stable medication regimen before enrollment and, ideally, to not have any medication changes during the course of the study, but at least 40% of patients did require medication changes during the study. Additionally, it is unclear whether all patients underwent specific testing to rule out secondary hypertension, as this was done at the discretion of the treating physician.

First-generation catheters?

The same type of catheter was used as in the earlier SYMPLICITY trials, and it had been used in many patients in clinical practice in countries where the catheter is routinely available. It is unknown, however, whether newer multisite denervation devices would yield better results than the first-generation devices used in SYMPLICITY HTN-3. But even this would not explain the discrepancies in data between earlier trials and this trial.

Operator inexperience?

It has been suggested that operator inexperience may have played a role, but an analysis of operator volume did not find any association between this variable and the outcomes. Each procedure was supervised by at least 1 and in most cases 2 certified Medtronic representatives, who made certain that meticulous attention was paid to procedure details and that no shortcuts were taken during the procedure.

Inadequate ablation?

While we can assume that the correct technique was followed in most cases, renal denervation is still a “blind” procedure, and there is no nerve mapping to ascertain the degree of ablation achieved. Notably, patients who had the most ablations reportedly had a greater average drop in systolic ambulatory blood pressure than those who received fewer ablations. Sympathetic nervous system activity is a potential marker of adequacy of ablation, but it was not routinely assessed in the SYMPLICITY HTN-3 trial. Techniques to assess sympathetic nerve activity such as norepinephrine spillover and muscle sympathetic nerve activity are highly specialized and available only at a few research centers, and are not available for routine clinical use.

While these points may explain the negative findings of this trial, they fail to account for the discrepant results between this study and previous trials that used exactly the same definitions and techniques.

 

 

Patient demographics?

Is it possible that renal denervation has a differential effect according to race? All previous renal denervation studies were conducted in Europe or Australia; therefore, few data are available on the efficacy of the procedure in other racial groups, such as black Americans. Most of the patients in this trial were white, but approximately 25% were black—a good representation. There was a statistically significant benefit favoring renal denervation in nonblack (mostly white) patients, but not in black patients. This may be related to racial differences in the pathophysiology of hypertension or possibly due to chance alone.

A Hawthorne effect?

A Hawthorne effect (patients being more compliant because physicians are paying more attention to them) is unlikely, since the renal denervation arm did not have any reduction in blood pressure medications. At 6 months, both the sham group and the procedure group were still on an average of 5 medications.

Additionally, while the blood pressure reduction in both treatment groups was significant, the systolic blood pressure at 6 months was still 166 mm Hg in the denervation group and 168 mm Hg in the sham group. If denervation was effective, one would have expected a greater reduction in blood pressure or at least a decrease in the number of medications needed, eg, 1 to 2 fewer medications in the denervation group compared with the sham procedure group.

Regression to the mean?

It is unknown whether the results represent a statistical error such as regression to the mean. But given the run-in period and the confirmatory data from 24-hour ambulatory blood pressure, this would be unlikely.

WHAT NOW?

Is renal denervation dead? SYMPLICITY HTN-3 is only a single trial with multiple shortcomings and lessons to learn from. Since its publication, there have been updates from 2 prospective, randomized, open-label trials concerning the efficacy of catheter-based renal denervation in lowering blood pressure.^10,11

DENERHTN (Renal Denervation for Hypertension)¹⁰ studied patients with ambulatory systolic blood pressure higher than 135 mm Hg, diastolic blood pressure higher than 80 mm Hg, or both (after excluding secondary etiologies), despite 4 weeks of standardized triple-drug treatment including a diuretic. Patients were randomized to standardized stepped-care antihypertensive treatment alone (control group) or standard care plus renal denervation. The latter resulted in a significant further reduction in ambulatory blood pressure at 6 months.

The Prague-15 trial¹¹ studied patients with resistant hypertension. Secondary etiologies were excluded and adherence to therapy was confirmed by measuring plasma medication levels. It showed that renal denervation along with optimal antihypertensive medical therapy (unchanged after randomization) resulted in a significant reduction in ambulatory blood pressure that was comparable to the effect of intensified antihypertensive medical therapy including spironolactone. (Studies have shown that spironolactone is effective when added on as a fourth-line medication in resistant hypertension.¹²) At 6 months, patients in the intensive medical therapy group were using an average of 0.3 more antihypertensive medications than those in the procedure group.

These two trials addressed some of the drawbacks of the SYMPLICITY HTN-3 trial. However, both have many limitations including and not limited to being open-label and nonblinded, lacking a sham procedure, using a lower blood pressure threshold than SYMPLICITY HTN-3 did to define resistant hypertension, and using the same catheter as in the SYMPLICITY trials.

 

 

Better technology is coming

Advanced renal denervation catheters are needed that are multielectrode, smaller, easier to manipulate, and capable of providing simultaneous, circumferential, more-intense, and deeper ablations. The ongoing Investigator-Steered Project on Intravascular Renal Denervation for Management of Drug-Resistant Hypertension (INSPIRED)¹⁶ and Renal Denervation Using the Vessix Renal Denervation System for the Treatment of Hypertension (REDUCE-HTN: REINFORCE)¹⁷ trials are using contemporary innovative ablation catheters to address the limitations of the first-generation Symplicity catheter.

Further, Fischell et al¹⁸ reported encouraging results of renal denervation performed by injecting ethanol into the adventitial space of the renal arteries. This is still an invasive procedure; however, ethanol can spread out in all directions and reach all targeted nerves, potentially resulting in a more complete renal artery sympathetic ablation.

As technology advances, the WAVE IV trial¹⁹ is examining renal denervation performed from the outside through the skin using high-intensity focused ultrasound, which eliminates the need for femoral arterial catheterization, a promising noninvasive approach.

Proposals for future trials

The European Clinical Consensus Conference for Renal Denervation²⁰ proposed that future trials of renal denervation include patients with moderate rather than resistant hypertension, reflecting the pathogenic importance of sympathetic activity in earlier stages of hypertension. The conference also proposed excluding patients with stiff large arteries, a cause of isolated systolic hypertension. Other proposals included standardizing concomitant antihypertensive therapy, preferably treating all patients with the combination of a renin-angiotensin system blocker, calcium channel blocker, and diuretic in the run-in period; monitoring drug adherence through the use of pill counts, electronic pill dispensers, and drug blood tests; and using change in ambulatory blood pressure as the primary efficacy end point and change in office blood pressure as a secondary end point.

Trials ongoing

To possibly address the limitations posed by the SYMPLICITY HTN-3 trial and to answer other important questions, several sham-controlled clinical trials of renal denervation are currently being conducted:

• INSPiRED¹⁶
• REDUCE-HTN: REINFORCE¹⁷
• Spyral HTN-Off Med²¹
• Spyral HTN-On Med²¹
• Study of the ReCor Medical Paradise System in Clinical Hypertension (RADIANCE-HTN).²²

We hope these new studies can more clearly identify subsets of patients who would benefit from this technology, determine predictors of blood pressure reduction in such patients, and lead to newer devices that may provide more complete ablation.

Obviously, we also need better ways to identify the exact location of these sympathetic nerves within the renal artery and have a clearer sense of procedural success.

Until then, our colleagues in Europe and Australia continue to treat patients with this technology as we appropriately and patiently wait for level 1 clinical evidence of its efficacy.

Acknowledgments: We thank Kathryn Brock, BA, Editorial Services Manager, Heart and Vascular Institute, Cleveland Clinic, for her assistance in the preparation of this paper.

Many patients, clinicians, and researchers had hoped that renal denervation would help control resistant hypertension. However, in the SYMPLICITY HTN-3 trial,¹ named for the catheter-based system used in the study (Symplicity RDN, Medtronic, Dublin, Ireland), this endovascular procedure failed to meet its primary and secondary efficacy end points, although it was found to be safe. These results were surprising, especially given the results of an earlier randomized trial (SYMPLICITY HTN-2),² which showed larger reductions in blood pressures 6 months after denervation than in the current trial.

See related editorial

Here, we discuss the results of the SYMPLICITY HTN-3 trial and offer possible explanations for its negative outcomes.

LEAD-UP TO SYMPLICITY HTN-3

Renal denervation consists of passing a catheter through the femoral artery into the renal arteries and ablating their sympathetic nerves using radiofrequency energy. In theory, this should interrupt efferent sympathetic communication between the brain and renal arteries, reducing muscular contraction of these arteries, increasing renal blood flow, reducing activation of the renin-angiotensin-adosterone system, thus reducing sodium retention, reducing afferent sympathetic communication between the kidneys and brain, and in turn reducing further sympathetic activity elsewhere in the body, such as in the heart. Blood pressure should fall.³

The results of the SYMPLICITY HTN-1 and 2 trials were discussed in an earlier article in this Journal,³ and the Medtronic-Ardian renal denervation system has been available in Europe and Australia for clinical use for over 2 years.⁴ Indeed, after the SYMPLICITY HTN-2 results were published in 2010, Boston Scientific’s Vessix, St. Jude Medical’s EnligHTN, and Covidien’s OneShot radiofrequency renal denervation devices—albeit each with some modifications—received a Conformité Européene (CE) mark and became available in Europe and Australia for clinical use. These devices are not available for clinical use or research in the United States.^3,5

Therefore, SYMPLICITY HTN-3, sponsored by Medtronic, was designed to obtain US Food and Drug Administration approval in the United States.⁶

SYMPLICITY HTN-3 DESIGN

Inclusion criteria were similar to those in the earlier SYMPLICITY trials. Patients had to have resistant hypertension, defined as a systolic blood pressure ≥ 160 mm Hg despite taking at least 3 blood pressure medications at maximum tolerated doses. Patients were excluded if they had a glomerular filtration rate of less than 45 mL/min/1.73 m², renal artery stenosis, or known secondary hypertension.

A total of 1,441 patients were enrolled, of whom 364 were eventually randomized to undergo renal denervation, and 171 were randomized to undergo a sham procedure. The mean systolic blood pressure at baseline was 188 mm Hg in each group. Most patients were taking maximum doses of blood pressure medications, and almost one-fourth were taking an aldosterone antagonist. Patients in both groups were taking an average of 5 medications.

The 2 groups were well matched for important covariates, including obstructive sleep apnea, diabetes mellitus, and renal insufficiency. Most of the patients were white; 25% of the renal denervation group and 29% of the sham procedure group were black.

The physicians conducting the follow-up appointments did not know which procedure the patients underwent, and neither did the patients. Medications were closely monitored, and patients had close follow-up. The catheter (Symplicity RDS, Medtronic) was of the same design that was used in the earlier SYMPLICITY trials and in clinical practice in countries where renal denervation was available.

Researchers expected that the systolic blood pressure, as measured in the office, would fall in both groups, but they hoped it would fall farther in the denervation group—at least 5 mm Hg farther, the primary end point of the trial. The secondary effectiveness end point was a 2-mm Hg greater reduction in 24-hour ambulatory systolic blood pressure.

 

 

SYMPLICITY HTN-3 RESULTS

No statistically significant difference in safety was observed between the denervation and control groups. However, the procedure was associated with 1 embolic event and 1 case of renal artery stenosis.

Blood pressure fell in both groups. However, at 6 months, office systolic pressure had fallen by a mean of 14.13 mm Hg in the denervation group and 11.74 mm Hg in the sham procedure group, a difference of only 2.39 mm Hg. The mean ambulatory systolic blood pressure had fallen by 6.75 vs 4.79 mm Hg, a difference of only 1.96 mm Hg. Neither difference was statistically significant.

A number of prespecified subgroup analyses were conducted, but the benefit of the procedure was statistically significant in only 3 subgroups: patients who were not black (P = .01), patients who were less than 65 years old (P = .04), and patients who had an estimated glomerular filtration rate of 60 mL/min/1.73 m² or higher (P = .05).

WHAT WENT WRONG?

The results of SYMPLICITY HTN-3 were disappointing and led companies that were developing renal denervation devices to discontinue or reevaluate their programs.

Although the results were surprising, many observers (including our group) raised concerns about the initial enthusiasm surrounding renal denervation.^3–7 Indeed, in 2010, we had concerns about the discrepancy between office-based blood pressure measurements (the primary end point of all renal denervation trials) and ambulatory blood pressure measurements in SYMPLICITY HTN-2.⁷

The enthusiasm surrounding this procedure led to the publication of 2 consensus documents on this novel therapy based on only 1 small randomized controlled study (SYMPLICITY HTN-2).^8,9 Renal denervation was even reported to be useful in other conditions involving the sympathorenal axis, including diabetes mellitus, metabolic syndrome, and obstructive sleep apnea, and also as a potential treatment adjunct in atrial fibrillation and other arrhythmias.⁵

What went wrong?

Shortcomings in trial design?

The trial was well designed. Both patients and operators were blinded to the procedure, and 24-hour ambulatory blood pressure monitoring was used. We presume that appropriate patients with resistant hypertension were enrolled—the mean baseline systolic blood pressure was 188 mm Hg, and patients in each group were taking an average of 5 medications.

On the other hand, true medication adherence is difficult to ascertain. Further, the term maximal “tolerated” doses of medications is vague, and we cannot rule out the possibility that some patients were enrolled who did not truly have resistant hypertension—they simply did not want to take medications.

Patients were required to be on a stable medication regimen before enrollment and, ideally, to not have any medication changes during the course of the study, but at least 40% of patients did require medication changes during the study. Additionally, it is unclear whether all patients underwent specific testing to rule out secondary hypertension, as this was done at the discretion of the treating physician.

First-generation catheters?

The same type of catheter was used as in the earlier SYMPLICITY trials, and it had been used in many patients in clinical practice in countries where the catheter is routinely available. It is unknown, however, whether newer multisite denervation devices would yield better results than the first-generation devices used in SYMPLICITY HTN-3. But even this would not explain the discrepancies in data between earlier trials and this trial.

Operator inexperience?

It has been suggested that operator inexperience may have played a role, but an analysis of operator volume did not find any association between this variable and the outcomes. Each procedure was supervised by at least 1 and in most cases 2 certified Medtronic representatives, who made certain that meticulous attention was paid to procedure details and that no shortcuts were taken during the procedure.

Inadequate ablation?

While we can assume that the correct technique was followed in most cases, renal denervation is still a “blind” procedure, and there is no nerve mapping to ascertain the degree of ablation achieved. Notably, patients who had the most ablations reportedly had a greater average drop in systolic ambulatory blood pressure than those who received fewer ablations. Sympathetic nervous system activity is a potential marker of adequacy of ablation, but it was not routinely assessed in the SYMPLICITY HTN-3 trial. Techniques to assess sympathetic nerve activity such as norepinephrine spillover and muscle sympathetic nerve activity are highly specialized and available only at a few research centers, and are not available for routine clinical use.

While these points may explain the negative findings of this trial, they fail to account for the discrepant results between this study and previous trials that used exactly the same definitions and techniques.

 

 

Patient demographics?

Is it possible that renal denervation has a differential effect according to race? All previous renal denervation studies were conducted in Europe or Australia; therefore, few data are available on the efficacy of the procedure in other racial groups, such as black Americans. Most of the patients in this trial were white, but approximately 25% were black—a good representation. There was a statistically significant benefit favoring renal denervation in nonblack (mostly white) patients, but not in black patients. This may be related to racial differences in the pathophysiology of hypertension or possibly due to chance alone.

A Hawthorne effect?

A Hawthorne effect (patients being more compliant because physicians are paying more attention to them) is unlikely, since the renal denervation arm did not have any reduction in blood pressure medications. At 6 months, both the sham group and the procedure group were still on an average of 5 medications.

Additionally, while the blood pressure reduction in both treatment groups was significant, the systolic blood pressure at 6 months was still 166 mm Hg in the denervation group and 168 mm Hg in the sham group. If denervation was effective, one would have expected a greater reduction in blood pressure or at least a decrease in the number of medications needed, eg, 1 to 2 fewer medications in the denervation group compared with the sham procedure group.

Regression to the mean?

It is unknown whether the results represent a statistical error such as regression to the mean. But given the run-in period and the confirmatory data from 24-hour ambulatory blood pressure, this would be unlikely.

WHAT NOW?

Is renal denervation dead? SYMPLICITY HTN-3 is only a single trial with multiple shortcomings and lessons to learn from. Since its publication, there have been updates from 2 prospective, randomized, open-label trials concerning the efficacy of catheter-based renal denervation in lowering blood pressure.^10,11

DENERHTN (Renal Denervation for Hypertension)¹⁰ studied patients with ambulatory systolic blood pressure higher than 135 mm Hg, diastolic blood pressure higher than 80 mm Hg, or both (after excluding secondary etiologies), despite 4 weeks of standardized triple-drug treatment including a diuretic. Patients were randomized to standardized stepped-care antihypertensive treatment alone (control group) or standard care plus renal denervation. The latter resulted in a significant further reduction in ambulatory blood pressure at 6 months.

The Prague-15 trial¹¹ studied patients with resistant hypertension. Secondary etiologies were excluded and adherence to therapy was confirmed by measuring plasma medication levels. It showed that renal denervation along with optimal antihypertensive medical therapy (unchanged after randomization) resulted in a significant reduction in ambulatory blood pressure that was comparable to the effect of intensified antihypertensive medical therapy including spironolactone. (Studies have shown that spironolactone is effective when added on as a fourth-line medication in resistant hypertension.¹²) At 6 months, patients in the intensive medical therapy group were using an average of 0.3 more antihypertensive medications than those in the procedure group.

These two trials addressed some of the drawbacks of the SYMPLICITY HTN-3 trial. However, both have many limitations including and not limited to being open-label and nonblinded, lacking a sham procedure, using a lower blood pressure threshold than SYMPLICITY HTN-3 did to define resistant hypertension, and using the same catheter as in the SYMPLICITY trials.

 

 

Better technology is coming

Advanced renal denervation catheters are needed that are multielectrode, smaller, easier to manipulate, and capable of providing simultaneous, circumferential, more-intense, and deeper ablations. The ongoing Investigator-Steered Project on Intravascular Renal Denervation for Management of Drug-Resistant Hypertension (INSPIRED)¹⁶ and Renal Denervation Using the Vessix Renal Denervation System for the Treatment of Hypertension (REDUCE-HTN: REINFORCE)¹⁷ trials are using contemporary innovative ablation catheters to address the limitations of the first-generation Symplicity catheter.

Further, Fischell et al¹⁸ reported encouraging results of renal denervation performed by injecting ethanol into the adventitial space of the renal arteries. This is still an invasive procedure; however, ethanol can spread out in all directions and reach all targeted nerves, potentially resulting in a more complete renal artery sympathetic ablation.

As technology advances, the WAVE IV trial¹⁹ is examining renal denervation performed from the outside through the skin using high-intensity focused ultrasound, which eliminates the need for femoral arterial catheterization, a promising noninvasive approach.

Proposals for future trials

The European Clinical Consensus Conference for Renal Denervation²⁰ proposed that future trials of renal denervation include patients with moderate rather than resistant hypertension, reflecting the pathogenic importance of sympathetic activity in earlier stages of hypertension. The conference also proposed excluding patients with stiff large arteries, a cause of isolated systolic hypertension. Other proposals included standardizing concomitant antihypertensive therapy, preferably treating all patients with the combination of a renin-angiotensin system blocker, calcium channel blocker, and diuretic in the run-in period; monitoring drug adherence through the use of pill counts, electronic pill dispensers, and drug blood tests; and using change in ambulatory blood pressure as the primary efficacy end point and change in office blood pressure as a secondary end point.

Trials ongoing

To possibly address the limitations posed by the SYMPLICITY HTN-3 trial and to answer other important questions, several sham-controlled clinical trials of renal denervation are currently being conducted:

• INSPiRED¹⁶
• REDUCE-HTN: REINFORCE¹⁷
• Spyral HTN-Off Med²¹
• Spyral HTN-On Med²¹
• Study of the ReCor Medical Paradise System in Clinical Hypertension (RADIANCE-HTN).²²

We hope these new studies can more clearly identify subsets of patients who would benefit from this technology, determine predictors of blood pressure reduction in such patients, and lead to newer devices that may provide more complete ablation.

Obviously, we also need better ways to identify the exact location of these sympathetic nerves within the renal artery and have a clearer sense of procedural success.

Until then, our colleagues in Europe and Australia continue to treat patients with this technology as we appropriately and patiently wait for level 1 clinical evidence of its efficacy.

Acknowledgments: We thank Kathryn Brock, BA, Editorial Services Manager, Heart and Vascular Institute, Cleveland Clinic, for her assistance in the preparation of this paper.

When renal sympathetic denervation, an endovascular procedure designed to treat resistant hypertension, failed to meet its efficacy goal in the SYMPLICITY HTN-3 trial,¹ the news was disappointing.

See related article

In this issue of the Cleveland Clinic Journal of Medicine, Shishehbor et al² provide a critical review of the findings of that trial and summarize its intricacies, as well as the results of other important trials of renal denervation therapy for hypertension. To their excellent observations, we would like to add some of our own.

HYPERTENSION: COMMON, OFTEN RESISTANT

The worldwide prevalence of hypertension is increasing. In the year 2000, about 26% of the adult world population had hypertension; by the year 2025, the number is projected to rise to 29%—1.56 billion people.³

Only about 50% of patients with hypertension are treated for it and, of those, about half have it adequately controlled. In one report, about 30% of US patients with hypertension had adequate blood pressure control.⁴

Patients who have uncontrolled hypertension are usually older and more obese, have higher baseline blood pressure and excessive salt intake, and are more likely to have chronic kidney disease, diabetes, obstructive sleep apnea, and aldosterone excess.⁵ Many of these conditions are also associated with increased sympathetic nervous system activity.⁶

Resistance and pseudoresistance

But lack of control of blood pressure is not the same as resistant hypertension. It is important to differentiate resistant hypertension from pseudoresistant hypertension, ie, hypertension that only seems to be resistant.⁷ Resistant hypertension affects 12.8% of all drug-treated hypertensive patients in the United States, according to data from the National Health and Nutrition Examination Survey.⁸

Factors that can cause pseudoresistant hypertension include:

Suboptimal antihypertensive regimens (truly resistant hypertension means blood pressure that remains high despite concurrent treatment with 3 antihypertensive drugs of different classes, 1 of which is a diuretic, in maximal doses)

The white coat effect (higher blood pressure in the office than at home, presumably due to the stress of an office visit)

• Suboptimal blood pressure measurement techniques (eg, use of a cuff that is too small, causing falsely high readings)
• Physician inertia (eg, failure to change a regimen that is not working)
• Lifestyle factors (eg, excessive sodium intake)
• Medications that interfere with blood pressure control (eg, nonsteroidal anti-inflammatory drugs)
• Poor adherence to prescribed medications.

Causes of secondary hypertension such as obstructive sleep apnea, primary aldosteronism, and renal artery stenosis should also be ruled out before concluding that a patient has resistant hypertension.

 

 

Treatment prevents complications

Hypertension causes a myriad of medical diseases, including accelerated atherosclerosis, myocardial ischemia and infarction, both systolic and diastolic heart failure, rhythm problems (eg, atrial fibrillation), and stroke.

Most patients with resistant hypertension have no identifiable reversible causes of it, exhibit increased sympathetic nervous system activity, and have increased risk of cardiovascular events. The risk can be reduced by treatment.^9,10

Adequate and sustained treatment of hypertension prevents and mitigates its complications. The classic Veterans Administration Cooperative Study in the 1960s demonstrated a 96% reduction in cardiovascular events over 18 months with the use of 3 antihypertensive medications in patients with severe hypertension.¹¹ A reduction of as little as 2 mm Hg in the mean blood pressure has been associated with a 10% reduction in the risk of stroke mortality and a 7% decrease in ischemic heart disease mortality.¹² This is an important consideration when evaluating the clinical end points of hypertension trials.

SYMPLICITY HTN-3 TRIAL: WHAT DID WE LEARN?

As controlling blood pressure is paramount in reducing cardiovascular complications, it is only natural to look for innovative strategies to supplement the medical treatments of hypertension.

The multicenter SYMPLICITY HTN-3 trial¹ was undertaken to establish the efficacy of renal-artery denervation using radiofrequency energy delivered by a catheter-based system (Symplicity RDN, Medtronic, Dublin, Ireland). This randomized, sham-controlled, blinded study did not show a benefit from this procedure with respect to either of its efficacy end points—at 6 months, a reduction in office systolic blood pressure of at least 5 mm Hg more than with medical therapy alone, or a reduction in mean ambulatory systolic pressure of at least 2 mm Hg more than with medical therapy alone.

Despite the negative results, this medium-size (N = 535) randomized clinical trial still represents the highest-level evidence in the field, and we ought to learn something from it.

Limitations of SYMPLICITY HTN-3

Several factors may have contributed to the negative results of the trial. 

Patient selection. For the most part, patients enrolled in renal denervation trials, including SYMPLICITY HTN-3, were not selected on the basis of heightened sympathetic nervous system activity. Assessment of sympathetic nervous system activity may identify the population most likely to achieve an adequate response.

Of note, the baseline blood pressure readings of patients in this trial were higher in the office than on ambulatory monitoring. Patients with white coat hypertension have increased sympathetic nervous system activity and thus might actually be good candidates for renal denervation therapy.

Adequacy of ablation was not measured. Many argue that an objective measure of the adequacy of the denervation procedure (qualitative or quantitative) should have been implemented and, if it had been, the results might have been different. For example, when ablation is performed in the main renal artery as well as the branches, the efficacy in reducing levels of norepinephrine is improved.¹³

Blood pressure fell in both groups. In SYMPLICITY HTN-3 and many other renal denervation trials, patients were assessed using both office and ambulatory blood pressure measurements. The primary end point was the office blood pressure measurement, with a 5-mm Hg difference in reduction chosen to define the superiority margin. This margin was chosen because even small reductions in blood pressure are known to decrease adverse events caused by hypertension. Notably, blood pressure fell significantly in both the control and intervention groups, with an intergroup difference of 2.39 mm Hg (not statistically significant) in favor of denervation.

Medication questions. The SYMPLICITY HTN-3 patients were supposed to be on stable medical regimens with maximal tolerated doses before the procedure. However, it was difficult to assess patients’ adherence to and tolerance of medical therapies. Many (about 40%) of the patients had their medications changed during the study.¹

Therefore, a critical look at the study enrollment criteria may shed more light on the reasons for the negative findings. Did these patients truly have resistant hypertension? Before they underwent the treatment, was their prestudy pharmacologic regimen adequately intensified?

 

 

ONGOING STUDIES

After the findings of the SYMPLICITY HTN-3 study were released, several other trials—such as the Renal Denervation for Hypertension (DENERHTN)¹⁴ and Prague-15 trials¹⁵—reported conflicting results. Notably, these were not sham-controlled trials.

Newer studies with robust trial designs are ongoing. A quick search of www.clinicaltrials.gov reveals that at least 89 active clinical trials of renal denervation are registered as of the date of this writing. Excluding those with unknown status, there are 63 trials open or ongoing.

Clinical trials are also ongoing to determine the effects of renal denervation in patients with heart failure, atrial fibrillation, sleep apnea, and chronic kidney disease, all of which are known to involve heightened sympathetic nervous system activity.

NOT READY FOR CLINICAL USE

Although nonpharmacologic treatments of hypertension continue to be studied and are supported by an avalanche of trials in animals and small, mostly nonrandomized trials in humans, one should not forget that the SYMPLICITY HTN-3 trial simply did not meet its primary efficacy end points. We need definitive clinical evidence showing that renal denervation reduces either blood pressure or clinical events before it becomes a mainstream therapy in humans.

Additional trials are being conducted that were designed in accordance with the recommendations of the European Clinical Consensus Conference for Renal Denervation¹⁶ in terms of study population, design, and end points. Well-designed studies that conform to those recommendations are critical.

Finally, although our enthusiasm for renal denervation as a treatment of hypertension is tempered, there have been no noteworthy safety concerns related to the procedure, which certainly helps maintain the research momentum in this field.              

When renal sympathetic denervation, an endovascular procedure designed to treat resistant hypertension, failed to meet its efficacy goal in the SYMPLICITY HTN-3 trial,¹ the news was disappointing.

See related article

In this issue of the Cleveland Clinic Journal of Medicine, Shishehbor et al² provide a critical review of the findings of that trial and summarize its intricacies, as well as the results of other important trials of renal denervation therapy for hypertension. To their excellent observations, we would like to add some of our own.

HYPERTENSION: COMMON, OFTEN RESISTANT

The worldwide prevalence of hypertension is increasing. In the year 2000, about 26% of the adult world population had hypertension; by the year 2025, the number is projected to rise to 29%—1.56 billion people.³

Only about 50% of patients with hypertension are treated for it and, of those, about half have it adequately controlled. In one report, about 30% of US patients with hypertension had adequate blood pressure control.⁴

Patients who have uncontrolled hypertension are usually older and more obese, have higher baseline blood pressure and excessive salt intake, and are more likely to have chronic kidney disease, diabetes, obstructive sleep apnea, and aldosterone excess.⁵ Many of these conditions are also associated with increased sympathetic nervous system activity.⁶

Resistance and pseudoresistance

But lack of control of blood pressure is not the same as resistant hypertension. It is important to differentiate resistant hypertension from pseudoresistant hypertension, ie, hypertension that only seems to be resistant.⁷ Resistant hypertension affects 12.8% of all drug-treated hypertensive patients in the United States, according to data from the National Health and Nutrition Examination Survey.⁸

Factors that can cause pseudoresistant hypertension include:

Suboptimal antihypertensive regimens (truly resistant hypertension means blood pressure that remains high despite concurrent treatment with 3 antihypertensive drugs of different classes, 1 of which is a diuretic, in maximal doses)

The white coat effect (higher blood pressure in the office than at home, presumably due to the stress of an office visit)

• Suboptimal blood pressure measurement techniques (eg, use of a cuff that is too small, causing falsely high readings)
• Physician inertia (eg, failure to change a regimen that is not working)
• Lifestyle factors (eg, excessive sodium intake)
• Medications that interfere with blood pressure control (eg, nonsteroidal anti-inflammatory drugs)
• Poor adherence to prescribed medications.

Causes of secondary hypertension such as obstructive sleep apnea, primary aldosteronism, and renal artery stenosis should also be ruled out before concluding that a patient has resistant hypertension.

 

 

Treatment prevents complications

Hypertension causes a myriad of medical diseases, including accelerated atherosclerosis, myocardial ischemia and infarction, both systolic and diastolic heart failure, rhythm problems (eg, atrial fibrillation), and stroke.

Most patients with resistant hypertension have no identifiable reversible causes of it, exhibit increased sympathetic nervous system activity, and have increased risk of cardiovascular events. The risk can be reduced by treatment.^9,10

Adequate and sustained treatment of hypertension prevents and mitigates its complications. The classic Veterans Administration Cooperative Study in the 1960s demonstrated a 96% reduction in cardiovascular events over 18 months with the use of 3 antihypertensive medications in patients with severe hypertension.¹¹ A reduction of as little as 2 mm Hg in the mean blood pressure has been associated with a 10% reduction in the risk of stroke mortality and a 7% decrease in ischemic heart disease mortality.¹² This is an important consideration when evaluating the clinical end points of hypertension trials.

SYMPLICITY HTN-3 TRIAL: WHAT DID WE LEARN?

As controlling blood pressure is paramount in reducing cardiovascular complications, it is only natural to look for innovative strategies to supplement the medical treatments of hypertension.

The multicenter SYMPLICITY HTN-3 trial¹ was undertaken to establish the efficacy of renal-artery denervation using radiofrequency energy delivered by a catheter-based system (Symplicity RDN, Medtronic, Dublin, Ireland). This randomized, sham-controlled, blinded study did not show a benefit from this procedure with respect to either of its efficacy end points—at 6 months, a reduction in office systolic blood pressure of at least 5 mm Hg more than with medical therapy alone, or a reduction in mean ambulatory systolic pressure of at least 2 mm Hg more than with medical therapy alone.

Despite the negative results, this medium-size (N = 535) randomized clinical trial still represents the highest-level evidence in the field, and we ought to learn something from it.

Limitations of SYMPLICITY HTN-3

Several factors may have contributed to the negative results of the trial. 

Patient selection. For the most part, patients enrolled in renal denervation trials, including SYMPLICITY HTN-3, were not selected on the basis of heightened sympathetic nervous system activity. Assessment of sympathetic nervous system activity may identify the population most likely to achieve an adequate response.

Of note, the baseline blood pressure readings of patients in this trial were higher in the office than on ambulatory monitoring. Patients with white coat hypertension have increased sympathetic nervous system activity and thus might actually be good candidates for renal denervation therapy.

Adequacy of ablation was not measured. Many argue that an objective measure of the adequacy of the denervation procedure (qualitative or quantitative) should have been implemented and, if it had been, the results might have been different. For example, when ablation is performed in the main renal artery as well as the branches, the efficacy in reducing levels of norepinephrine is improved.¹³

Blood pressure fell in both groups. In SYMPLICITY HTN-3 and many other renal denervation trials, patients were assessed using both office and ambulatory blood pressure measurements. The primary end point was the office blood pressure measurement, with a 5-mm Hg difference in reduction chosen to define the superiority margin. This margin was chosen because even small reductions in blood pressure are known to decrease adverse events caused by hypertension. Notably, blood pressure fell significantly in both the control and intervention groups, with an intergroup difference of 2.39 mm Hg (not statistically significant) in favor of denervation.

Medication questions. The SYMPLICITY HTN-3 patients were supposed to be on stable medical regimens with maximal tolerated doses before the procedure. However, it was difficult to assess patients’ adherence to and tolerance of medical therapies. Many (about 40%) of the patients had their medications changed during the study.¹

Therefore, a critical look at the study enrollment criteria may shed more light on the reasons for the negative findings. Did these patients truly have resistant hypertension? Before they underwent the treatment, was their prestudy pharmacologic regimen adequately intensified?

 

 

ONGOING STUDIES

After the findings of the SYMPLICITY HTN-3 study were released, several other trials—such as the Renal Denervation for Hypertension (DENERHTN)¹⁴ and Prague-15 trials¹⁵—reported conflicting results. Notably, these were not sham-controlled trials.

Newer studies with robust trial designs are ongoing. A quick search of www.clinicaltrials.gov reveals that at least 89 active clinical trials of renal denervation are registered as of the date of this writing. Excluding those with unknown status, there are 63 trials open or ongoing.

Clinical trials are also ongoing to determine the effects of renal denervation in patients with heart failure, atrial fibrillation, sleep apnea, and chronic kidney disease, all of which are known to involve heightened sympathetic nervous system activity.

NOT READY FOR CLINICAL USE

Although nonpharmacologic treatments of hypertension continue to be studied and are supported by an avalanche of trials in animals and small, mostly nonrandomized trials in humans, one should not forget that the SYMPLICITY HTN-3 trial simply did not meet its primary efficacy end points. We need definitive clinical evidence showing that renal denervation reduces either blood pressure or clinical events before it becomes a mainstream therapy in humans.

Additional trials are being conducted that were designed in accordance with the recommendations of the European Clinical Consensus Conference for Renal Denervation¹⁶ in terms of study population, design, and end points. Well-designed studies that conform to those recommendations are critical.

Finally, although our enthusiasm for renal denervation as a treatment of hypertension is tempered, there have been no noteworthy safety concerns related to the procedure, which certainly helps maintain the research momentum in this field.              

When renal sympathetic denervation, an endovascular procedure designed to treat resistant hypertension, failed to meet its efficacy goal in the SYMPLICITY HTN-3 trial,¹ the news was disappointing.

See related article

In this issue of the Cleveland Clinic Journal of Medicine, Shishehbor et al² provide a critical review of the findings of that trial and summarize its intricacies, as well as the results of other important trials of renal denervation therapy for hypertension. To their excellent observations, we would like to add some of our own.

HYPERTENSION: COMMON, OFTEN RESISTANT

The worldwide prevalence of hypertension is increasing. In the year 2000, about 26% of the adult world population had hypertension; by the year 2025, the number is projected to rise to 29%—1.56 billion people.³

Only about 50% of patients with hypertension are treated for it and, of those, about half have it adequately controlled. In one report, about 30% of US patients with hypertension had adequate blood pressure control.⁴

Patients who have uncontrolled hypertension are usually older and more obese, have higher baseline blood pressure and excessive salt intake, and are more likely to have chronic kidney disease, diabetes, obstructive sleep apnea, and aldosterone excess.⁵ Many of these conditions are also associated with increased sympathetic nervous system activity.⁶

Resistance and pseudoresistance

But lack of control of blood pressure is not the same as resistant hypertension. It is important to differentiate resistant hypertension from pseudoresistant hypertension, ie, hypertension that only seems to be resistant.⁷ Resistant hypertension affects 12.8% of all drug-treated hypertensive patients in the United States, according to data from the National Health and Nutrition Examination Survey.⁸

Factors that can cause pseudoresistant hypertension include:

Suboptimal antihypertensive regimens (truly resistant hypertension means blood pressure that remains high despite concurrent treatment with 3 antihypertensive drugs of different classes, 1 of which is a diuretic, in maximal doses)

The white coat effect (higher blood pressure in the office than at home, presumably due to the stress of an office visit)

• Suboptimal blood pressure measurement techniques (eg, use of a cuff that is too small, causing falsely high readings)
• Physician inertia (eg, failure to change a regimen that is not working)
• Lifestyle factors (eg, excessive sodium intake)
• Medications that interfere with blood pressure control (eg, nonsteroidal anti-inflammatory drugs)
• Poor adherence to prescribed medications.

Causes of secondary hypertension such as obstructive sleep apnea, primary aldosteronism, and renal artery stenosis should also be ruled out before concluding that a patient has resistant hypertension.

 

 

Treatment prevents complications

Hypertension causes a myriad of medical diseases, including accelerated atherosclerosis, myocardial ischemia and infarction, both systolic and diastolic heart failure, rhythm problems (eg, atrial fibrillation), and stroke.

Most patients with resistant hypertension have no identifiable reversible causes of it, exhibit increased sympathetic nervous system activity, and have increased risk of cardiovascular events. The risk can be reduced by treatment.^9,10

Adequate and sustained treatment of hypertension prevents and mitigates its complications. The classic Veterans Administration Cooperative Study in the 1960s demonstrated a 96% reduction in cardiovascular events over 18 months with the use of 3 antihypertensive medications in patients with severe hypertension.¹¹ A reduction of as little as 2 mm Hg in the mean blood pressure has been associated with a 10% reduction in the risk of stroke mortality and a 7% decrease in ischemic heart disease mortality.¹² This is an important consideration when evaluating the clinical end points of hypertension trials.

SYMPLICITY HTN-3 TRIAL: WHAT DID WE LEARN?

As controlling blood pressure is paramount in reducing cardiovascular complications, it is only natural to look for innovative strategies to supplement the medical treatments of hypertension.

The multicenter SYMPLICITY HTN-3 trial¹ was undertaken to establish the efficacy of renal-artery denervation using radiofrequency energy delivered by a catheter-based system (Symplicity RDN, Medtronic, Dublin, Ireland). This randomized, sham-controlled, blinded study did not show a benefit from this procedure with respect to either of its efficacy end points—at 6 months, a reduction in office systolic blood pressure of at least 5 mm Hg more than with medical therapy alone, or a reduction in mean ambulatory systolic pressure of at least 2 mm Hg more than with medical therapy alone.

Despite the negative results, this medium-size (N = 535) randomized clinical trial still represents the highest-level evidence in the field, and we ought to learn something from it.

Limitations of SYMPLICITY HTN-3

Several factors may have contributed to the negative results of the trial. 

Patient selection. For the most part, patients enrolled in renal denervation trials, including SYMPLICITY HTN-3, were not selected on the basis of heightened sympathetic nervous system activity. Assessment of sympathetic nervous system activity may identify the population most likely to achieve an adequate response.

Of note, the baseline blood pressure readings of patients in this trial were higher in the office than on ambulatory monitoring. Patients with white coat hypertension have increased sympathetic nervous system activity and thus might actually be good candidates for renal denervation therapy.

Adequacy of ablation was not measured. Many argue that an objective measure of the adequacy of the denervation procedure (qualitative or quantitative) should have been implemented and, if it had been, the results might have been different. For example, when ablation is performed in the main renal artery as well as the branches, the efficacy in reducing levels of norepinephrine is improved.¹³

Blood pressure fell in both groups. In SYMPLICITY HTN-3 and many other renal denervation trials, patients were assessed using both office and ambulatory blood pressure measurements. The primary end point was the office blood pressure measurement, with a 5-mm Hg difference in reduction chosen to define the superiority margin. This margin was chosen because even small reductions in blood pressure are known to decrease adverse events caused by hypertension. Notably, blood pressure fell significantly in both the control and intervention groups, with an intergroup difference of 2.39 mm Hg (not statistically significant) in favor of denervation.

Medication questions. The SYMPLICITY HTN-3 patients were supposed to be on stable medical regimens with maximal tolerated doses before the procedure. However, it was difficult to assess patients’ adherence to and tolerance of medical therapies. Many (about 40%) of the patients had their medications changed during the study.¹

Therefore, a critical look at the study enrollment criteria may shed more light on the reasons for the negative findings. Did these patients truly have resistant hypertension? Before they underwent the treatment, was their prestudy pharmacologic regimen adequately intensified?

 

 

ONGOING STUDIES

After the findings of the SYMPLICITY HTN-3 study were released, several other trials—such as the Renal Denervation for Hypertension (DENERHTN)¹⁴ and Prague-15 trials¹⁵—reported conflicting results. Notably, these were not sham-controlled trials.

Newer studies with robust trial designs are ongoing. A quick search of www.clinicaltrials.gov reveals that at least 89 active clinical trials of renal denervation are registered as of the date of this writing. Excluding those with unknown status, there are 63 trials open or ongoing.

Clinical trials are also ongoing to determine the effects of renal denervation in patients with heart failure, atrial fibrillation, sleep apnea, and chronic kidney disease, all of which are known to involve heightened sympathetic nervous system activity.

NOT READY FOR CLINICAL USE

Although nonpharmacologic treatments of hypertension continue to be studied and are supported by an avalanche of trials in animals and small, mostly nonrandomized trials in humans, one should not forget that the SYMPLICITY HTN-3 trial simply did not meet its primary efficacy end points. We need definitive clinical evidence showing that renal denervation reduces either blood pressure or clinical events before it becomes a mainstream therapy in humans.

Additional trials are being conducted that were designed in accordance with the recommendations of the European Clinical Consensus Conference for Renal Denervation¹⁶ in terms of study population, design, and end points. Well-designed studies that conform to those recommendations are critical.

Finally, although our enthusiasm for renal denervation as a treatment of hypertension is tempered, there have been no noteworthy safety concerns related to the procedure, which certainly helps maintain the research momentum in this field.              

Developing an effective social media marketing campaign can expand your practice to bring you more of the type of patient you want to treat. Although ObGyns are often not trained in marketing, we can bring our practices to the attention of women who need our services with a few simple processes.

The American Marketing Association defines marketing as “the activity, set of institutions, and processes for creating, communicating, delivering, and exchanging offerings that have value for customers, clients, partners, and society at large.”¹ Social media is described as various forms of online and mobile electronic communication with user-generated content.² Social media marketing is the application of traditional marketing strategies to a social media platform. Delivering an effective social media marketing campaign requires focused targeting of a particular community to match the needs of those patients with the value of services and products your practice provides.

By communicating and connecting with the spoken and unspoken needs and desires of potential patients, you will generate greater enthusiasm for your medical services. Social media marketing benefits include: accessibility, low cost, the ability to build brand recognition and social capital, and the availability of analytics that provide large amounts of data to measure the effectiveness of the campaign.³

Though social media is pervasive, the medical community has not rapidly embraced it for marketing.^4,5 Creating a social media strategy, rather than randomly or impulsively posting on social media, allows for more effective marketing. The discussion here focuses on Facebook, which has 2 billion monthly users,⁶ but these strategies and tactics can be applied to any social media platform, including YouTube, Instagram, and Twitter.⁷

Use Facebook to create a business page

Your medical practice needs to have a Facebook account and a Facebook page, separate from your personal account. A business-related Facebook page is similar to a personal Facebook profile except that pages are designed for organizations, brands, businesses, and public figures to share photos, stories, and events with the public.

If you do not have a Facebook account, you can create a new account and profile at http://www.facebook.com. After creating a profile, click on the “create a Facebook page” link. Follow the instructions and select the page category you would like to create; most physicians would select the “Company,” “Organization,” or “Institution” category. Next, follow the instructions to complete the registration.⁸ Once your Facebook page is created, build an audience asking others to “like” your page. Start posting content and use hashtags in your posts to make them discoverable to others (ie, #fibroids #noscar #singlesitesurgery).⁹

Related article:
Using the Internet in your practice. Part 2: Generating new patients using social media

One benefit to having a practice-based Facebook page is the automated visible analytics that come with the page, which are not available for personal profiles. When you write a post or upload a photo or video, Facebook provides the demographics of those engaged with your posts plus analytics on that post, including the number of people who viewed the post, clicked on a photo, and viewed the video for more than 3 seconds.

Read how to get patients interested in your practice

Develop a social media marketing strategy

There are several key factors to consider when planning a strategy. First, know the mission of your organization and the specific service, value, or benefit you would like to provide to the targeted community.⁸

Segment, target, and position (STP)

It is tempting to try to reach out to all women because your ObGyn practice entails pre‑natal care, family planning, and gynecologic surgery, but by narrowing your target audience, your campaign will be better focused. A very specific target audience can reduce the costs for “boosting” (paid promotion of your posts on Facebook to a chosen audience based on demographics, interests, and behaviors) your posts and improve your return on investment (ROI).

Create different marketing campaigns, but focus on one at a time. Decide on the ideal patient you want to serve in your practice. The more detailed and focused you are about the demographics and type of medical needs to be served, the better you can target this patient.¹⁰

Segment. Divide the communities you are considering into different segments. For instance, even though you may do obstetrics and gynecologic surgery, consider breaking up the campaign to focus on 1 specific group, such as those interested in fibroid management.

Target. Identify the kinds of communities where you might find this patient. For example, if you want to focus on laparoscopic hysterectomies or myomectomies, start looking on Facebook for groups, pages, or website discussion boards or blogs that discuss abnormal uterine bleeding or fibroids and follow those pages.

Also, think about what other characteristics are associated with these ideal patients. For example, you might narrow it down to perimenopausal women with fibroids. A potential targeted group could be 40- to 50-year-old women who participate in yoga or running who have concerns about fibroids interfering in their active lifestyle. Perhaps this type of patient would want a minimally invasive surgical approach. A holistic health activist might be interested in nonsurgical management of fibroids.

Position. Once you have identified the specific community to target, position your practice within the community with the value proposition you are offering. For example, as an ObGyn who is focused on surgery, your position might be that your practice will provide the best experience for those medical services, with specific counseling to patients about resuming their active lifestyle.

Related article:
Four pillars of a successful practice: 2. Attract new patients

Get your potential patient to “raise her hand.” In the campaign, you are not trying to convince everyone up front to schedule an appointment from one post. First, try to get people who may be interested in your service(s) to “raise their hands.” Once your target market has expressed interest, either by their likes of your post, likes of your page, or other engagement, reach out to them with links for more information, such as free fibroid surgery education materials located on your website. On your website, create an opt-in page asking them to register their email address; once you have a compiled email list, send out monthly newsletters on your practice.¹¹

Read how to guide patients to your office

Understand that marketing is a process

Think of marketing as an overall process in which you are guiding potential patients to come to your office. Your campaign has several steps; recognize that just one post will not make a huge difference. Use Facebook analytics to measure cost per engagement to calculate your return on investment and the campaign’s effectiveness, and revise as necessary.

Rather than just considering social media as a soap box to advertise your practice, break up the marketing process into 3 units: the before unit, the during unit, and the after unit.¹¹ The word “unit” denotes the service, benefit, or product you are providing.

The before unit refers to the initial marketing that identifies potential patients—initially getting them to raise their hands and ultimately building an audience. (Once a potential patient provides her email address, you can send her a monthly newsletter or updates about your practice to continue the engagement.) Statistics show that an ObGyn needs to have 7 contacts, on average, with a patient over 18 months to “penetrate” her consciousness in a given market.¹² Of course if there is an urgent or emergent need to see a physician, that timeline would be much shorter.

The during unit occurs when the patient comes to your practice and service is being provided. Since you know what she is coming for, you can create informational packets focused on her particular needs, perhaps about different management options for fibroids.

The after unit includes following up with the patient in some automated way. For those being treated for fibroids, it may be a reminder email that discusses the value of follow-up ultrasonography or the various kinds of surgical interventions for fibroids.

In order to continue your campaign, it is helpful to have a designated social media manager who will continue the social media posts and engagement.

When creating the posts, consider developing prescheduled assets (posts that are already produced with photos or links to articles), which can be done through Facebook or Hootsuite (http://www.hootsuite.com).

Manage the risks of social media interaction

There are risks associated with social media. Some things to consider are:

• Policy. Develop a policy for your practice; if you work for an institution, align your policy with the institution’s.
• Postings. Supervise content being posted. Never allow social media to be placed by someone without supervision. Either you should do this or assign a manager to be accountable to check on social media interactions so that any inappropriate comments can be addressed immediately.
• Privacy. Never mention patients’ private health information or use the platform to publicly engage with a patient or future patient about their care. Do not post any references to patients or their photos without written consent.
• Images. Use photographs and other images properly: obtain releases and obey copyright laws.

Related article:
Your patients are talking: Isn’t it time you take responsibility for your online reputation?

Bottom line

Social media is a powerful platform. Combined with good marketing strategies, social media campaigns can have a significant impact on expanding your practice to offer the kind of medical services you want to provide.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Developing an effective social media marketing campaign can expand your practice to bring you more of the type of patient you want to treat. Although ObGyns are often not trained in marketing, we can bring our practices to the attention of women who need our services with a few simple processes.

The American Marketing Association defines marketing as “the activity, set of institutions, and processes for creating, communicating, delivering, and exchanging offerings that have value for customers, clients, partners, and society at large.”¹ Social media is described as various forms of online and mobile electronic communication with user-generated content.² Social media marketing is the application of traditional marketing strategies to a social media platform. Delivering an effective social media marketing campaign requires focused targeting of a particular community to match the needs of those patients with the value of services and products your practice provides.

By communicating and connecting with the spoken and unspoken needs and desires of potential patients, you will generate greater enthusiasm for your medical services. Social media marketing benefits include: accessibility, low cost, the ability to build brand recognition and social capital, and the availability of analytics that provide large amounts of data to measure the effectiveness of the campaign.³

Though social media is pervasive, the medical community has not rapidly embraced it for marketing.^4,5 Creating a social media strategy, rather than randomly or impulsively posting on social media, allows for more effective marketing. The discussion here focuses on Facebook, which has 2 billion monthly users,⁶ but these strategies and tactics can be applied to any social media platform, including YouTube, Instagram, and Twitter.⁷

Use Facebook to create a business page

Your medical practice needs to have a Facebook account and a Facebook page, separate from your personal account. A business-related Facebook page is similar to a personal Facebook profile except that pages are designed for organizations, brands, businesses, and public figures to share photos, stories, and events with the public.

If you do not have a Facebook account, you can create a new account and profile at http://www.facebook.com. After creating a profile, click on the “create a Facebook page” link. Follow the instructions and select the page category you would like to create; most physicians would select the “Company,” “Organization,” or “Institution” category. Next, follow the instructions to complete the registration.⁸ Once your Facebook page is created, build an audience asking others to “like” your page. Start posting content and use hashtags in your posts to make them discoverable to others (ie, #fibroids #noscar #singlesitesurgery).⁹

Related article:
Using the Internet in your practice. Part 2: Generating new patients using social media

One benefit to having a practice-based Facebook page is the automated visible analytics that come with the page, which are not available for personal profiles. When you write a post or upload a photo or video, Facebook provides the demographics of those engaged with your posts plus analytics on that post, including the number of people who viewed the post, clicked on a photo, and viewed the video for more than 3 seconds.

Read how to get patients interested in your practice

Develop a social media marketing strategy

There are several key factors to consider when planning a strategy. First, know the mission of your organization and the specific service, value, or benefit you would like to provide to the targeted community.⁸

Segment, target, and position (STP)

It is tempting to try to reach out to all women because your ObGyn practice entails pre‑natal care, family planning, and gynecologic surgery, but by narrowing your target audience, your campaign will be better focused. A very specific target audience can reduce the costs for “boosting” (paid promotion of your posts on Facebook to a chosen audience based on demographics, interests, and behaviors) your posts and improve your return on investment (ROI).

Create different marketing campaigns, but focus on one at a time. Decide on the ideal patient you want to serve in your practice. The more detailed and focused you are about the demographics and type of medical needs to be served, the better you can target this patient.¹⁰

Segment. Divide the communities you are considering into different segments. For instance, even though you may do obstetrics and gynecologic surgery, consider breaking up the campaign to focus on 1 specific group, such as those interested in fibroid management.

Target. Identify the kinds of communities where you might find this patient. For example, if you want to focus on laparoscopic hysterectomies or myomectomies, start looking on Facebook for groups, pages, or website discussion boards or blogs that discuss abnormal uterine bleeding or fibroids and follow those pages.

Also, think about what other characteristics are associated with these ideal patients. For example, you might narrow it down to perimenopausal women with fibroids. A potential targeted group could be 40- to 50-year-old women who participate in yoga or running who have concerns about fibroids interfering in their active lifestyle. Perhaps this type of patient would want a minimally invasive surgical approach. A holistic health activist might be interested in nonsurgical management of fibroids.

Position. Once you have identified the specific community to target, position your practice within the community with the value proposition you are offering. For example, as an ObGyn who is focused on surgery, your position might be that your practice will provide the best experience for those medical services, with specific counseling to patients about resuming their active lifestyle.

Related article:
Four pillars of a successful practice: 2. Attract new patients

Get your potential patient to “raise her hand.” In the campaign, you are not trying to convince everyone up front to schedule an appointment from one post. First, try to get people who may be interested in your service(s) to “raise their hands.” Once your target market has expressed interest, either by their likes of your post, likes of your page, or other engagement, reach out to them with links for more information, such as free fibroid surgery education materials located on your website. On your website, create an opt-in page asking them to register their email address; once you have a compiled email list, send out monthly newsletters on your practice.¹¹

Read how to guide patients to your office

Understand that marketing is a process

Think of marketing as an overall process in which you are guiding potential patients to come to your office. Your campaign has several steps; recognize that just one post will not make a huge difference. Use Facebook analytics to measure cost per engagement to calculate your return on investment and the campaign’s effectiveness, and revise as necessary.

Rather than just considering social media as a soap box to advertise your practice, break up the marketing process into 3 units: the before unit, the during unit, and the after unit.¹¹ The word “unit” denotes the service, benefit, or product you are providing.

The before unit refers to the initial marketing that identifies potential patients—initially getting them to raise their hands and ultimately building an audience. (Once a potential patient provides her email address, you can send her a monthly newsletter or updates about your practice to continue the engagement.) Statistics show that an ObGyn needs to have 7 contacts, on average, with a patient over 18 months to “penetrate” her consciousness in a given market.¹² Of course if there is an urgent or emergent need to see a physician, that timeline would be much shorter.

The during unit occurs when the patient comes to your practice and service is being provided. Since you know what she is coming for, you can create informational packets focused on her particular needs, perhaps about different management options for fibroids.

The after unit includes following up with the patient in some automated way. For those being treated for fibroids, it may be a reminder email that discusses the value of follow-up ultrasonography or the various kinds of surgical interventions for fibroids.

In order to continue your campaign, it is helpful to have a designated social media manager who will continue the social media posts and engagement.

When creating the posts, consider developing prescheduled assets (posts that are already produced with photos or links to articles), which can be done through Facebook or Hootsuite (http://www.hootsuite.com).

Manage the risks of social media interaction

There are risks associated with social media. Some things to consider are:

• Policy. Develop a policy for your practice; if you work for an institution, align your policy with the institution’s.
• Postings. Supervise content being posted. Never allow social media to be placed by someone without supervision. Either you should do this or assign a manager to be accountable to check on social media interactions so that any inappropriate comments can be addressed immediately.
• Privacy. Never mention patients’ private health information or use the platform to publicly engage with a patient or future patient about their care. Do not post any references to patients or their photos without written consent.
• Images. Use photographs and other images properly: obtain releases and obey copyright laws.

Related article:
Your patients are talking: Isn’t it time you take responsibility for your online reputation?

Bottom line

Social media is a powerful platform. Combined with good marketing strategies, social media campaigns can have a significant impact on expanding your practice to offer the kind of medical services you want to provide.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Developing an effective social media marketing campaign can expand your practice to bring you more of the type of patient you want to treat. Although ObGyns are often not trained in marketing, we can bring our practices to the attention of women who need our services with a few simple processes.

The American Marketing Association defines marketing as “the activity, set of institutions, and processes for creating, communicating, delivering, and exchanging offerings that have value for customers, clients, partners, and society at large.”¹ Social media is described as various forms of online and mobile electronic communication with user-generated content.² Social media marketing is the application of traditional marketing strategies to a social media platform. Delivering an effective social media marketing campaign requires focused targeting of a particular community to match the needs of those patients with the value of services and products your practice provides.

By communicating and connecting with the spoken and unspoken needs and desires of potential patients, you will generate greater enthusiasm for your medical services. Social media marketing benefits include: accessibility, low cost, the ability to build brand recognition and social capital, and the availability of analytics that provide large amounts of data to measure the effectiveness of the campaign.³

Though social media is pervasive, the medical community has not rapidly embraced it for marketing.^4,5 Creating a social media strategy, rather than randomly or impulsively posting on social media, allows for more effective marketing. The discussion here focuses on Facebook, which has 2 billion monthly users,⁶ but these strategies and tactics can be applied to any social media platform, including YouTube, Instagram, and Twitter.⁷

Use Facebook to create a business page

Your medical practice needs to have a Facebook account and a Facebook page, separate from your personal account. A business-related Facebook page is similar to a personal Facebook profile except that pages are designed for organizations, brands, businesses, and public figures to share photos, stories, and events with the public.

If you do not have a Facebook account, you can create a new account and profile at http://www.facebook.com. After creating a profile, click on the “create a Facebook page” link. Follow the instructions and select the page category you would like to create; most physicians would select the “Company,” “Organization,” or “Institution” category. Next, follow the instructions to complete the registration.⁸ Once your Facebook page is created, build an audience asking others to “like” your page. Start posting content and use hashtags in your posts to make them discoverable to others (ie, #fibroids #noscar #singlesitesurgery).⁹

Related article:
Using the Internet in your practice. Part 2: Generating new patients using social media

One benefit to having a practice-based Facebook page is the automated visible analytics that come with the page, which are not available for personal profiles. When you write a post or upload a photo or video, Facebook provides the demographics of those engaged with your posts plus analytics on that post, including the number of people who viewed the post, clicked on a photo, and viewed the video for more than 3 seconds.

Read how to get patients interested in your practice

Develop a social media marketing strategy

There are several key factors to consider when planning a strategy. First, know the mission of your organization and the specific service, value, or benefit you would like to provide to the targeted community.⁸

Segment, target, and position (STP)

It is tempting to try to reach out to all women because your ObGyn practice entails pre‑natal care, family planning, and gynecologic surgery, but by narrowing your target audience, your campaign will be better focused. A very specific target audience can reduce the costs for “boosting” (paid promotion of your posts on Facebook to a chosen audience based on demographics, interests, and behaviors) your posts and improve your return on investment (ROI).

Create different marketing campaigns, but focus on one at a time. Decide on the ideal patient you want to serve in your practice. The more detailed and focused you are about the demographics and type of medical needs to be served, the better you can target this patient.¹⁰

Segment. Divide the communities you are considering into different segments. For instance, even though you may do obstetrics and gynecologic surgery, consider breaking up the campaign to focus on 1 specific group, such as those interested in fibroid management.

Target. Identify the kinds of communities where you might find this patient. For example, if you want to focus on laparoscopic hysterectomies or myomectomies, start looking on Facebook for groups, pages, or website discussion boards or blogs that discuss abnormal uterine bleeding or fibroids and follow those pages.

Also, think about what other characteristics are associated with these ideal patients. For example, you might narrow it down to perimenopausal women with fibroids. A potential targeted group could be 40- to 50-year-old women who participate in yoga or running who have concerns about fibroids interfering in their active lifestyle. Perhaps this type of patient would want a minimally invasive surgical approach. A holistic health activist might be interested in nonsurgical management of fibroids.

Position. Once you have identified the specific community to target, position your practice within the community with the value proposition you are offering. For example, as an ObGyn who is focused on surgery, your position might be that your practice will provide the best experience for those medical services, with specific counseling to patients about resuming their active lifestyle.

Related article:
Four pillars of a successful practice: 2. Attract new patients

Get your potential patient to “raise her hand.” In the campaign, you are not trying to convince everyone up front to schedule an appointment from one post. First, try to get people who may be interested in your service(s) to “raise their hands.” Once your target market has expressed interest, either by their likes of your post, likes of your page, or other engagement, reach out to them with links for more information, such as free fibroid surgery education materials located on your website. On your website, create an opt-in page asking them to register their email address; once you have a compiled email list, send out monthly newsletters on your practice.¹¹

Read how to guide patients to your office

Understand that marketing is a process

Think of marketing as an overall process in which you are guiding potential patients to come to your office. Your campaign has several steps; recognize that just one post will not make a huge difference. Use Facebook analytics to measure cost per engagement to calculate your return on investment and the campaign’s effectiveness, and revise as necessary.

Rather than just considering social media as a soap box to advertise your practice, break up the marketing process into 3 units: the before unit, the during unit, and the after unit.¹¹ The word “unit” denotes the service, benefit, or product you are providing.

The before unit refers to the initial marketing that identifies potential patients—initially getting them to raise their hands and ultimately building an audience. (Once a potential patient provides her email address, you can send her a monthly newsletter or updates about your practice to continue the engagement.) Statistics show that an ObGyn needs to have 7 contacts, on average, with a patient over 18 months to “penetrate” her consciousness in a given market.¹² Of course if there is an urgent or emergent need to see a physician, that timeline would be much shorter.

The during unit occurs when the patient comes to your practice and service is being provided. Since you know what she is coming for, you can create informational packets focused on her particular needs, perhaps about different management options for fibroids.

The after unit includes following up with the patient in some automated way. For those being treated for fibroids, it may be a reminder email that discusses the value of follow-up ultrasonography or the various kinds of surgical interventions for fibroids.

In order to continue your campaign, it is helpful to have a designated social media manager who will continue the social media posts and engagement.

When creating the posts, consider developing prescheduled assets (posts that are already produced with photos or links to articles), which can be done through Facebook or Hootsuite (http://www.hootsuite.com).

Manage the risks of social media interaction

There are risks associated with social media. Some things to consider are:

• Policy. Develop a policy for your practice; if you work for an institution, align your policy with the institution’s.
• Postings. Supervise content being posted. Never allow social media to be placed by someone without supervision. Either you should do this or assign a manager to be accountable to check on social media interactions so that any inappropriate comments can be addressed immediately.
• Privacy. Never mention patients’ private health information or use the platform to publicly engage with a patient or future patient about their care. Do not post any references to patients or their photos without written consent.
• Images. Use photographs and other images properly: obtain releases and obey copyright laws.

Related article:
Your patients are talking: Isn’t it time you take responsibility for your online reputation?

Bottom line

Social media is a powerful platform. Combined with good marketing strategies, social media campaigns can have a significant impact on expanding your practice to offer the kind of medical services you want to provide.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

There are no large randomized clinical trials exploring the relationship between COCs and the risk of developing cancer. Many epidemiological studies, however, have investigated the possible association between COC use and the risk of cancer. Such prospective and retrospective studies consistently report that the use of COCs significantly decreases the risk of ovarian and endometrial cancer. The epidemiological data are less consistent concerning the possible association between COC use and the risk of breast cancer. Meta-analyses conclude that current use of COCs may be associated with a small increase in breast cancer risk. In addition, prolonged use of COCs may be associated with an increased risk of cervical cancer.

Ovarian cancer

• 0.78 (0.73–0.83) for 2.4 years
• 0.64 (0.59–0.69) for 6.8 years
• 0.56 (0.50–0.62) for 11.6 years
• 0.42 (0.36–0.49) for 18.3 years.

In the Royal College of General Practitioners Oral Contraceptive (RCGPOC) study, about 23,000 womenwho did not use COCs and 23,000 current users of COCs were recruited around 1968 and followed for a median of 41 years. In this study, current and recent use of COCs was associated with a decreased RR for ovarian cancer (0.49) and the risk reduction persisted for at least 35 years following COC discontinuation (RR, 0.50; 99% CI, 0.29–0.84).²

In the prospective Nurses’ Health Study (NHS) I, 121,700 nurses were recruited in 1976 and followed for more than 30 years.³ For nurses who reported using COCs for more than 5 years, the rate ratio for ovarian cancer at 20 years or less and greater than 20 years since last use was 0.58 (95% CI, 0.61–0.87) and 0.92 (95% CI, 0.61–1.39), respectively. These studies show that the association between COC use and a decreased risk of ovarian cancer persists for many years after discontinuing COCs.

Endometrial cancer

In the RCGPOC study of 46,000 women, the RR of endometrial cancer among current and recent users of COCs was 0.61, and the reduced risk (0.83) persisted for more than 35 years after discontinuing the COC.²

Related article:
2016 Update on cancer: Endometrial cancer

It is thought that the progestin in the COC provides most of the beneficial effect. Progestin-only contraceptives, such as depotmedroxyprogesterone acetate, progestin implants, and levonorgestrel-releasingintrauterine devices (LNG-IUDs) are also thought to reduce endometrial cancer risk. For instance, in a study of 93,842 Finnish women who used the LNG-IUD, the standardized incidence ratio for endometrial cancer was 0.50 among LNG-IUD users compared with the general population.⁵

Read about the effects of COC use in breast and cervical cancer.

Breast cancer

In the prospective NHS study of 116,608 nurses with 1,246,967 years of follow-up, the multivariate relative risk (mRR) of breast cancer with current COC use was 1.33 (95% CI, 1.03–1.73). Past use of COCs was not associated with a significantly increased risk of breast cancer (mRR, 1.12; 95% CI, 0.95–1.33; NS).⁷

In the RCGPOC study (approximately 46,000 women), current use of COCs was associated with an increased risk of breast cancer (incidence rate ratio [IRR], 1.48; 95% CI,1.10–1.97). Five to 15 years after stopping COCs, there was no significant association between prior COC use and breast cancer (IRR, 1.12; 99% CI, 0.91–1.39; NS).²

Related article:
Webcast: Oral contraceptives and breast cancer: What’s the risk?

It is important to note that it is not possible to conclude from these data whether the reported association between current use of COCs and breast cancer is due to early and accelerated diagnosis of breast cancer, the biological effects of hormones contained in COCs on breast tissue and nascent tumors, or both. In addition, formulations of COCs prescribed in the 1960s and 1970s contained higher doses of estrogen, raising the possibility that the association between COCs and breast cancer is due to COC formulations that are no longer prescribed. However, in animal models and postmenopausal women certain combinations of estrogen plus progestin clearly influence breast cancer biology and cancer risk.^8,9

Cervical cancer

• less than 5 years, 0.73 (95% CI, 0.52–1.03)
• 5 to 9 years, 2.82 (95% CI, 1.46–5.42)
• ≥10 years, 4.03 (95% CI, 2.09–8.02).

It is not possible to conclude from these data whether the association between COC use and cervical cancer is due to the biological effects of hormones on the initiation and progression of HPV disease or confounding factors that have yet to be identified. It is known that estrogens and progestins influence the immune defense system of the lower genital tract, and this may be a pathway that influences the acquisition and progression of viral disease.¹² From a clinical perspective, cervical cancer is largely preventable with HPV vaccination and screening. Therefore, the risk between COC use and cervical cancer is likely limited to women who have not been vaccinated and who are not actively participating in cervical cancer screening.

The bottom line

COC use markedly reduces the risk of ovarian and endometrial cancers, and slightly increases the risk of breast cancer. Prolonged COC use may be associated with an increased risk of cervical cancer. Using available epidemiological data, investigators attempted to project the impact of these competing risks on the approximate 12,300,000 females who live in Australia. Based on the pattern of COC use and the cancer incidence in Australia in 2010, the investigators calculated that COC use would cause about 105 breast and 52 cervical cancers and prevent 1,032 endometrial and 308 ovarian cancers.¹³ This analysis indicates that the balance of risks and benefits related to COC use and cancer generally favors COC use.

Prevention of unintended pregnancy is a major public health goal. Many women choose COCs as their preferred approach to preventing unintended pregnancy. Evaluated from a whole-life perspective the health benefits of COCs are substantial and represent a great advance in women’s health.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

There are no large randomized clinical trials exploring the relationship between COCs and the risk of developing cancer. Many epidemiological studies, however, have investigated the possible association between COC use and the risk of cancer. Such prospective and retrospective studies consistently report that the use of COCs significantly decreases the risk of ovarian and endometrial cancer. The epidemiological data are less consistent concerning the possible association between COC use and the risk of breast cancer. Meta-analyses conclude that current use of COCs may be associated with a small increase in breast cancer risk. In addition, prolonged use of COCs may be associated with an increased risk of cervical cancer.

Ovarian cancer

• 0.78 (0.73–0.83) for 2.4 years
• 0.64 (0.59–0.69) for 6.8 years
• 0.56 (0.50–0.62) for 11.6 years
• 0.42 (0.36–0.49) for 18.3 years.

In the Royal College of General Practitioners Oral Contraceptive (RCGPOC) study, about 23,000 womenwho did not use COCs and 23,000 current users of COCs were recruited around 1968 and followed for a median of 41 years. In this study, current and recent use of COCs was associated with a decreased RR for ovarian cancer (0.49) and the risk reduction persisted for at least 35 years following COC discontinuation (RR, 0.50; 99% CI, 0.29–0.84).²

In the prospective Nurses’ Health Study (NHS) I, 121,700 nurses were recruited in 1976 and followed for more than 30 years.³ For nurses who reported using COCs for more than 5 years, the rate ratio for ovarian cancer at 20 years or less and greater than 20 years since last use was 0.58 (95% CI, 0.61–0.87) and 0.92 (95% CI, 0.61–1.39), respectively. These studies show that the association between COC use and a decreased risk of ovarian cancer persists for many years after discontinuing COCs.

Endometrial cancer

In the RCGPOC study of 46,000 women, the RR of endometrial cancer among current and recent users of COCs was 0.61, and the reduced risk (0.83) persisted for more than 35 years after discontinuing the COC.²

Related article:
2016 Update on cancer: Endometrial cancer

It is thought that the progestin in the COC provides most of the beneficial effect. Progestin-only contraceptives, such as depotmedroxyprogesterone acetate, progestin implants, and levonorgestrel-releasingintrauterine devices (LNG-IUDs) are also thought to reduce endometrial cancer risk. For instance, in a study of 93,842 Finnish women who used the LNG-IUD, the standardized incidence ratio for endometrial cancer was 0.50 among LNG-IUD users compared with the general population.⁵

Read about the effects of COC use in breast and cervical cancer.

Breast cancer

In the prospective NHS study of 116,608 nurses with 1,246,967 years of follow-up, the multivariate relative risk (mRR) of breast cancer with current COC use was 1.33 (95% CI, 1.03–1.73). Past use of COCs was not associated with a significantly increased risk of breast cancer (mRR, 1.12; 95% CI, 0.95–1.33; NS).⁷

In the RCGPOC study (approximately 46,000 women), current use of COCs was associated with an increased risk of breast cancer (incidence rate ratio [IRR], 1.48; 95% CI,1.10–1.97). Five to 15 years after stopping COCs, there was no significant association between prior COC use and breast cancer (IRR, 1.12; 99% CI, 0.91–1.39; NS).²

Related article:
Webcast: Oral contraceptives and breast cancer: What’s the risk?

It is important to note that it is not possible to conclude from these data whether the reported association between current use of COCs and breast cancer is due to early and accelerated diagnosis of breast cancer, the biological effects of hormones contained in COCs on breast tissue and nascent tumors, or both. In addition, formulations of COCs prescribed in the 1960s and 1970s contained higher doses of estrogen, raising the possibility that the association between COCs and breast cancer is due to COC formulations that are no longer prescribed. However, in animal models and postmenopausal women certain combinations of estrogen plus progestin clearly influence breast cancer biology and cancer risk.^8,9

Cervical cancer

• less than 5 years, 0.73 (95% CI, 0.52–1.03)
• 5 to 9 years, 2.82 (95% CI, 1.46–5.42)
• ≥10 years, 4.03 (95% CI, 2.09–8.02).

It is not possible to conclude from these data whether the association between COC use and cervical cancer is due to the biological effects of hormones on the initiation and progression of HPV disease or confounding factors that have yet to be identified. It is known that estrogens and progestins influence the immune defense system of the lower genital tract, and this may be a pathway that influences the acquisition and progression of viral disease.¹² From a clinical perspective, cervical cancer is largely preventable with HPV vaccination and screening. Therefore, the risk between COC use and cervical cancer is likely limited to women who have not been vaccinated and who are not actively participating in cervical cancer screening.

The bottom line

COC use markedly reduces the risk of ovarian and endometrial cancers, and slightly increases the risk of breast cancer. Prolonged COC use may be associated with an increased risk of cervical cancer. Using available epidemiological data, investigators attempted to project the impact of these competing risks on the approximate 12,300,000 females who live in Australia. Based on the pattern of COC use and the cancer incidence in Australia in 2010, the investigators calculated that COC use would cause about 105 breast and 52 cervical cancers and prevent 1,032 endometrial and 308 ovarian cancers.¹³ This analysis indicates that the balance of risks and benefits related to COC use and cancer generally favors COC use.

Prevention of unintended pregnancy is a major public health goal. Many women choose COCs as their preferred approach to preventing unintended pregnancy. Evaluated from a whole-life perspective the health benefits of COCs are substantial and represent a great advance in women’s health.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

There are no large randomized clinical trials exploring the relationship between COCs and the risk of developing cancer. Many epidemiological studies, however, have investigated the possible association between COC use and the risk of cancer. Such prospective and retrospective studies consistently report that the use of COCs significantly decreases the risk of ovarian and endometrial cancer. The epidemiological data are less consistent concerning the possible association between COC use and the risk of breast cancer. Meta-analyses conclude that current use of COCs may be associated with a small increase in breast cancer risk. In addition, prolonged use of COCs may be associated with an increased risk of cervical cancer.

Ovarian cancer

• 0.78 (0.73–0.83) for 2.4 years
• 0.64 (0.59–0.69) for 6.8 years
• 0.56 (0.50–0.62) for 11.6 years
• 0.42 (0.36–0.49) for 18.3 years.

In the Royal College of General Practitioners Oral Contraceptive (RCGPOC) study, about 23,000 womenwho did not use COCs and 23,000 current users of COCs were recruited around 1968 and followed for a median of 41 years. In this study, current and recent use of COCs was associated with a decreased RR for ovarian cancer (0.49) and the risk reduction persisted for at least 35 years following COC discontinuation (RR, 0.50; 99% CI, 0.29–0.84).²

In the prospective Nurses’ Health Study (NHS) I, 121,700 nurses were recruited in 1976 and followed for more than 30 years.³ For nurses who reported using COCs for more than 5 years, the rate ratio for ovarian cancer at 20 years or less and greater than 20 years since last use was 0.58 (95% CI, 0.61–0.87) and 0.92 (95% CI, 0.61–1.39), respectively. These studies show that the association between COC use and a decreased risk of ovarian cancer persists for many years after discontinuing COCs.

Endometrial cancer

In the RCGPOC study of 46,000 women, the RR of endometrial cancer among current and recent users of COCs was 0.61, and the reduced risk (0.83) persisted for more than 35 years after discontinuing the COC.²

Related article:
2016 Update on cancer: Endometrial cancer

It is thought that the progestin in the COC provides most of the beneficial effect. Progestin-only contraceptives, such as depotmedroxyprogesterone acetate, progestin implants, and levonorgestrel-releasingintrauterine devices (LNG-IUDs) are also thought to reduce endometrial cancer risk. For instance, in a study of 93,842 Finnish women who used the LNG-IUD, the standardized incidence ratio for endometrial cancer was 0.50 among LNG-IUD users compared with the general population.⁵

Read about the effects of COC use in breast and cervical cancer.

Breast cancer

In the prospective NHS study of 116,608 nurses with 1,246,967 years of follow-up, the multivariate relative risk (mRR) of breast cancer with current COC use was 1.33 (95% CI, 1.03–1.73). Past use of COCs was not associated with a significantly increased risk of breast cancer (mRR, 1.12; 95% CI, 0.95–1.33; NS).⁷

In the RCGPOC study (approximately 46,000 women), current use of COCs was associated with an increased risk of breast cancer (incidence rate ratio [IRR], 1.48; 95% CI,1.10–1.97). Five to 15 years after stopping COCs, there was no significant association between prior COC use and breast cancer (IRR, 1.12; 99% CI, 0.91–1.39; NS).²

Related article:
Webcast: Oral contraceptives and breast cancer: What’s the risk?

It is important to note that it is not possible to conclude from these data whether the reported association between current use of COCs and breast cancer is due to early and accelerated diagnosis of breast cancer, the biological effects of hormones contained in COCs on breast tissue and nascent tumors, or both. In addition, formulations of COCs prescribed in the 1960s and 1970s contained higher doses of estrogen, raising the possibility that the association between COCs and breast cancer is due to COC formulations that are no longer prescribed. However, in animal models and postmenopausal women certain combinations of estrogen plus progestin clearly influence breast cancer biology and cancer risk.^8,9

Cervical cancer

• less than 5 years, 0.73 (95% CI, 0.52–1.03)
• 5 to 9 years, 2.82 (95% CI, 1.46–5.42)
• ≥10 years, 4.03 (95% CI, 2.09–8.02).

It is not possible to conclude from these data whether the association between COC use and cervical cancer is due to the biological effects of hormones on the initiation and progression of HPV disease or confounding factors that have yet to be identified. It is known that estrogens and progestins influence the immune defense system of the lower genital tract, and this may be a pathway that influences the acquisition and progression of viral disease.¹² From a clinical perspective, cervical cancer is largely preventable with HPV vaccination and screening. Therefore, the risk between COC use and cervical cancer is likely limited to women who have not been vaccinated and who are not actively participating in cervical cancer screening.

The bottom line

COC use markedly reduces the risk of ovarian and endometrial cancers, and slightly increases the risk of breast cancer. Prolonged COC use may be associated with an increased risk of cervical cancer. Using available epidemiological data, investigators attempted to project the impact of these competing risks on the approximate 12,300,000 females who live in Australia. Based on the pattern of COC use and the cancer incidence in Australia in 2010, the investigators calculated that COC use would cause about 105 breast and 52 cervical cancers and prevent 1,032 endometrial and 308 ovarian cancers.¹³ This analysis indicates that the balance of risks and benefits related to COC use and cancer generally favors COC use.

Prevention of unintended pregnancy is a major public health goal. Many women choose COCs as their preferred approach to preventing unintended pregnancy. Evaluated from a whole-life perspective the health benefits of COCs are substantial and represent a great advance in women’s health.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Supplement Editor:
Aanchal Kapoor, MD

Contents

Introduction: Biostatistics and epidemiology lecture series, part 1
Aanchal Kapoor, MD

The architecture of clinical research
James K. Stoller

Basics of study design: Practical considerations
Robert L. Chatburn

Chi-square and Fisher's exact tests
Amy Nowacki

Supplement Editor:
Aanchal Kapoor, MD

Contents

Introduction: Biostatistics and epidemiology lecture series, part 1
Aanchal Kapoor, MD

The architecture of clinical research
James K. Stoller

Basics of study design: Practical considerations
Robert L. Chatburn

Chi-square and Fisher's exact tests
Amy Nowacki

Supplement Editor:
Aanchal Kapoor, MD

Contents

Introduction: Biostatistics and epidemiology lecture series, part 1
Aanchal Kapoor, MD

The architecture of clinical research
James K. Stoller

Basics of study design: Practical considerations
Robert L. Chatburn

Chi-square and Fisher's exact tests
Amy Nowacki