A 67-year-old man presented to the emergency department with four days of nausea, vomiting, and chills. He was originally from the Philippines but lived in the United States for six years. His past medical history was notable for nephrolithiasis for which a ureteral stent had been placed and was subsequently removed three years prior. He reported no abdominal pain, diarrhea, dysuria, urinary frequency, hematuria, cough, headache, or fever. He was a retired high school teacher and a lifelong nonsmoker.

This patient presents with a nonspecific constellation of constitutional and gastrointestinal (GI) symptoms. A system-based approach may be helpful when considering the differential diagnosis. Chills most often suggest infection, especially in older patients. With regard to GI causes, acute gastroenteritis and other food-borne infections can cause nausea, vomiting, and chills, but these are typically accompanied by abdominal pain and diarrhea and often resolve in less than four days. Abdominal pain would also be expected with cholecystitis as well as more life-threatening causes of nausea such as acute pancreatitis, mesenteric ischemia, and bowel obstruction. In contrast, abdominal pain would not be expected with a central nervous system (CNS) infection such as a brain abscess, which may cause nausea from increased intracranial pressure. Headaches occur in a majority of these cases, making CNS etiologies of nausea less likely. Cardiovascular causes, including myocardial ischemia and infarction, may lead to nausea and vomiting, but these are less likely given the absence of chest pain. Genitourinary causes must be considered, especially given his history of both nephrolithiasis and instrumentation. A stricture or recurrence of nephrolithiasis could lead to acute pyelonephritis or perinephric abscess, although both commonly present with urinary tract symptoms. Uremia, possibly from obstructive uropathy given the patient’s history of nephrolithiasis, could also lead to this constellation of symptoms.

On examination, temperature was 101.6 °F, heart rate 126 beats per minute, respiratory rate 18 breaths per minute, blood pressure 120/76 mm Hg, and oxygen saturation 98% on room air. The oral mucosa was moist, heart sounds were normal without murmurs, lungs were clear to auscultation, and abdomen was soft, nontender, and nondistended. There was no flank tenderness, and penile, testicular, and prostate examination findings were normal.

Laboratory studies revealed a serum sodium of 126 mEq/L, potassium 5.0 mEq/L, chloride 98 mEq/L, bicarbonate 15 mEq/L, blood urea nitrogen 88 mg/dL, creatinine 9.0 mg/dL, calcium 8 mg/dL, glucose 110 mg/dL, and albumin 3.3 g/dL. One year prior, serum creatinine was 1.4 mg/dL. His white blood cell (WBC) count was 8.0 k/uL with normal differential, hemoglobin 11.4 g/dL with normal MCV, and platelet count was normal. Serum osmolality was 286 mOsm/kg and serum parathyroid hormone (PTH) level 63 pg/mL (normal, 10-65). The urinalysis revealed cloudy urine with a specific gravity 1.009, 54 red blood cells (RBC), 236 WBC, large leukocyte esterase, negative nitrite, trace protein, and no casts or dysmorphic RBCs. A random urine specimen revealed sodium of 86 mEq/L, potassium 16 mEq/L, chloride 80 mEq/L, and creatinine 70 mg/dL.

Fever and tachycardia support an infectious cause of his symptoms. Absent flank tenderness and a normal genitourinary examination have only moderate negative predictive values for acute pyelonephritis and prostatitis, respectively. The most striking laboratory finding is his azotemia. Acute kidney injury (AKI) is more likely than chronic kidney disease (CKD) given that the PTH level is normal and the serum creatinine from a year ago was near normal. The most useful finding to differentiate AKI from CKD is the presence of atrophic kidneys on imaging. The low bicarbonate level indicates a metabolic acidosis. His serum anion gap is 13 mEq/L, which falls above most normal ranges. A mildly elevated serum anion gap together with a “delta serum anion gap/delta serum bicarbonate” ratio less than one suggest concomitant anion gap metabolic acidosis and non anion gap metabolic acidosis. The latter, coupled with a history of nephrolithiasis, may point to the possibility of renal tubular acidosis and AKI caused by urinary tract obstruction. This could also account for the marked hyponatremia. Moreover, his high fractional excretion of sodium (9%) is not suggestive of prerenal injury, the most common acute renal injury among patients who present to the emergency department. Hematuria carries a broad differential diagnosis, but most common causes include nephrolithiasis, urinary tract infection (UTI), prostatitis, neoplasm, and glomerulonephritis (GN). The lack of casts and dysmorphic RBCs makes GN unlikely. Taken together, his vital signs, examination, and laboratory studies suggest a high likelihood of an upper UTI (acute obstructive pyelonephritis) in the context of AKI due to obstructive uropathy.

Despite both a normal serum WBC count (which has only a moderate negative predictive value) and his low risk of developing life-threating organ dysfunction from sepsis based on a quick Sequential Organ Failure Assessment (qSOFA) score of zero, it is appropriate to start antibiotics after drawing blood and doing urine cultures. The next step should include administration of a broad-spectrum regimen that is appropriately dose-adjusted for renal dysfunction, such as an antipseudomonal carbapenem and vancomycin to cover extended-spectrum beta-lactamase (ESBL)-producing organisms, Pseudomonas aeruginosa, and methicillin-resistant Staphylococcus aureus (MRSA). This broad coverage is indicated for empiric treatment of complicated obstructive pyelonephritis, a condition that may arise from significant urinary obstruction and that carries a high risk of rapid clinical deterioration. He should undergo a rapid bedside test to assess for urethral or bladder outlet obstruction: either a bladder ultrasound or temporary insertion of a bladder catheter. He should also have an urgent computed tomography (CT) of his abdomen and pelvis without intravenous (IV) contrast, looking for evidence of urinary tract obstruction. A CT is preferred over ultrasound of the kidneys and bladder as CT has higher sensitivity and specificity for nephrolithiasis and neoplasm.

A CT of the abdomen and pelvis without IV contrast revealed bilateral hydroureter and hydronephrosis with multiple punctate calcified stones within the right calyces and the distal right ureter (Figure 1, Figure 2). However, these appeared too small to cause the degree of obstruction visualized. There were no stones noted in the left ureter to account for the obstruction, though small stones were noted in the left calyces. The bladder appeared normal.

More commonly, bilateral hydroureter with bilateral hydronephrosis is caused by an obstruction of the bladder or urethra. CT scans can reveal prostatic hyperplasia (occasionally with protrusion into the bladder) and increased bladder wall thickness as a result of chronic bladder outlet obstruction, but the negative predictive value of either finding is modest. More revealing is that the patient reported neither an inability to pass urine (in fact, a “random” urine sample was obtained) nor suprapubic discomfort. Both symptoms would be pronounced with acute bladder obstruction but may be minimal with slowly progressive obstruction. In either case, a distended bladder would have been seen on the CT scan.

Regardless of the cause or whether the obstruction is in the upper or lower urinary tract, emergency intervention is needed to relieve the obstruction when AKI presents with bilateral hydronephrosis. A urology consultation should be sought urgently to determine the best strategy to relieve the obstruction. This may include bilateral percutaneous nephrostomy tubes given that the obstruction appears to be above the level of the bladder. Their findings will also direct additional diagnostic workup.

The patient received ceftriaxone and underwent cystoscopy, which revealed a stricture of the distal bulbar urethra. The ureters and bladder could not be completely visualized due to hematuria. The urethral stricture was dilated, and a Foley catheter was placed. In the operating room, the patient had a fever of 103 °F and developed severe hypotension unresponsive to 3 L of intravenous normal saline. Norepinephrine infusion was initiated for refractory hypotension.

Except for transurethral prostate resections, endoscopic urologic procedures rarely lead to a stricture of any segment of the urethra, suggesting that the previous ureteral stent placement and retrieval were not causal. Longstanding Mycobacterium tuberculosis or Schistosoma haematobium infection occasionally causes urethral strictures presenting as bilateral hydronephrosis. The multiple punctate calcified “stones” demonstrated on CT may suggest either diagnosis if they were actually calcified granulomas.

Regardless of the cause, most patients with a urethral stricture have chronic lower urinary tract symptoms such as decreased stream and the feeling of incomplete bladder emptying. Since this patient does not report these symptoms, it is important to consider if the stricture might be merely incidental. The absence of pain is more telling than the absence of chronic or recurrent symptoms. Lack of pain argues strongly against a pure de novo acute obstruction because abrupt stretching of the renal capsules and the walls of the collecting system is usually painful. Slow stretching caused by a progressive stricture may mask the pain of a superimposed acute obstruction. A blood clot, for example, may have precipitated an acute-on-chronic obstruction upon lodging at the urethral stricture.

The worsening systemic response to the procedure may be due to increased intravesical pressure by dilation and cystoscopy, which may have caused subsequent backflow of bacteria from the renal parenchyma into the circulation (pyelorenal backflow). The broad-spectrum antibiotic regimen suggested above and IV crystalloid infusion should be continued with close hemodynamic monitoring.

Treatment for severe sepsis was initiated with empiric piperacillin-tazobactam, ceftriaxone was discontinued, and the patient was transferred to the intensive care unit (ICU). Norepinephrine was discontinued after 24 hours. Despite the indwelling Foley catheter, his kidney function worsened (creatinine increased to 10.5 over the next 36 hours, and he remained oliguric). Therefore, bilateral percutaneous nephrostomy tubes were placed to relieve the ongoing obstruction. In the ICU, he remained febrile, despite receiving piperacillin-tazobactam, through hospital day 7. Serial blood and urine cultures all remained negative. HIV testing was negative. His chest radiograph was unremarkable, and transthoracic echocardiogram was normal. His creatinine improved but plateaued at 2.5 mg/dL by day 7.

Worsening renal function (alongside oliguria or anuria) despite a functioning Foley catheter suggests either intrinsic renal disease or bilateral ureteral obstructions. The initial attempt at relieving the obstruction with a Foley catheter did not take into consideration the bilateral ureteral strictures. As a result, soon thereafter, the insertion of percutaneous nephrostomy tubes was necessary. Given the severity of his illness, underlying obstructive uropathy, and persistent fever, suggesting an ongoing infection, one strategy would be to continue antibiotics with broader coverage than piperacillin-tazobactam. This approach may be reasonable, given the emergence of ESBL organisms and the possibility of MRSA due to instrumentation. However, it is important to note that only sterile pyuria has been identified to date, which raises the possibility of nonbacterial infections. Although chronic infection with Schistosoma haematobium can cause bilateral ureteral strictures, associated fever is limited to the acute phase of infection and not the chronic obstructive phase, unless there is a superimposed infection. Genitourinary Mycobacterium tuberculosis remains a likely possibility, regardless of the unrevealing chest radiograph. Urine nucleic acid amplification and acid-fast bacilli (AFB) smear and culture, the best initial diagnostic test, should be sent. Although less definitive, a tuberculin skin test and an interferon-gamma release assay should also be conducted. Histopathology of the ureters obtained by repeat cystoscopy may be diagnostic, but given the limited visualization during the last cystoscopy and the recent dilation of the urethra, this option should be kept in reserve for now.

Antibiotics were discontinued on day 7, but the patient continued to experience ongoing fever. Urine Histoplasma and serum cryptococcal antigens were negative. His urine AFB smear was 1+ positive. Liver function tests revealed a total protein of 7.0 g/dL, albumin 3.0 g/dL, total bilirubin 1.2 mg/dL, direct bilirubin 0.3 mg/dL, alkaline phosphatase 418 U/L, aspartate aminotransferase 65 U/L, alanine aminotransferase 88 U/L, gamma-glutamyltransferase (GGT) 609 U/L (normal, 3-60), and lactate dehydrogenase 284 U/L (normal, 85-210).

Acid-fast bacillus in the urine strongly suggests Mycobacterium tuberculosis (MTB) with several reports of likelihood ratios greater than 10. Nevertheless, confirmation is needed to rule out nontuberculous mycobacteria because of potential hepatotoxicity from treatment. Up to six urine samples should be sent for mycobacterium culture. However, false negative rates of up to 90% are reported, and final test results can take up to two months, so other methods of confirmation should be simultaneously sought. A nucleic acid amplification test of urine could rule in a pathogenic species within 24 hours. Alternatively, the probability of a nonpathogenic colonizing species would be negligible if a caseating granuloma was found. Biopsy could be obtained from the ureters, as suggested above. Liver biopsy should also be considered, especially if the moderate elevations in alkaline phosphatase and GGT (the most common liver enzyme abnormalities in hepatic tuberculosis) did not merely wax and wane with sepsis.

A CT of the thorax without IV contrast was done to evaluate for evidence of pulmonary disease given the positive urine AFB. This demonstrated bilateral fibrotic upper lobe opacities suggestive of prior granulomatous disease but no cavitary lung lesions (Figure 3). Three sputum smears were negative for AFB, but one sample showed Mycobacterium tuberculosis detected by a polymerase chain reaction (PCR) probe.

The two-month initiation phase of treatment with four antituberculosis drugs should begin while drug susceptibility tests are pending. Potential hepatotoxicity should be closely monitored, ideally by a clinician with experience treating tuberculosis in patients with existing liver disease. As a general precaution, alcohol should be avoided as should medications such as acetaminophen that are known to be hepatotoxic. Urology follow-up is also needed because about one-third of tuberculous ureteral strictures treated initially with percutaneous nephrostomy do not resolve with antituberculosis therapy.

The patient was started on weight-based antituberculosis treatment with four antimicrobial agents (rifampin, ethambutol, pyrazinamide, and isoniazid). He was seen in the infectious disease clinic two weeks later; his fever had resolved, and his liver function tests showed normalization of AST and LDH as well as a 45% reduction in his GGT and alkaline phosphatase levels. Two months following discharge, a nuclear medicine radionuclide angiogram renal flow scan showed normal right kidney function. The right nephrostomy tube was subsequently removed. He continued to have left kidney outflow obstruction due to a residual ureteral stricture (Figure 4). Repeat cystoscopy and attempted left ureteral stenting was unsuccessful. The left nephrostomy tube remained in place.

According to the Centers for Disease Control, in 2017, 10 million people became sick with TB, and there were 1.3 million TB-related deaths worldwide with 9,150 cases reported in the United States. Extrapulmonary TB (EPTB) constitutes 10% of all TB cases globally.^1-4 GUTB is the second most common form of EPTB after lymph node TB, and it occurs in up to 20% of all pulmonary TB cases.^2,3

Mycobacteria reach the genitourinary (GU) tract via hematogenous spread during primary infection or reactivation of TB. This leads to cortical and medullary lesions, which can heal spontaneously or eventually (average of 22 years) rupture into the tubules and onto the collecting system, ureters, and bladder.^5,6 Spread to the ureter and bladder leads to multiple ureteral strictures and contracture of the bladder with disruption of the ureterovesical junction (UVJ), which causes hydroureter and hydronephrosis.⁷ Unilateral kidney involvement is most common, but bilateral involvement can occur following exacerbated hematogenous spread, particularly in immune deficient patients. Bilateral kidney involvement is also possible from retrograde spread to the good kidney due to bladder contracture and UVJ disruption.^8,9 Distal infection can involve all aspects of the male and female genital tracts, but urethral strictures are extremely rare.^10,11

GUTB affects males more than females (2:1) and presents insidiously at 40 to 60 years of age.¹² Other risk factors for TB include birth in TB endemic areas, prior TB infection, immunosuppression, malnutrition, severe systemic disease, diabetes, and cirrhosis. It is crucial to assess these risk factors when creating and refining differential diagnoses. Many patients have hematuria and sterile pyuria as incidental initial findings. The most common symptoms arise from bladder involvement, including frequency, urgency, and dysuria. Low back pain and gross hematuria are also common, but fever and constitutional symptoms are uncommon.¹⁰ Bilateral ureteral strictures can lead to obstructive renal failure, and involvement of the genital tracts can lead to pelvic or scrotal pain, swelling, and fistula formation.¹⁰

Diagnosis involves the demonstration of TB bacilli in urine or GU tissue. The urinalysis reveals hematuria and sterile pyuria.¹³ Urine AFB stains are positive in 52% of cases but are not diagnostic as nontuberculous mycobacteria may also cause a positive test result.^13,14 Urine cultures for Mycobacterium tuberculosis are positive in up to 90% of cases after six to eight weeks. As many as three to six morning urine samples are required to achieve diagnostic accuracy.^10,14 Urine PCR for Mycobacterium tuberculosis has 96% sensitivity and up to 98% specificity,¹⁴ while PCR on GU tissue has a sensitivity of 88% and specificity of 87%.¹⁵ The rapid nucleic acid amplification assay Xpert MTB/RIF in urine has a sensitivity of 83%, and specificity of 98%.¹⁶ Imaging is required to evaluate for obstruction, and the CT scan is abnormal in up to 90% of cases, showing multiple ureteral stenoses, hydroureter and hydronephrosis, and a contracted bladder.^10,17

GUTB is treated with standard antituberculosis regimens.¹⁸ Patients with urinary obstruction benefit from ureteral stenting or percutaneous nephrostomy, bladder diversion, or ureteral reconstruction surgery. Unilateral nephrectomy for a nonfunctioning kidney with extensive disease is occasionally required.¹⁹ Following treatment, relapse occurs in up to 6% of patients over five years, and long-term follow-up with urine cultures and PCR every six months is recommended.^10,20 Appropriate screening and treatment for latent tuberculosis infection greatly reduces the risk of reactivation GUTB.

This patient presented with features of an infection, which, combined with his history of renal stones and his urinalysis, led to an appropriate suspicion of and empiric treatment for an upper UTI. Given the AKI and nephrolithiasis, imaging was done to exclude obstruction. The CT finding of bilateral hydroureters and hydronephrosis absent an obstructing stone or mass or abnormal bladder was the initial clue that this was not a typical bacterial infection and that there was likely an underlying infectious pathologic process such as TB involving the GU tract diffusely. The care team treated the patient as an individual with fever and sterile pyuria in the context of multiple urinary tract strictures and an initial unrevealing infectious diagnostic workup. They recognized that the clues to the ultimate diagnosis of GUTB were all in the stream.

• GUTB is a significant cause of sterile pyuria.
• In the presence of bilateral hydronephrosis, it is vital to determine the level of obstruction. If the bladder is not distended or contracted, then obstruction is likely at the level of the ureters and initial use of percutaneous nephrostomy tubes to relieve obstruction may be preferred.
• Imaging abnormalities such as multiple ureteral strictures, hydroureter and hydronephrosis (absent an obstructing stone or mass), and the finding of a contracted bladder are highly suggestive of GUTB.
• The mainstay of treatment for GUTB is standard antituberculosis treatment regimens in combination with the relief of urinary obstruction by ureteral stenting, percutaneous nephrostomy or open surgery.
• GUTB can relapse in up to 6% of treated cases over five years, and long-term follow-up and surveillance with urine culture and PCR every six months are recommended.

Disclosures

Benjamin Mba, Nathan Houchens, Marie Jennifer Seares, and Udit Joshi have no financial conflicts of interest and no disclosures.

Funding

Brian P. Lucas receives funding from the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development and Dartmouth SYNERGY, National Institutes of Health, and National Center for Translational Science (UL1TR001086).

A 67-year-old man presented to the emergency department with four days of nausea, vomiting, and chills. He was originally from the Philippines but lived in the United States for six years. His past medical history was notable for nephrolithiasis for which a ureteral stent had been placed and was subsequently removed three years prior. He reported no abdominal pain, diarrhea, dysuria, urinary frequency, hematuria, cough, headache, or fever. He was a retired high school teacher and a lifelong nonsmoker.

This patient presents with a nonspecific constellation of constitutional and gastrointestinal (GI) symptoms. A system-based approach may be helpful when considering the differential diagnosis. Chills most often suggest infection, especially in older patients. With regard to GI causes, acute gastroenteritis and other food-borne infections can cause nausea, vomiting, and chills, but these are typically accompanied by abdominal pain and diarrhea and often resolve in less than four days. Abdominal pain would also be expected with cholecystitis as well as more life-threatening causes of nausea such as acute pancreatitis, mesenteric ischemia, and bowel obstruction. In contrast, abdominal pain would not be expected with a central nervous system (CNS) infection such as a brain abscess, which may cause nausea from increased intracranial pressure. Headaches occur in a majority of these cases, making CNS etiologies of nausea less likely. Cardiovascular causes, including myocardial ischemia and infarction, may lead to nausea and vomiting, but these are less likely given the absence of chest pain. Genitourinary causes must be considered, especially given his history of both nephrolithiasis and instrumentation. A stricture or recurrence of nephrolithiasis could lead to acute pyelonephritis or perinephric abscess, although both commonly present with urinary tract symptoms. Uremia, possibly from obstructive uropathy given the patient’s history of nephrolithiasis, could also lead to this constellation of symptoms.

On examination, temperature was 101.6 °F, heart rate 126 beats per minute, respiratory rate 18 breaths per minute, blood pressure 120/76 mm Hg, and oxygen saturation 98% on room air. The oral mucosa was moist, heart sounds were normal without murmurs, lungs were clear to auscultation, and abdomen was soft, nontender, and nondistended. There was no flank tenderness, and penile, testicular, and prostate examination findings were normal.

Laboratory studies revealed a serum sodium of 126 mEq/L, potassium 5.0 mEq/L, chloride 98 mEq/L, bicarbonate 15 mEq/L, blood urea nitrogen 88 mg/dL, creatinine 9.0 mg/dL, calcium 8 mg/dL, glucose 110 mg/dL, and albumin 3.3 g/dL. One year prior, serum creatinine was 1.4 mg/dL. His white blood cell (WBC) count was 8.0 k/uL with normal differential, hemoglobin 11.4 g/dL with normal MCV, and platelet count was normal. Serum osmolality was 286 mOsm/kg and serum parathyroid hormone (PTH) level 63 pg/mL (normal, 10-65). The urinalysis revealed cloudy urine with a specific gravity 1.009, 54 red blood cells (RBC), 236 WBC, large leukocyte esterase, negative nitrite, trace protein, and no casts or dysmorphic RBCs. A random urine specimen revealed sodium of 86 mEq/L, potassium 16 mEq/L, chloride 80 mEq/L, and creatinine 70 mg/dL.

Fever and tachycardia support an infectious cause of his symptoms. Absent flank tenderness and a normal genitourinary examination have only moderate negative predictive values for acute pyelonephritis and prostatitis, respectively. The most striking laboratory finding is his azotemia. Acute kidney injury (AKI) is more likely than chronic kidney disease (CKD) given that the PTH level is normal and the serum creatinine from a year ago was near normal. The most useful finding to differentiate AKI from CKD is the presence of atrophic kidneys on imaging. The low bicarbonate level indicates a metabolic acidosis. His serum anion gap is 13 mEq/L, which falls above most normal ranges. A mildly elevated serum anion gap together with a “delta serum anion gap/delta serum bicarbonate” ratio less than one suggest concomitant anion gap metabolic acidosis and non anion gap metabolic acidosis. The latter, coupled with a history of nephrolithiasis, may point to the possibility of renal tubular acidosis and AKI caused by urinary tract obstruction. This could also account for the marked hyponatremia. Moreover, his high fractional excretion of sodium (9%) is not suggestive of prerenal injury, the most common acute renal injury among patients who present to the emergency department. Hematuria carries a broad differential diagnosis, but most common causes include nephrolithiasis, urinary tract infection (UTI), prostatitis, neoplasm, and glomerulonephritis (GN). The lack of casts and dysmorphic RBCs makes GN unlikely. Taken together, his vital signs, examination, and laboratory studies suggest a high likelihood of an upper UTI (acute obstructive pyelonephritis) in the context of AKI due to obstructive uropathy.

Despite both a normal serum WBC count (which has only a moderate negative predictive value) and his low risk of developing life-threating organ dysfunction from sepsis based on a quick Sequential Organ Failure Assessment (qSOFA) score of zero, it is appropriate to start antibiotics after drawing blood and doing urine cultures. The next step should include administration of a broad-spectrum regimen that is appropriately dose-adjusted for renal dysfunction, such as an antipseudomonal carbapenem and vancomycin to cover extended-spectrum beta-lactamase (ESBL)-producing organisms, Pseudomonas aeruginosa, and methicillin-resistant Staphylococcus aureus (MRSA). This broad coverage is indicated for empiric treatment of complicated obstructive pyelonephritis, a condition that may arise from significant urinary obstruction and that carries a high risk of rapid clinical deterioration. He should undergo a rapid bedside test to assess for urethral or bladder outlet obstruction: either a bladder ultrasound or temporary insertion of a bladder catheter. He should also have an urgent computed tomography (CT) of his abdomen and pelvis without intravenous (IV) contrast, looking for evidence of urinary tract obstruction. A CT is preferred over ultrasound of the kidneys and bladder as CT has higher sensitivity and specificity for nephrolithiasis and neoplasm.

A CT of the abdomen and pelvis without IV contrast revealed bilateral hydroureter and hydronephrosis with multiple punctate calcified stones within the right calyces and the distal right ureter (Figure 1, Figure 2). However, these appeared too small to cause the degree of obstruction visualized. There were no stones noted in the left ureter to account for the obstruction, though small stones were noted in the left calyces. The bladder appeared normal.

More commonly, bilateral hydroureter with bilateral hydronephrosis is caused by an obstruction of the bladder or urethra. CT scans can reveal prostatic hyperplasia (occasionally with protrusion into the bladder) and increased bladder wall thickness as a result of chronic bladder outlet obstruction, but the negative predictive value of either finding is modest. More revealing is that the patient reported neither an inability to pass urine (in fact, a “random” urine sample was obtained) nor suprapubic discomfort. Both symptoms would be pronounced with acute bladder obstruction but may be minimal with slowly progressive obstruction. In either case, a distended bladder would have been seen on the CT scan.

Regardless of the cause or whether the obstruction is in the upper or lower urinary tract, emergency intervention is needed to relieve the obstruction when AKI presents with bilateral hydronephrosis. A urology consultation should be sought urgently to determine the best strategy to relieve the obstruction. This may include bilateral percutaneous nephrostomy tubes given that the obstruction appears to be above the level of the bladder. Their findings will also direct additional diagnostic workup.

The patient received ceftriaxone and underwent cystoscopy, which revealed a stricture of the distal bulbar urethra. The ureters and bladder could not be completely visualized due to hematuria. The urethral stricture was dilated, and a Foley catheter was placed. In the operating room, the patient had a fever of 103 °F and developed severe hypotension unresponsive to 3 L of intravenous normal saline. Norepinephrine infusion was initiated for refractory hypotension.

Except for transurethral prostate resections, endoscopic urologic procedures rarely lead to a stricture of any segment of the urethra, suggesting that the previous ureteral stent placement and retrieval were not causal. Longstanding Mycobacterium tuberculosis or Schistosoma haematobium infection occasionally causes urethral strictures presenting as bilateral hydronephrosis. The multiple punctate calcified “stones” demonstrated on CT may suggest either diagnosis if they were actually calcified granulomas.

Regardless of the cause, most patients with a urethral stricture have chronic lower urinary tract symptoms such as decreased stream and the feeling of incomplete bladder emptying. Since this patient does not report these symptoms, it is important to consider if the stricture might be merely incidental. The absence of pain is more telling than the absence of chronic or recurrent symptoms. Lack of pain argues strongly against a pure de novo acute obstruction because abrupt stretching of the renal capsules and the walls of the collecting system is usually painful. Slow stretching caused by a progressive stricture may mask the pain of a superimposed acute obstruction. A blood clot, for example, may have precipitated an acute-on-chronic obstruction upon lodging at the urethral stricture.

The worsening systemic response to the procedure may be due to increased intravesical pressure by dilation and cystoscopy, which may have caused subsequent backflow of bacteria from the renal parenchyma into the circulation (pyelorenal backflow). The broad-spectrum antibiotic regimen suggested above and IV crystalloid infusion should be continued with close hemodynamic monitoring.

Treatment for severe sepsis was initiated with empiric piperacillin-tazobactam, ceftriaxone was discontinued, and the patient was transferred to the intensive care unit (ICU). Norepinephrine was discontinued after 24 hours. Despite the indwelling Foley catheter, his kidney function worsened (creatinine increased to 10.5 over the next 36 hours, and he remained oliguric). Therefore, bilateral percutaneous nephrostomy tubes were placed to relieve the ongoing obstruction. In the ICU, he remained febrile, despite receiving piperacillin-tazobactam, through hospital day 7. Serial blood and urine cultures all remained negative. HIV testing was negative. His chest radiograph was unremarkable, and transthoracic echocardiogram was normal. His creatinine improved but plateaued at 2.5 mg/dL by day 7.

Worsening renal function (alongside oliguria or anuria) despite a functioning Foley catheter suggests either intrinsic renal disease or bilateral ureteral obstructions. The initial attempt at relieving the obstruction with a Foley catheter did not take into consideration the bilateral ureteral strictures. As a result, soon thereafter, the insertion of percutaneous nephrostomy tubes was necessary. Given the severity of his illness, underlying obstructive uropathy, and persistent fever, suggesting an ongoing infection, one strategy would be to continue antibiotics with broader coverage than piperacillin-tazobactam. This approach may be reasonable, given the emergence of ESBL organisms and the possibility of MRSA due to instrumentation. However, it is important to note that only sterile pyuria has been identified to date, which raises the possibility of nonbacterial infections. Although chronic infection with Schistosoma haematobium can cause bilateral ureteral strictures, associated fever is limited to the acute phase of infection and not the chronic obstructive phase, unless there is a superimposed infection. Genitourinary Mycobacterium tuberculosis remains a likely possibility, regardless of the unrevealing chest radiograph. Urine nucleic acid amplification and acid-fast bacilli (AFB) smear and culture, the best initial diagnostic test, should be sent. Although less definitive, a tuberculin skin test and an interferon-gamma release assay should also be conducted. Histopathology of the ureters obtained by repeat cystoscopy may be diagnostic, but given the limited visualization during the last cystoscopy and the recent dilation of the urethra, this option should be kept in reserve for now.

Antibiotics were discontinued on day 7, but the patient continued to experience ongoing fever. Urine Histoplasma and serum cryptococcal antigens were negative. His urine AFB smear was 1+ positive. Liver function tests revealed a total protein of 7.0 g/dL, albumin 3.0 g/dL, total bilirubin 1.2 mg/dL, direct bilirubin 0.3 mg/dL, alkaline phosphatase 418 U/L, aspartate aminotransferase 65 U/L, alanine aminotransferase 88 U/L, gamma-glutamyltransferase (GGT) 609 U/L (normal, 3-60), and lactate dehydrogenase 284 U/L (normal, 85-210).

Acid-fast bacillus in the urine strongly suggests Mycobacterium tuberculosis (MTB) with several reports of likelihood ratios greater than 10. Nevertheless, confirmation is needed to rule out nontuberculous mycobacteria because of potential hepatotoxicity from treatment. Up to six urine samples should be sent for mycobacterium culture. However, false negative rates of up to 90% are reported, and final test results can take up to two months, so other methods of confirmation should be simultaneously sought. A nucleic acid amplification test of urine could rule in a pathogenic species within 24 hours. Alternatively, the probability of a nonpathogenic colonizing species would be negligible if a caseating granuloma was found. Biopsy could be obtained from the ureters, as suggested above. Liver biopsy should also be considered, especially if the moderate elevations in alkaline phosphatase and GGT (the most common liver enzyme abnormalities in hepatic tuberculosis) did not merely wax and wane with sepsis.

A CT of the thorax without IV contrast was done to evaluate for evidence of pulmonary disease given the positive urine AFB. This demonstrated bilateral fibrotic upper lobe opacities suggestive of prior granulomatous disease but no cavitary lung lesions (Figure 3). Three sputum smears were negative for AFB, but one sample showed Mycobacterium tuberculosis detected by a polymerase chain reaction (PCR) probe.

The two-month initiation phase of treatment with four antituberculosis drugs should begin while drug susceptibility tests are pending. Potential hepatotoxicity should be closely monitored, ideally by a clinician with experience treating tuberculosis in patients with existing liver disease. As a general precaution, alcohol should be avoided as should medications such as acetaminophen that are known to be hepatotoxic. Urology follow-up is also needed because about one-third of tuberculous ureteral strictures treated initially with percutaneous nephrostomy do not resolve with antituberculosis therapy.

The patient was started on weight-based antituberculosis treatment with four antimicrobial agents (rifampin, ethambutol, pyrazinamide, and isoniazid). He was seen in the infectious disease clinic two weeks later; his fever had resolved, and his liver function tests showed normalization of AST and LDH as well as a 45% reduction in his GGT and alkaline phosphatase levels. Two months following discharge, a nuclear medicine radionuclide angiogram renal flow scan showed normal right kidney function. The right nephrostomy tube was subsequently removed. He continued to have left kidney outflow obstruction due to a residual ureteral stricture (Figure 4). Repeat cystoscopy and attempted left ureteral stenting was unsuccessful. The left nephrostomy tube remained in place.

According to the Centers for Disease Control, in 2017, 10 million people became sick with TB, and there were 1.3 million TB-related deaths worldwide with 9,150 cases reported in the United States. Extrapulmonary TB (EPTB) constitutes 10% of all TB cases globally.^1-4 GUTB is the second most common form of EPTB after lymph node TB, and it occurs in up to 20% of all pulmonary TB cases.^2,3

Mycobacteria reach the genitourinary (GU) tract via hematogenous spread during primary infection or reactivation of TB. This leads to cortical and medullary lesions, which can heal spontaneously or eventually (average of 22 years) rupture into the tubules and onto the collecting system, ureters, and bladder.^5,6 Spread to the ureter and bladder leads to multiple ureteral strictures and contracture of the bladder with disruption of the ureterovesical junction (UVJ), which causes hydroureter and hydronephrosis.⁷ Unilateral kidney involvement is most common, but bilateral involvement can occur following exacerbated hematogenous spread, particularly in immune deficient patients. Bilateral kidney involvement is also possible from retrograde spread to the good kidney due to bladder contracture and UVJ disruption.^8,9 Distal infection can involve all aspects of the male and female genital tracts, but urethral strictures are extremely rare.^10,11

GUTB affects males more than females (2:1) and presents insidiously at 40 to 60 years of age.¹² Other risk factors for TB include birth in TB endemic areas, prior TB infection, immunosuppression, malnutrition, severe systemic disease, diabetes, and cirrhosis. It is crucial to assess these risk factors when creating and refining differential diagnoses. Many patients have hematuria and sterile pyuria as incidental initial findings. The most common symptoms arise from bladder involvement, including frequency, urgency, and dysuria. Low back pain and gross hematuria are also common, but fever and constitutional symptoms are uncommon.¹⁰ Bilateral ureteral strictures can lead to obstructive renal failure, and involvement of the genital tracts can lead to pelvic or scrotal pain, swelling, and fistula formation.¹⁰

Diagnosis involves the demonstration of TB bacilli in urine or GU tissue. The urinalysis reveals hematuria and sterile pyuria.¹³ Urine AFB stains are positive in 52% of cases but are not diagnostic as nontuberculous mycobacteria may also cause a positive test result.^13,14 Urine cultures for Mycobacterium tuberculosis are positive in up to 90% of cases after six to eight weeks. As many as three to six morning urine samples are required to achieve diagnostic accuracy.^10,14 Urine PCR for Mycobacterium tuberculosis has 96% sensitivity and up to 98% specificity,¹⁴ while PCR on GU tissue has a sensitivity of 88% and specificity of 87%.¹⁵ The rapid nucleic acid amplification assay Xpert MTB/RIF in urine has a sensitivity of 83%, and specificity of 98%.¹⁶ Imaging is required to evaluate for obstruction, and the CT scan is abnormal in up to 90% of cases, showing multiple ureteral stenoses, hydroureter and hydronephrosis, and a contracted bladder.^10,17

GUTB is treated with standard antituberculosis regimens.¹⁸ Patients with urinary obstruction benefit from ureteral stenting or percutaneous nephrostomy, bladder diversion, or ureteral reconstruction surgery. Unilateral nephrectomy for a nonfunctioning kidney with extensive disease is occasionally required.¹⁹ Following treatment, relapse occurs in up to 6% of patients over five years, and long-term follow-up with urine cultures and PCR every six months is recommended.^10,20 Appropriate screening and treatment for latent tuberculosis infection greatly reduces the risk of reactivation GUTB.

This patient presented with features of an infection, which, combined with his history of renal stones and his urinalysis, led to an appropriate suspicion of and empiric treatment for an upper UTI. Given the AKI and nephrolithiasis, imaging was done to exclude obstruction. The CT finding of bilateral hydroureters and hydronephrosis absent an obstructing stone or mass or abnormal bladder was the initial clue that this was not a typical bacterial infection and that there was likely an underlying infectious pathologic process such as TB involving the GU tract diffusely. The care team treated the patient as an individual with fever and sterile pyuria in the context of multiple urinary tract strictures and an initial unrevealing infectious diagnostic workup. They recognized that the clues to the ultimate diagnosis of GUTB were all in the stream.

• GUTB is a significant cause of sterile pyuria.
• In the presence of bilateral hydronephrosis, it is vital to determine the level of obstruction. If the bladder is not distended or contracted, then obstruction is likely at the level of the ureters and initial use of percutaneous nephrostomy tubes to relieve obstruction may be preferred.
• Imaging abnormalities such as multiple ureteral strictures, hydroureter and hydronephrosis (absent an obstructing stone or mass), and the finding of a contracted bladder are highly suggestive of GUTB.
• The mainstay of treatment for GUTB is standard antituberculosis treatment regimens in combination with the relief of urinary obstruction by ureteral stenting, percutaneous nephrostomy or open surgery.
• GUTB can relapse in up to 6% of treated cases over five years, and long-term follow-up and surveillance with urine culture and PCR every six months are recommended.

Disclosures

Benjamin Mba, Nathan Houchens, Marie Jennifer Seares, and Udit Joshi have no financial conflicts of interest and no disclosures.

Funding

Brian P. Lucas receives funding from the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development and Dartmouth SYNERGY, National Institutes of Health, and National Center for Translational Science (UL1TR001086).

A 67-year-old man presented to the emergency department with four days of nausea, vomiting, and chills. He was originally from the Philippines but lived in the United States for six years. His past medical history was notable for nephrolithiasis for which a ureteral stent had been placed and was subsequently removed three years prior. He reported no abdominal pain, diarrhea, dysuria, urinary frequency, hematuria, cough, headache, or fever. He was a retired high school teacher and a lifelong nonsmoker.

This patient presents with a nonspecific constellation of constitutional and gastrointestinal (GI) symptoms. A system-based approach may be helpful when considering the differential diagnosis. Chills most often suggest infection, especially in older patients. With regard to GI causes, acute gastroenteritis and other food-borne infections can cause nausea, vomiting, and chills, but these are typically accompanied by abdominal pain and diarrhea and often resolve in less than four days. Abdominal pain would also be expected with cholecystitis as well as more life-threatening causes of nausea such as acute pancreatitis, mesenteric ischemia, and bowel obstruction. In contrast, abdominal pain would not be expected with a central nervous system (CNS) infection such as a brain abscess, which may cause nausea from increased intracranial pressure. Headaches occur in a majority of these cases, making CNS etiologies of nausea less likely. Cardiovascular causes, including myocardial ischemia and infarction, may lead to nausea and vomiting, but these are less likely given the absence of chest pain. Genitourinary causes must be considered, especially given his history of both nephrolithiasis and instrumentation. A stricture or recurrence of nephrolithiasis could lead to acute pyelonephritis or perinephric abscess, although both commonly present with urinary tract symptoms. Uremia, possibly from obstructive uropathy given the patient’s history of nephrolithiasis, could also lead to this constellation of symptoms.

On examination, temperature was 101.6 °F, heart rate 126 beats per minute, respiratory rate 18 breaths per minute, blood pressure 120/76 mm Hg, and oxygen saturation 98% on room air. The oral mucosa was moist, heart sounds were normal without murmurs, lungs were clear to auscultation, and abdomen was soft, nontender, and nondistended. There was no flank tenderness, and penile, testicular, and prostate examination findings were normal.

Laboratory studies revealed a serum sodium of 126 mEq/L, potassium 5.0 mEq/L, chloride 98 mEq/L, bicarbonate 15 mEq/L, blood urea nitrogen 88 mg/dL, creatinine 9.0 mg/dL, calcium 8 mg/dL, glucose 110 mg/dL, and albumin 3.3 g/dL. One year prior, serum creatinine was 1.4 mg/dL. His white blood cell (WBC) count was 8.0 k/uL with normal differential, hemoglobin 11.4 g/dL with normal MCV, and platelet count was normal. Serum osmolality was 286 mOsm/kg and serum parathyroid hormone (PTH) level 63 pg/mL (normal, 10-65). The urinalysis revealed cloudy urine with a specific gravity 1.009, 54 red blood cells (RBC), 236 WBC, large leukocyte esterase, negative nitrite, trace protein, and no casts or dysmorphic RBCs. A random urine specimen revealed sodium of 86 mEq/L, potassium 16 mEq/L, chloride 80 mEq/L, and creatinine 70 mg/dL.

Fever and tachycardia support an infectious cause of his symptoms. Absent flank tenderness and a normal genitourinary examination have only moderate negative predictive values for acute pyelonephritis and prostatitis, respectively. The most striking laboratory finding is his azotemia. Acute kidney injury (AKI) is more likely than chronic kidney disease (CKD) given that the PTH level is normal and the serum creatinine from a year ago was near normal. The most useful finding to differentiate AKI from CKD is the presence of atrophic kidneys on imaging. The low bicarbonate level indicates a metabolic acidosis. His serum anion gap is 13 mEq/L, which falls above most normal ranges. A mildly elevated serum anion gap together with a “delta serum anion gap/delta serum bicarbonate” ratio less than one suggest concomitant anion gap metabolic acidosis and non anion gap metabolic acidosis. The latter, coupled with a history of nephrolithiasis, may point to the possibility of renal tubular acidosis and AKI caused by urinary tract obstruction. This could also account for the marked hyponatremia. Moreover, his high fractional excretion of sodium (9%) is not suggestive of prerenal injury, the most common acute renal injury among patients who present to the emergency department. Hematuria carries a broad differential diagnosis, but most common causes include nephrolithiasis, urinary tract infection (UTI), prostatitis, neoplasm, and glomerulonephritis (GN). The lack of casts and dysmorphic RBCs makes GN unlikely. Taken together, his vital signs, examination, and laboratory studies suggest a high likelihood of an upper UTI (acute obstructive pyelonephritis) in the context of AKI due to obstructive uropathy.

Despite both a normal serum WBC count (which has only a moderate negative predictive value) and his low risk of developing life-threating organ dysfunction from sepsis based on a quick Sequential Organ Failure Assessment (qSOFA) score of zero, it is appropriate to start antibiotics after drawing blood and doing urine cultures. The next step should include administration of a broad-spectrum regimen that is appropriately dose-adjusted for renal dysfunction, such as an antipseudomonal carbapenem and vancomycin to cover extended-spectrum beta-lactamase (ESBL)-producing organisms, Pseudomonas aeruginosa, and methicillin-resistant Staphylococcus aureus (MRSA). This broad coverage is indicated for empiric treatment of complicated obstructive pyelonephritis, a condition that may arise from significant urinary obstruction and that carries a high risk of rapid clinical deterioration. He should undergo a rapid bedside test to assess for urethral or bladder outlet obstruction: either a bladder ultrasound or temporary insertion of a bladder catheter. He should also have an urgent computed tomography (CT) of his abdomen and pelvis without intravenous (IV) contrast, looking for evidence of urinary tract obstruction. A CT is preferred over ultrasound of the kidneys and bladder as CT has higher sensitivity and specificity for nephrolithiasis and neoplasm.

A CT of the abdomen and pelvis without IV contrast revealed bilateral hydroureter and hydronephrosis with multiple punctate calcified stones within the right calyces and the distal right ureter (Figure 1, Figure 2). However, these appeared too small to cause the degree of obstruction visualized. There were no stones noted in the left ureter to account for the obstruction, though small stones were noted in the left calyces. The bladder appeared normal.

More commonly, bilateral hydroureter with bilateral hydronephrosis is caused by an obstruction of the bladder or urethra. CT scans can reveal prostatic hyperplasia (occasionally with protrusion into the bladder) and increased bladder wall thickness as a result of chronic bladder outlet obstruction, but the negative predictive value of either finding is modest. More revealing is that the patient reported neither an inability to pass urine (in fact, a “random” urine sample was obtained) nor suprapubic discomfort. Both symptoms would be pronounced with acute bladder obstruction but may be minimal with slowly progressive obstruction. In either case, a distended bladder would have been seen on the CT scan.

Regardless of the cause or whether the obstruction is in the upper or lower urinary tract, emergency intervention is needed to relieve the obstruction when AKI presents with bilateral hydronephrosis. A urology consultation should be sought urgently to determine the best strategy to relieve the obstruction. This may include bilateral percutaneous nephrostomy tubes given that the obstruction appears to be above the level of the bladder. Their findings will also direct additional diagnostic workup.

The patient received ceftriaxone and underwent cystoscopy, which revealed a stricture of the distal bulbar urethra. The ureters and bladder could not be completely visualized due to hematuria. The urethral stricture was dilated, and a Foley catheter was placed. In the operating room, the patient had a fever of 103 °F and developed severe hypotension unresponsive to 3 L of intravenous normal saline. Norepinephrine infusion was initiated for refractory hypotension.

Except for transurethral prostate resections, endoscopic urologic procedures rarely lead to a stricture of any segment of the urethra, suggesting that the previous ureteral stent placement and retrieval were not causal. Longstanding Mycobacterium tuberculosis or Schistosoma haematobium infection occasionally causes urethral strictures presenting as bilateral hydronephrosis. The multiple punctate calcified “stones” demonstrated on CT may suggest either diagnosis if they were actually calcified granulomas.

Regardless of the cause, most patients with a urethral stricture have chronic lower urinary tract symptoms such as decreased stream and the feeling of incomplete bladder emptying. Since this patient does not report these symptoms, it is important to consider if the stricture might be merely incidental. The absence of pain is more telling than the absence of chronic or recurrent symptoms. Lack of pain argues strongly against a pure de novo acute obstruction because abrupt stretching of the renal capsules and the walls of the collecting system is usually painful. Slow stretching caused by a progressive stricture may mask the pain of a superimposed acute obstruction. A blood clot, for example, may have precipitated an acute-on-chronic obstruction upon lodging at the urethral stricture.

The worsening systemic response to the procedure may be due to increased intravesical pressure by dilation and cystoscopy, which may have caused subsequent backflow of bacteria from the renal parenchyma into the circulation (pyelorenal backflow). The broad-spectrum antibiotic regimen suggested above and IV crystalloid infusion should be continued with close hemodynamic monitoring.

Treatment for severe sepsis was initiated with empiric piperacillin-tazobactam, ceftriaxone was discontinued, and the patient was transferred to the intensive care unit (ICU). Norepinephrine was discontinued after 24 hours. Despite the indwelling Foley catheter, his kidney function worsened (creatinine increased to 10.5 over the next 36 hours, and he remained oliguric). Therefore, bilateral percutaneous nephrostomy tubes were placed to relieve the ongoing obstruction. In the ICU, he remained febrile, despite receiving piperacillin-tazobactam, through hospital day 7. Serial blood and urine cultures all remained negative. HIV testing was negative. His chest radiograph was unremarkable, and transthoracic echocardiogram was normal. His creatinine improved but plateaued at 2.5 mg/dL by day 7.

Worsening renal function (alongside oliguria or anuria) despite a functioning Foley catheter suggests either intrinsic renal disease or bilateral ureteral obstructions. The initial attempt at relieving the obstruction with a Foley catheter did not take into consideration the bilateral ureteral strictures. As a result, soon thereafter, the insertion of percutaneous nephrostomy tubes was necessary. Given the severity of his illness, underlying obstructive uropathy, and persistent fever, suggesting an ongoing infection, one strategy would be to continue antibiotics with broader coverage than piperacillin-tazobactam. This approach may be reasonable, given the emergence of ESBL organisms and the possibility of MRSA due to instrumentation. However, it is important to note that only sterile pyuria has been identified to date, which raises the possibility of nonbacterial infections. Although chronic infection with Schistosoma haematobium can cause bilateral ureteral strictures, associated fever is limited to the acute phase of infection and not the chronic obstructive phase, unless there is a superimposed infection. Genitourinary Mycobacterium tuberculosis remains a likely possibility, regardless of the unrevealing chest radiograph. Urine nucleic acid amplification and acid-fast bacilli (AFB) smear and culture, the best initial diagnostic test, should be sent. Although less definitive, a tuberculin skin test and an interferon-gamma release assay should also be conducted. Histopathology of the ureters obtained by repeat cystoscopy may be diagnostic, but given the limited visualization during the last cystoscopy and the recent dilation of the urethra, this option should be kept in reserve for now.

Antibiotics were discontinued on day 7, but the patient continued to experience ongoing fever. Urine Histoplasma and serum cryptococcal antigens were negative. His urine AFB smear was 1+ positive. Liver function tests revealed a total protein of 7.0 g/dL, albumin 3.0 g/dL, total bilirubin 1.2 mg/dL, direct bilirubin 0.3 mg/dL, alkaline phosphatase 418 U/L, aspartate aminotransferase 65 U/L, alanine aminotransferase 88 U/L, gamma-glutamyltransferase (GGT) 609 U/L (normal, 3-60), and lactate dehydrogenase 284 U/L (normal, 85-210).

Acid-fast bacillus in the urine strongly suggests Mycobacterium tuberculosis (MTB) with several reports of likelihood ratios greater than 10. Nevertheless, confirmation is needed to rule out nontuberculous mycobacteria because of potential hepatotoxicity from treatment. Up to six urine samples should be sent for mycobacterium culture. However, false negative rates of up to 90% are reported, and final test results can take up to two months, so other methods of confirmation should be simultaneously sought. A nucleic acid amplification test of urine could rule in a pathogenic species within 24 hours. Alternatively, the probability of a nonpathogenic colonizing species would be negligible if a caseating granuloma was found. Biopsy could be obtained from the ureters, as suggested above. Liver biopsy should also be considered, especially if the moderate elevations in alkaline phosphatase and GGT (the most common liver enzyme abnormalities in hepatic tuberculosis) did not merely wax and wane with sepsis.

A CT of the thorax without IV contrast was done to evaluate for evidence of pulmonary disease given the positive urine AFB. This demonstrated bilateral fibrotic upper lobe opacities suggestive of prior granulomatous disease but no cavitary lung lesions (Figure 3). Three sputum smears were negative for AFB, but one sample showed Mycobacterium tuberculosis detected by a polymerase chain reaction (PCR) probe.

The two-month initiation phase of treatment with four antituberculosis drugs should begin while drug susceptibility tests are pending. Potential hepatotoxicity should be closely monitored, ideally by a clinician with experience treating tuberculosis in patients with existing liver disease. As a general precaution, alcohol should be avoided as should medications such as acetaminophen that are known to be hepatotoxic. Urology follow-up is also needed because about one-third of tuberculous ureteral strictures treated initially with percutaneous nephrostomy do not resolve with antituberculosis therapy.

The patient was started on weight-based antituberculosis treatment with four antimicrobial agents (rifampin, ethambutol, pyrazinamide, and isoniazid). He was seen in the infectious disease clinic two weeks later; his fever had resolved, and his liver function tests showed normalization of AST and LDH as well as a 45% reduction in his GGT and alkaline phosphatase levels. Two months following discharge, a nuclear medicine radionuclide angiogram renal flow scan showed normal right kidney function. The right nephrostomy tube was subsequently removed. He continued to have left kidney outflow obstruction due to a residual ureteral stricture (Figure 4). Repeat cystoscopy and attempted left ureteral stenting was unsuccessful. The left nephrostomy tube remained in place.

According to the Centers for Disease Control, in 2017, 10 million people became sick with TB, and there were 1.3 million TB-related deaths worldwide with 9,150 cases reported in the United States. Extrapulmonary TB (EPTB) constitutes 10% of all TB cases globally.^1-4 GUTB is the second most common form of EPTB after lymph node TB, and it occurs in up to 20% of all pulmonary TB cases.^2,3

Mycobacteria reach the genitourinary (GU) tract via hematogenous spread during primary infection or reactivation of TB. This leads to cortical and medullary lesions, which can heal spontaneously or eventually (average of 22 years) rupture into the tubules and onto the collecting system, ureters, and bladder.^5,6 Spread to the ureter and bladder leads to multiple ureteral strictures and contracture of the bladder with disruption of the ureterovesical junction (UVJ), which causes hydroureter and hydronephrosis.⁷ Unilateral kidney involvement is most common, but bilateral involvement can occur following exacerbated hematogenous spread, particularly in immune deficient patients. Bilateral kidney involvement is also possible from retrograde spread to the good kidney due to bladder contracture and UVJ disruption.^8,9 Distal infection can involve all aspects of the male and female genital tracts, but urethral strictures are extremely rare.^10,11

GUTB affects males more than females (2:1) and presents insidiously at 40 to 60 years of age.¹² Other risk factors for TB include birth in TB endemic areas, prior TB infection, immunosuppression, malnutrition, severe systemic disease, diabetes, and cirrhosis. It is crucial to assess these risk factors when creating and refining differential diagnoses. Many patients have hematuria and sterile pyuria as incidental initial findings. The most common symptoms arise from bladder involvement, including frequency, urgency, and dysuria. Low back pain and gross hematuria are also common, but fever and constitutional symptoms are uncommon.¹⁰ Bilateral ureteral strictures can lead to obstructive renal failure, and involvement of the genital tracts can lead to pelvic or scrotal pain, swelling, and fistula formation.¹⁰

Diagnosis involves the demonstration of TB bacilli in urine or GU tissue. The urinalysis reveals hematuria and sterile pyuria.¹³ Urine AFB stains are positive in 52% of cases but are not diagnostic as nontuberculous mycobacteria may also cause a positive test result.^13,14 Urine cultures for Mycobacterium tuberculosis are positive in up to 90% of cases after six to eight weeks. As many as three to six morning urine samples are required to achieve diagnostic accuracy.^10,14 Urine PCR for Mycobacterium tuberculosis has 96% sensitivity and up to 98% specificity,¹⁴ while PCR on GU tissue has a sensitivity of 88% and specificity of 87%.¹⁵ The rapid nucleic acid amplification assay Xpert MTB/RIF in urine has a sensitivity of 83%, and specificity of 98%.¹⁶ Imaging is required to evaluate for obstruction, and the CT scan is abnormal in up to 90% of cases, showing multiple ureteral stenoses, hydroureter and hydronephrosis, and a contracted bladder.^10,17

GUTB is treated with standard antituberculosis regimens.¹⁸ Patients with urinary obstruction benefit from ureteral stenting or percutaneous nephrostomy, bladder diversion, or ureteral reconstruction surgery. Unilateral nephrectomy for a nonfunctioning kidney with extensive disease is occasionally required.¹⁹ Following treatment, relapse occurs in up to 6% of patients over five years, and long-term follow-up with urine cultures and PCR every six months is recommended.^10,20 Appropriate screening and treatment for latent tuberculosis infection greatly reduces the risk of reactivation GUTB.

This patient presented with features of an infection, which, combined with his history of renal stones and his urinalysis, led to an appropriate suspicion of and empiric treatment for an upper UTI. Given the AKI and nephrolithiasis, imaging was done to exclude obstruction. The CT finding of bilateral hydroureters and hydronephrosis absent an obstructing stone or mass or abnormal bladder was the initial clue that this was not a typical bacterial infection and that there was likely an underlying infectious pathologic process such as TB involving the GU tract diffusely. The care team treated the patient as an individual with fever and sterile pyuria in the context of multiple urinary tract strictures and an initial unrevealing infectious diagnostic workup. They recognized that the clues to the ultimate diagnosis of GUTB were all in the stream.

• GUTB is a significant cause of sterile pyuria.
• In the presence of bilateral hydronephrosis, it is vital to determine the level of obstruction. If the bladder is not distended or contracted, then obstruction is likely at the level of the ureters and initial use of percutaneous nephrostomy tubes to relieve obstruction may be preferred.
• Imaging abnormalities such as multiple ureteral strictures, hydroureter and hydronephrosis (absent an obstructing stone or mass), and the finding of a contracted bladder are highly suggestive of GUTB.
• The mainstay of treatment for GUTB is standard antituberculosis treatment regimens in combination with the relief of urinary obstruction by ureteral stenting, percutaneous nephrostomy or open surgery.
• GUTB can relapse in up to 6% of treated cases over five years, and long-term follow-up and surveillance with urine culture and PCR every six months are recommended.

Disclosures

Benjamin Mba, Nathan Houchens, Marie Jennifer Seares, and Udit Joshi have no financial conflicts of interest and no disclosures.

Funding

Brian P. Lucas receives funding from the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development and Dartmouth SYNERGY, National Institutes of Health, and National Center for Translational Science (UL1TR001086).

In recognizing the importance of Hospital Medicine (HM) and its practitioners, the Centers for Medicare and Medicaid Services (CMS) awarded the field a specialty designation in 2016. The code is self-selected by hospitalists and used by the CMS for programmatic and claims processing purposes. The HM code (“C6”), submitted to the CMS by the provider or their designee through the Provider Enrollment Chain and Ownership System (PECOS), in turn links to the National Provider Identification provider data.

The Society of Hospital Medicine^® sought the designation given the growth of hospitalists practicing nationally, their impact on the practice of medicine in the inpatient setting,¹ and their secondary effects on global care.² In fact, early efforts by the CMS to transition physician payments to the value-based payment used specialty designations to create benchmarks in cost metrics, heightening the importance for hospitalists to be able to assess their performance. The need to identify any shifts in resource utilization and workforce mix in the broader context of health reforms necessitated action. Essentially, to understand the “why’s” of hospital medicine, the field required an accounting of the “who’s” and “where’s.”

The CMS granted the C6 designation in 2016, and it went live in April 2017. Despite the code’s brief two-year tenure, calls for its creation long predated its existence. As such, the new modifier requires an initial look to help steer the role of HM in any future CMS and managed care organization (MCO) quality, payment, or practice improvement activities.

We analyzed publicly available 2017 Medicare Part B utilization data³ to explore the rates of Evaluation & Management (E&M) codes used across specialties, using the C6 designation to identify hospitalists.

To try to estimate the percentage of hospitalists who were likely billing under the C6 designation, we then compared the rates of C6 billing to expected rates of hospitalist E&M billing based on an analysis of hospitalist prevalence in the 2012 Medicare physician payment data. Prior work to identify hospitalists before the implementation of the C6 designation relied on thresholds of inpatient codes for various inpatient E&M services.^4,5 We used our previously published approach of a threshold of 60% of inpatient E&M hospital services to differentiate hospitalists from their parent specialties.⁶ We also calculated the expected rates of E&M billing for other select specialty services by applying the 2012 E&M coding trends to the 2017 data.

Table 1 shows the distribution of inpatient E&M codes billed by hospitalists using the C6 identification, as well as the use of those codes by other specialists. Hospitalists identified by the C6 designation billed only 2%-5% of inpatient and 6% of observation codes. As an example, in 2017, discharge CPT codes 99238 and 99239 were used 7,872,323 times. However, C6-identified hospitalists accounted for only 441,420 of these codes.

Table 2 compares the observed billing rates by specialty using the C6 designation to identify hospitalists with what would be the expected rates with the 2012 threshold-based specialty billing designation applied to the 2017 data. This comparison demonstrates that hospitalist billing based on the C6 modifier use is approximately one-tenth of what would have been their expected volume of E&M services.

We examined the patterns of hospitalist billing using the C6 hospital medicine specialty modifier, comparing billing patterns with what we would expect hospitalist activity to be if we had used a threshold-based approach. The difference between the C6 and the threshold-based approaches to assessing hospitalist activity suggests that as few as 10% of hospitalists have adopted the C6 code.

Why is the adoption of the C6 modifier so low? Although administrative data do not allow us to identify the reasons why providers chose to disregard the C6 designation, we can speculate on causes. There are, to date, low direct risks and recognized benefits with using the code. We hypothesize that several factors could be impeding whether providers use the modifier to bring about potential gains. The first may be knowledge-related; ie, hospitalists might not be familiar with the specialty code or unaware of the importance of accurately capturing hospitalist practice patterns. They may also wrongly assume that their practices are aware of the revision or have submitted the appropriate paperwork. Similarly, practice personnel may lack knowledge regarding the code or the importance of its use. The second factor may be logistical; ie, administrative barriers such as difficulty accessing the Provider Enrollment, Chain and Ownership System (PECOS) and out-of-date paper registration forms impede fast uptake. The final reason might be related to professionals whose tenures as hospitalists will be brief, and their unease of carrying an identifier into their next non-HM position prompts hesitation. Providers may have a misperception that using the C6 code may somehow impact or limit their future scope of practice, when, in fact, they may change their Medicare specialty designation at any time.

Changes in reimbursement models, including the Bundled Payments for Care Improvement Advanced (BPCI-A) and other value-based initiatives, heighten the need for a more accurate identification of the specialty. Classifying individual providers and groups to make valid performance comparisons is relevant for the same reasons. The CMS continues to advance cost and efficiency measures in its publicly accessible physiciancompare.gov website.⁷ Without an improved ability to identify services provided by hospitalists—by both CMS and commercial entities—the potential benefits delivered by hospitalists in terms of improved care quality, safety, or efficiency could go undetected by payers and policymakers. Moreover, C6 may be used in other ways by the CMS throughout its payment systems and programmatic efforts that use specialty to differentiate between Medicare providers.⁸ Finally, the C6 is an identifier for the Medicare fee-for-service system; state programs and MCOs may not identify hospitalists in the same manner, or at all. Therefore, it may make it more difficult for those groups and HM researchers to study the trends in care delivery changes. The specialty needs to engage with these other payers to assist in revising their information systems to better account for how hospitalists care for their insured populations.

Although we would expect a natural increase in C6 adoption over time, optimally meeting stakeholders’ data needs requires more rapid uptake. Our analysis is limited by our assumption that specialty patterns of code use remain similar from 2012 to 2017. Regardless, the magnitude of the difference between the estimate of hospitalists using the C6 versus billing thresholds strongly suggests underuse of the C6 designation. The CMS and MCOs have an increasing need for valid and representative data, and C6 can be used to assess “HM-adjusted” resource utilization, relative value units (RVUs), and performance evaluations. Therefore, hospitalists may see more incentives to use the C6 specialty code in a manner consistent with other recognized subspecialties. 

Disclaimer

The research reported here was supported by the Department of Veterans Affairs, Veterans Health Administration, and the Health Services Research and Development Service. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs.

In recognizing the importance of Hospital Medicine (HM) and its practitioners, the Centers for Medicare and Medicaid Services (CMS) awarded the field a specialty designation in 2016. The code is self-selected by hospitalists and used by the CMS for programmatic and claims processing purposes. The HM code (“C6”), submitted to the CMS by the provider or their designee through the Provider Enrollment Chain and Ownership System (PECOS), in turn links to the National Provider Identification provider data.

The Society of Hospital Medicine^® sought the designation given the growth of hospitalists practicing nationally, their impact on the practice of medicine in the inpatient setting,¹ and their secondary effects on global care.² In fact, early efforts by the CMS to transition physician payments to the value-based payment used specialty designations to create benchmarks in cost metrics, heightening the importance for hospitalists to be able to assess their performance. The need to identify any shifts in resource utilization and workforce mix in the broader context of health reforms necessitated action. Essentially, to understand the “why’s” of hospital medicine, the field required an accounting of the “who’s” and “where’s.”

The CMS granted the C6 designation in 2016, and it went live in April 2017. Despite the code’s brief two-year tenure, calls for its creation long predated its existence. As such, the new modifier requires an initial look to help steer the role of HM in any future CMS and managed care organization (MCO) quality, payment, or practice improvement activities.

We analyzed publicly available 2017 Medicare Part B utilization data³ to explore the rates of Evaluation & Management (E&M) codes used across specialties, using the C6 designation to identify hospitalists.

To try to estimate the percentage of hospitalists who were likely billing under the C6 designation, we then compared the rates of C6 billing to expected rates of hospitalist E&M billing based on an analysis of hospitalist prevalence in the 2012 Medicare physician payment data. Prior work to identify hospitalists before the implementation of the C6 designation relied on thresholds of inpatient codes for various inpatient E&M services.^4,5 We used our previously published approach of a threshold of 60% of inpatient E&M hospital services to differentiate hospitalists from their parent specialties.⁶ We also calculated the expected rates of E&M billing for other select specialty services by applying the 2012 E&M coding trends to the 2017 data.

Table 1 shows the distribution of inpatient E&M codes billed by hospitalists using the C6 identification, as well as the use of those codes by other specialists. Hospitalists identified by the C6 designation billed only 2%-5% of inpatient and 6% of observation codes. As an example, in 2017, discharge CPT codes 99238 and 99239 were used 7,872,323 times. However, C6-identified hospitalists accounted for only 441,420 of these codes.

Table 2 compares the observed billing rates by specialty using the C6 designation to identify hospitalists with what would be the expected rates with the 2012 threshold-based specialty billing designation applied to the 2017 data. This comparison demonstrates that hospitalist billing based on the C6 modifier use is approximately one-tenth of what would have been their expected volume of E&M services.

We examined the patterns of hospitalist billing using the C6 hospital medicine specialty modifier, comparing billing patterns with what we would expect hospitalist activity to be if we had used a threshold-based approach. The difference between the C6 and the threshold-based approaches to assessing hospitalist activity suggests that as few as 10% of hospitalists have adopted the C6 code.

Why is the adoption of the C6 modifier so low? Although administrative data do not allow us to identify the reasons why providers chose to disregard the C6 designation, we can speculate on causes. There are, to date, low direct risks and recognized benefits with using the code. We hypothesize that several factors could be impeding whether providers use the modifier to bring about potential gains. The first may be knowledge-related; ie, hospitalists might not be familiar with the specialty code or unaware of the importance of accurately capturing hospitalist practice patterns. They may also wrongly assume that their practices are aware of the revision or have submitted the appropriate paperwork. Similarly, practice personnel may lack knowledge regarding the code or the importance of its use. The second factor may be logistical; ie, administrative barriers such as difficulty accessing the Provider Enrollment, Chain and Ownership System (PECOS) and out-of-date paper registration forms impede fast uptake. The final reason might be related to professionals whose tenures as hospitalists will be brief, and their unease of carrying an identifier into their next non-HM position prompts hesitation. Providers may have a misperception that using the C6 code may somehow impact or limit their future scope of practice, when, in fact, they may change their Medicare specialty designation at any time.

Changes in reimbursement models, including the Bundled Payments for Care Improvement Advanced (BPCI-A) and other value-based initiatives, heighten the need for a more accurate identification of the specialty. Classifying individual providers and groups to make valid performance comparisons is relevant for the same reasons. The CMS continues to advance cost and efficiency measures in its publicly accessible physiciancompare.gov website.⁷ Without an improved ability to identify services provided by hospitalists—by both CMS and commercial entities—the potential benefits delivered by hospitalists in terms of improved care quality, safety, or efficiency could go undetected by payers and policymakers. Moreover, C6 may be used in other ways by the CMS throughout its payment systems and programmatic efforts that use specialty to differentiate between Medicare providers.⁸ Finally, the C6 is an identifier for the Medicare fee-for-service system; state programs and MCOs may not identify hospitalists in the same manner, or at all. Therefore, it may make it more difficult for those groups and HM researchers to study the trends in care delivery changes. The specialty needs to engage with these other payers to assist in revising their information systems to better account for how hospitalists care for their insured populations.

Although we would expect a natural increase in C6 adoption over time, optimally meeting stakeholders’ data needs requires more rapid uptake. Our analysis is limited by our assumption that specialty patterns of code use remain similar from 2012 to 2017. Regardless, the magnitude of the difference between the estimate of hospitalists using the C6 versus billing thresholds strongly suggests underuse of the C6 designation. The CMS and MCOs have an increasing need for valid and representative data, and C6 can be used to assess “HM-adjusted” resource utilization, relative value units (RVUs), and performance evaluations. Therefore, hospitalists may see more incentives to use the C6 specialty code in a manner consistent with other recognized subspecialties. 

Disclaimer

The research reported here was supported by the Department of Veterans Affairs, Veterans Health Administration, and the Health Services Research and Development Service. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs.

In recognizing the importance of Hospital Medicine (HM) and its practitioners, the Centers for Medicare and Medicaid Services (CMS) awarded the field a specialty designation in 2016. The code is self-selected by hospitalists and used by the CMS for programmatic and claims processing purposes. The HM code (“C6”), submitted to the CMS by the provider or their designee through the Provider Enrollment Chain and Ownership System (PECOS), in turn links to the National Provider Identification provider data.

The Society of Hospital Medicine^® sought the designation given the growth of hospitalists practicing nationally, their impact on the practice of medicine in the inpatient setting,¹ and their secondary effects on global care.² In fact, early efforts by the CMS to transition physician payments to the value-based payment used specialty designations to create benchmarks in cost metrics, heightening the importance for hospitalists to be able to assess their performance. The need to identify any shifts in resource utilization and workforce mix in the broader context of health reforms necessitated action. Essentially, to understand the “why’s” of hospital medicine, the field required an accounting of the “who’s” and “where’s.”

The CMS granted the C6 designation in 2016, and it went live in April 2017. Despite the code’s brief two-year tenure, calls for its creation long predated its existence. As such, the new modifier requires an initial look to help steer the role of HM in any future CMS and managed care organization (MCO) quality, payment, or practice improvement activities.

We analyzed publicly available 2017 Medicare Part B utilization data³ to explore the rates of Evaluation & Management (E&M) codes used across specialties, using the C6 designation to identify hospitalists.

To try to estimate the percentage of hospitalists who were likely billing under the C6 designation, we then compared the rates of C6 billing to expected rates of hospitalist E&M billing based on an analysis of hospitalist prevalence in the 2012 Medicare physician payment data. Prior work to identify hospitalists before the implementation of the C6 designation relied on thresholds of inpatient codes for various inpatient E&M services.^4,5 We used our previously published approach of a threshold of 60% of inpatient E&M hospital services to differentiate hospitalists from their parent specialties.⁶ We also calculated the expected rates of E&M billing for other select specialty services by applying the 2012 E&M coding trends to the 2017 data.

Table 1 shows the distribution of inpatient E&M codes billed by hospitalists using the C6 identification, as well as the use of those codes by other specialists. Hospitalists identified by the C6 designation billed only 2%-5% of inpatient and 6% of observation codes. As an example, in 2017, discharge CPT codes 99238 and 99239 were used 7,872,323 times. However, C6-identified hospitalists accounted for only 441,420 of these codes.

Table 2 compares the observed billing rates by specialty using the C6 designation to identify hospitalists with what would be the expected rates with the 2012 threshold-based specialty billing designation applied to the 2017 data. This comparison demonstrates that hospitalist billing based on the C6 modifier use is approximately one-tenth of what would have been their expected volume of E&M services.

We examined the patterns of hospitalist billing using the C6 hospital medicine specialty modifier, comparing billing patterns with what we would expect hospitalist activity to be if we had used a threshold-based approach. The difference between the C6 and the threshold-based approaches to assessing hospitalist activity suggests that as few as 10% of hospitalists have adopted the C6 code.

Why is the adoption of the C6 modifier so low? Although administrative data do not allow us to identify the reasons why providers chose to disregard the C6 designation, we can speculate on causes. There are, to date, low direct risks and recognized benefits with using the code. We hypothesize that several factors could be impeding whether providers use the modifier to bring about potential gains. The first may be knowledge-related; ie, hospitalists might not be familiar with the specialty code or unaware of the importance of accurately capturing hospitalist practice patterns. They may also wrongly assume that their practices are aware of the revision or have submitted the appropriate paperwork. Similarly, practice personnel may lack knowledge regarding the code or the importance of its use. The second factor may be logistical; ie, administrative barriers such as difficulty accessing the Provider Enrollment, Chain and Ownership System (PECOS) and out-of-date paper registration forms impede fast uptake. The final reason might be related to professionals whose tenures as hospitalists will be brief, and their unease of carrying an identifier into their next non-HM position prompts hesitation. Providers may have a misperception that using the C6 code may somehow impact or limit their future scope of practice, when, in fact, they may change their Medicare specialty designation at any time.

Changes in reimbursement models, including the Bundled Payments for Care Improvement Advanced (BPCI-A) and other value-based initiatives, heighten the need for a more accurate identification of the specialty. Classifying individual providers and groups to make valid performance comparisons is relevant for the same reasons. The CMS continues to advance cost and efficiency measures in its publicly accessible physiciancompare.gov website.⁷ Without an improved ability to identify services provided by hospitalists—by both CMS and commercial entities—the potential benefits delivered by hospitalists in terms of improved care quality, safety, or efficiency could go undetected by payers and policymakers. Moreover, C6 may be used in other ways by the CMS throughout its payment systems and programmatic efforts that use specialty to differentiate between Medicare providers.⁸ Finally, the C6 is an identifier for the Medicare fee-for-service system; state programs and MCOs may not identify hospitalists in the same manner, or at all. Therefore, it may make it more difficult for those groups and HM researchers to study the trends in care delivery changes. The specialty needs to engage with these other payers to assist in revising their information systems to better account for how hospitalists care for their insured populations.

Although we would expect a natural increase in C6 adoption over time, optimally meeting stakeholders’ data needs requires more rapid uptake. Our analysis is limited by our assumption that specialty patterns of code use remain similar from 2012 to 2017. Regardless, the magnitude of the difference between the estimate of hospitalists using the C6 versus billing thresholds strongly suggests underuse of the C6 designation. The CMS and MCOs have an increasing need for valid and representative data, and C6 can be used to assess “HM-adjusted” resource utilization, relative value units (RVUs), and performance evaluations. Therefore, hospitalists may see more incentives to use the C6 specialty code in a manner consistent with other recognized subspecialties. 

Disclaimer

The research reported here was supported by the Department of Veterans Affairs, Veterans Health Administration, and the Health Services Research and Development Service. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs.

“Lead, follow, or get out of the way” sounds pejorative—even arrogant—but it ultimately speaks truth about most situations involving a team. A leader must know, or at least sense, the right action to take at any given moment; sometimes that action entails yielding leadership to another team member. So let’s break down this quote to identify the functional behavioral requirements of leadership.

Northouse presents the notion that leadership is a relationship or process of collaboration in which each team member is needed. The leader should be cognizant of each member’s interests, ideas, passions, attitudes, and motivations.¹

As a leader, you must reflect on all of your output. This includes how you relate to those you lead; how you collaborate with and affect the actions of your teammates; and how you communicate the process and influence a team toward a goal—which is crucial to the entire team’s success. Allow me to illustrate these core principles.

Relating
Early in the NP movement, it was necessary to develop a collective vision for the profession’s future. What was the purpose of an NP? What could we add to the existing health care landscape? The founders and early proponents of our profession, recognizing that there was power in numbers and strength in collaboration, identified a mission: Provide health care services for those who were underserved. Working as a group, NPs leveraged strength in numbers, creating a more efficient way to move forward and achieve that mission.² In those early NP pioneers, I recognize the leadership skills—ability to engage individuals and coordinate activities to move an agenda forward—that are key components of any relationship.

Collaborating
Later, in 1984, a small group of like-minded NPs (of which I was one) joined together to investigate the possibility of a starting an organization dedicated to NPs. As a profession, we were woefully underrepresented nationally. Our role was not fully understood, especially by legislators, and there were laws in place that impeded patients’ access to care by NPs. The existing nursing organizations were in no position to dedicate their resources to represent us professionally or politically.

Several colleagues and I were willing to take a risk to move our profession forward, even if it meant alienating other NPs. Each of us was able to work autonomously, as well as in a team, and we all viewed adversity as an opportunity. This gave us the impetus and motivation to carry out the footwork needed to achieve our goal. These skills—determination, energy, persistence—are essential for anyone looking to start a business or get involved in an organization.

Maybe when my colleagues and I formed the American Academy of Nurse Practitioners (AANP), we weren’t all leaders … but our relationship consisted of the passion and collective vision needed to work together and achieve. We knew we had to build on each other’s strengths and remain open and respectful of each other’s ideas. We believed we had nothing to lose and everything to gain and—honestly—we succeeded on all fronts!

Continue to: Influencing

Influencing
One success story happened in 1988 when Title VIII of the Public Health Service Act—the Nurse Education Act—was under review. New provisions in the bill included specific penalties for NPs and nurses if they defaulted on their student loans—penalties that did not apply to other health care professionals. My colleagues and I were outraged! Like many others, I had such a loan, which had allowed me to pursue my dream of becoming an NP.

The AANP got the word out, and we bombarded our legislators’ offices with calls and a threat to “march on Washington.” For my part, I personally spoke with Senator Edward “Ted” Kennedy and asked him if he realized the revisions made him look like a “loan shark.” I told him that NPs were in direct competition with physicians in settings identified as “loan repayments sites” and that physicians were more apt to be hired in these settings than NPs. I quickly offered up alternatives to increase the number of eligible sites where NPs could work for loan repayment, such as community health centers—a system for which he had secured funding decades earlier.

The end result of our influence? Community health centers throughout the country would be considered “loan repayment” sites, which helped to expand the opportunities for NPs to fulfill their financial obligations. If that doesn’t show you that being a leader requires you to challenge unfairness and identify solutions to correct inequity, I don’t know what does.

In a health care organization, we all have multiple roles that require us to be leaders. We are collaborators, providers of care, advocates for our patients, problem-solvers, and idealists. We are also role models for nascent health care providers. A leader’s responsibility spans the breadth of the organization, and today’s health care system continues to demand strong leaders capable of utilizing a variety of skills.

Next Thursday, I will continue my investigation of how to become an effective leader. In our fourth and final part of this series, we will discuss how acknowledging our specific personality traits can strengthen the efforts of a leader.

“Lead, follow, or get out of the way” sounds pejorative—even arrogant—but it ultimately speaks truth about most situations involving a team. A leader must know, or at least sense, the right action to take at any given moment; sometimes that action entails yielding leadership to another team member. So let’s break down this quote to identify the functional behavioral requirements of leadership.

Northouse presents the notion that leadership is a relationship or process of collaboration in which each team member is needed. The leader should be cognizant of each member’s interests, ideas, passions, attitudes, and motivations.¹

As a leader, you must reflect on all of your output. This includes how you relate to those you lead; how you collaborate with and affect the actions of your teammates; and how you communicate the process and influence a team toward a goal—which is crucial to the entire team’s success. Allow me to illustrate these core principles.

Relating
Early in the NP movement, it was necessary to develop a collective vision for the profession’s future. What was the purpose of an NP? What could we add to the existing health care landscape? The founders and early proponents of our profession, recognizing that there was power in numbers and strength in collaboration, identified a mission: Provide health care services for those who were underserved. Working as a group, NPs leveraged strength in numbers, creating a more efficient way to move forward and achieve that mission.² In those early NP pioneers, I recognize the leadership skills—ability to engage individuals and coordinate activities to move an agenda forward—that are key components of any relationship.

Collaborating
Later, in 1984, a small group of like-minded NPs (of which I was one) joined together to investigate the possibility of a starting an organization dedicated to NPs. As a profession, we were woefully underrepresented nationally. Our role was not fully understood, especially by legislators, and there were laws in place that impeded patients’ access to care by NPs. The existing nursing organizations were in no position to dedicate their resources to represent us professionally or politically.

Several colleagues and I were willing to take a risk to move our profession forward, even if it meant alienating other NPs. Each of us was able to work autonomously, as well as in a team, and we all viewed adversity as an opportunity. This gave us the impetus and motivation to carry out the footwork needed to achieve our goal. These skills—determination, energy, persistence—are essential for anyone looking to start a business or get involved in an organization.

Maybe when my colleagues and I formed the American Academy of Nurse Practitioners (AANP), we weren’t all leaders … but our relationship consisted of the passion and collective vision needed to work together and achieve. We knew we had to build on each other’s strengths and remain open and respectful of each other’s ideas. We believed we had nothing to lose and everything to gain and—honestly—we succeeded on all fronts!

Continue to: Influencing

Influencing
One success story happened in 1988 when Title VIII of the Public Health Service Act—the Nurse Education Act—was under review. New provisions in the bill included specific penalties for NPs and nurses if they defaulted on their student loans—penalties that did not apply to other health care professionals. My colleagues and I were outraged! Like many others, I had such a loan, which had allowed me to pursue my dream of becoming an NP.

The AANP got the word out, and we bombarded our legislators’ offices with calls and a threat to “march on Washington.” For my part, I personally spoke with Senator Edward “Ted” Kennedy and asked him if he realized the revisions made him look like a “loan shark.” I told him that NPs were in direct competition with physicians in settings identified as “loan repayments sites” and that physicians were more apt to be hired in these settings than NPs. I quickly offered up alternatives to increase the number of eligible sites where NPs could work for loan repayment, such as community health centers—a system for which he had secured funding decades earlier.

The end result of our influence? Community health centers throughout the country would be considered “loan repayment” sites, which helped to expand the opportunities for NPs to fulfill their financial obligations. If that doesn’t show you that being a leader requires you to challenge unfairness and identify solutions to correct inequity, I don’t know what does.

In a health care organization, we all have multiple roles that require us to be leaders. We are collaborators, providers of care, advocates for our patients, problem-solvers, and idealists. We are also role models for nascent health care providers. A leader’s responsibility spans the breadth of the organization, and today’s health care system continues to demand strong leaders capable of utilizing a variety of skills.

Next Thursday, I will continue my investigation of how to become an effective leader. In our fourth and final part of this series, we will discuss how acknowledging our specific personality traits can strengthen the efforts of a leader.

“Lead, follow, or get out of the way” sounds pejorative—even arrogant—but it ultimately speaks truth about most situations involving a team. A leader must know, or at least sense, the right action to take at any given moment; sometimes that action entails yielding leadership to another team member. So let’s break down this quote to identify the functional behavioral requirements of leadership.

Northouse presents the notion that leadership is a relationship or process of collaboration in which each team member is needed. The leader should be cognizant of each member’s interests, ideas, passions, attitudes, and motivations.¹

As a leader, you must reflect on all of your output. This includes how you relate to those you lead; how you collaborate with and affect the actions of your teammates; and how you communicate the process and influence a team toward a goal—which is crucial to the entire team’s success. Allow me to illustrate these core principles.

Relating
Early in the NP movement, it was necessary to develop a collective vision for the profession’s future. What was the purpose of an NP? What could we add to the existing health care landscape? The founders and early proponents of our profession, recognizing that there was power in numbers and strength in collaboration, identified a mission: Provide health care services for those who were underserved. Working as a group, NPs leveraged strength in numbers, creating a more efficient way to move forward and achieve that mission.² In those early NP pioneers, I recognize the leadership skills—ability to engage individuals and coordinate activities to move an agenda forward—that are key components of any relationship.

Collaborating
Later, in 1984, a small group of like-minded NPs (of which I was one) joined together to investigate the possibility of a starting an organization dedicated to NPs. As a profession, we were woefully underrepresented nationally. Our role was not fully understood, especially by legislators, and there were laws in place that impeded patients’ access to care by NPs. The existing nursing organizations were in no position to dedicate their resources to represent us professionally or politically.

Several colleagues and I were willing to take a risk to move our profession forward, even if it meant alienating other NPs. Each of us was able to work autonomously, as well as in a team, and we all viewed adversity as an opportunity. This gave us the impetus and motivation to carry out the footwork needed to achieve our goal. These skills—determination, energy, persistence—are essential for anyone looking to start a business or get involved in an organization.

Maybe when my colleagues and I formed the American Academy of Nurse Practitioners (AANP), we weren’t all leaders … but our relationship consisted of the passion and collective vision needed to work together and achieve. We knew we had to build on each other’s strengths and remain open and respectful of each other’s ideas. We believed we had nothing to lose and everything to gain and—honestly—we succeeded on all fronts!

Continue to: Influencing

Influencing
One success story happened in 1988 when Title VIII of the Public Health Service Act—the Nurse Education Act—was under review. New provisions in the bill included specific penalties for NPs and nurses if they defaulted on their student loans—penalties that did not apply to other health care professionals. My colleagues and I were outraged! Like many others, I had such a loan, which had allowed me to pursue my dream of becoming an NP.

The AANP got the word out, and we bombarded our legislators’ offices with calls and a threat to “march on Washington.” For my part, I personally spoke with Senator Edward “Ted” Kennedy and asked him if he realized the revisions made him look like a “loan shark.” I told him that NPs were in direct competition with physicians in settings identified as “loan repayments sites” and that physicians were more apt to be hired in these settings than NPs. I quickly offered up alternatives to increase the number of eligible sites where NPs could work for loan repayment, such as community health centers—a system for which he had secured funding decades earlier.

The end result of our influence? Community health centers throughout the country would be considered “loan repayment” sites, which helped to expand the opportunities for NPs to fulfill their financial obligations. If that doesn’t show you that being a leader requires you to challenge unfairness and identify solutions to correct inequity, I don’t know what does.

In a health care organization, we all have multiple roles that require us to be leaders. We are collaborators, providers of care, advocates for our patients, problem-solvers, and idealists. We are also role models for nascent health care providers. A leader’s responsibility spans the breadth of the organization, and today’s health care system continues to demand strong leaders capable of utilizing a variety of skills.

Next Thursday, I will continue my investigation of how to become an effective leader. In our fourth and final part of this series, we will discuss how acknowledging our specific personality traits can strengthen the efforts of a leader.

The Food and Drug Administration has granted the Breakthrough Device Designation to the Virtue sirolimus-eluting balloon (SEB) for below-the-knee peripheral arterial disease, according to a statement from Orchestra BioMed.

According to the FDA, this designation indicates that the Virtue SEB could provide a “more effective treatment option ... for a life-threatening or irreversibly debilitating disease”; as the release notes, below-the-knee atherosclerosis presents a high rate of amputation and poor survival outcomes but has limited treatment options. The designation leads to expedited development, assessment, and review.

Darren R. Sherman, president, CEO, and cofounder of Orchestra BioMed, noted that the Virtue SEB “has the potential to improve long-term outcomes and reduce periprocedural complications” that can “extend hospital stay and increase cost of treatment.” The system had previously received this designation for coronary in-stent restenosis based upon the 3-year results of the European SABRE trial.

cpalmer@mdedge.com

The Food and Drug Administration has granted the Breakthrough Device Designation to the Virtue sirolimus-eluting balloon (SEB) for below-the-knee peripheral arterial disease, according to a statement from Orchestra BioMed.

According to the FDA, this designation indicates that the Virtue SEB could provide a “more effective treatment option ... for a life-threatening or irreversibly debilitating disease”; as the release notes, below-the-knee atherosclerosis presents a high rate of amputation and poor survival outcomes but has limited treatment options. The designation leads to expedited development, assessment, and review.

Darren R. Sherman, president, CEO, and cofounder of Orchestra BioMed, noted that the Virtue SEB “has the potential to improve long-term outcomes and reduce periprocedural complications” that can “extend hospital stay and increase cost of treatment.” The system had previously received this designation for coronary in-stent restenosis based upon the 3-year results of the European SABRE trial.

cpalmer@mdedge.com

The Food and Drug Administration has granted the Breakthrough Device Designation to the Virtue sirolimus-eluting balloon (SEB) for below-the-knee peripheral arterial disease, according to a statement from Orchestra BioMed.

According to the FDA, this designation indicates that the Virtue SEB could provide a “more effective treatment option ... for a life-threatening or irreversibly debilitating disease”; as the release notes, below-the-knee atherosclerosis presents a high rate of amputation and poor survival outcomes but has limited treatment options. The designation leads to expedited development, assessment, and review.

Darren R. Sherman, president, CEO, and cofounder of Orchestra BioMed, noted that the Virtue SEB “has the potential to improve long-term outcomes and reduce periprocedural complications” that can “extend hospital stay and increase cost of treatment.” The system had previously received this designation for coronary in-stent restenosis based upon the 3-year results of the European SABRE trial.

cpalmer@mdedge.com

Three major indicators of rheumatoid arthritis burden in the United States all increased more rapidly than did global averages from 1990 to 2017, according to a new analysis of RA activity in 195 countries.

Percentage changes in the incidence, prevalence, and disability-adjusted life-year (DALY) rates for RA all reached double digits in the United States over the study period, but global increases for those measures stayed in the single digits, except for DALY, which did not increase, Saeid Safiri, PhD, of Tabriz (Iran) University of Medical Sciences and associates wrote in Annals of the Rheumatic Diseases.

Data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 show that RA incidence in the United States had the largest increase (20.7%) among the three measures, rising from 19.3 cases per 100,000 population in 1990 to 23.4 in 2017. Overall incidence for the 195 countries included in the study went from 13.7 to 14.9 cases per 100,000, for an increase of 8.2%, the investigators reported.

That pattern largely repeats for prevalence: an increase of 17.5% in the United States as the number of cases went from 336.5 per 100,000 in 1990 to 395.5 in 2017, and an increase of 7.4% globally, with the number of prevalent cases rising from 229.6 to 246.5 per 100,000, they said.

The DALY numbers – think of each DALY as 1 lost year of “healthy” life, the World Health Organization says – tell a somewhat different story. The United States had DALY rate of 53.2 per 100,000 in 1990, but by 2017 it had climbed to 60 per 100,000, an increase of 12.8%. Over that same time period, the global rate fell by 3.6% as it went from 44.9 to 43.3, Dr. Safiri and associates reported.

That long-term decline does, however, disguise a more recent trend. The global DALY rate “decreased from 1990 to 2012 but then increased and reached higher than expected levels in the following 5 years to 2017,” they wrote.

RA rates in the United States in 2017 were, as noted, above average, but they were not the highest. The United Kingdom achieved the RA trifecta of highest incidence (27.5 per 100,000), highest prevalence (471.8 per 100,000), and highest DALY rate (73 per 100,000) among the 195 countries in the study. At the other end of the three scales, Indonesia had the lowest incidence (5.6 per 100,000) and prevalence (91.1 per 100,000), and Sri Lanka had the lowest DALY rate (14.2 per 100,000), they said.

“Age-standardized prevalence and incidence rates are overall increasing globally. Increasing population awareness regarding RA, its risk factors and the importance of early diagnosis and treatment with disease-modifying agents is warranted to reduce the future burden of this condition,” the research team concluded.

GBD is funded by the Bill and Melinda Gates Foundation. The current analysis also was supported by Social Determinants of Health Research Center, Shahid Beheshti University of Medical Sciences in Tehran, Iran. The investigators did not declare any conflicts of interest.

rfranki@mdedge.com

SOURCE: Safiri S et al. Ann Rheum Dis. 2019 Sep 11. doi: 10.1136/annrheumdis-2019-215920.

Three major indicators of rheumatoid arthritis burden in the United States all increased more rapidly than did global averages from 1990 to 2017, according to a new analysis of RA activity in 195 countries.

Percentage changes in the incidence, prevalence, and disability-adjusted life-year (DALY) rates for RA all reached double digits in the United States over the study period, but global increases for those measures stayed in the single digits, except for DALY, which did not increase, Saeid Safiri, PhD, of Tabriz (Iran) University of Medical Sciences and associates wrote in Annals of the Rheumatic Diseases.

Data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 show that RA incidence in the United States had the largest increase (20.7%) among the three measures, rising from 19.3 cases per 100,000 population in 1990 to 23.4 in 2017. Overall incidence for the 195 countries included in the study went from 13.7 to 14.9 cases per 100,000, for an increase of 8.2%, the investigators reported.

That pattern largely repeats for prevalence: an increase of 17.5% in the United States as the number of cases went from 336.5 per 100,000 in 1990 to 395.5 in 2017, and an increase of 7.4% globally, with the number of prevalent cases rising from 229.6 to 246.5 per 100,000, they said.

The DALY numbers – think of each DALY as 1 lost year of “healthy” life, the World Health Organization says – tell a somewhat different story. The United States had DALY rate of 53.2 per 100,000 in 1990, but by 2017 it had climbed to 60 per 100,000, an increase of 12.8%. Over that same time period, the global rate fell by 3.6% as it went from 44.9 to 43.3, Dr. Safiri and associates reported.

That long-term decline does, however, disguise a more recent trend. The global DALY rate “decreased from 1990 to 2012 but then increased and reached higher than expected levels in the following 5 years to 2017,” they wrote.

RA rates in the United States in 2017 were, as noted, above average, but they were not the highest. The United Kingdom achieved the RA trifecta of highest incidence (27.5 per 100,000), highest prevalence (471.8 per 100,000), and highest DALY rate (73 per 100,000) among the 195 countries in the study. At the other end of the three scales, Indonesia had the lowest incidence (5.6 per 100,000) and prevalence (91.1 per 100,000), and Sri Lanka had the lowest DALY rate (14.2 per 100,000), they said.

“Age-standardized prevalence and incidence rates are overall increasing globally. Increasing population awareness regarding RA, its risk factors and the importance of early diagnosis and treatment with disease-modifying agents is warranted to reduce the future burden of this condition,” the research team concluded.

GBD is funded by the Bill and Melinda Gates Foundation. The current analysis also was supported by Social Determinants of Health Research Center, Shahid Beheshti University of Medical Sciences in Tehran, Iran. The investigators did not declare any conflicts of interest.

rfranki@mdedge.com

SOURCE: Safiri S et al. Ann Rheum Dis. 2019 Sep 11. doi: 10.1136/annrheumdis-2019-215920.

Three major indicators of rheumatoid arthritis burden in the United States all increased more rapidly than did global averages from 1990 to 2017, according to a new analysis of RA activity in 195 countries.

Percentage changes in the incidence, prevalence, and disability-adjusted life-year (DALY) rates for RA all reached double digits in the United States over the study period, but global increases for those measures stayed in the single digits, except for DALY, which did not increase, Saeid Safiri, PhD, of Tabriz (Iran) University of Medical Sciences and associates wrote in Annals of the Rheumatic Diseases.

Data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 show that RA incidence in the United States had the largest increase (20.7%) among the three measures, rising from 19.3 cases per 100,000 population in 1990 to 23.4 in 2017. Overall incidence for the 195 countries included in the study went from 13.7 to 14.9 cases per 100,000, for an increase of 8.2%, the investigators reported.

That pattern largely repeats for prevalence: an increase of 17.5% in the United States as the number of cases went from 336.5 per 100,000 in 1990 to 395.5 in 2017, and an increase of 7.4% globally, with the number of prevalent cases rising from 229.6 to 246.5 per 100,000, they said.

The DALY numbers – think of each DALY as 1 lost year of “healthy” life, the World Health Organization says – tell a somewhat different story. The United States had DALY rate of 53.2 per 100,000 in 1990, but by 2017 it had climbed to 60 per 100,000, an increase of 12.8%. Over that same time period, the global rate fell by 3.6% as it went from 44.9 to 43.3, Dr. Safiri and associates reported.

That long-term decline does, however, disguise a more recent trend. The global DALY rate “decreased from 1990 to 2012 but then increased and reached higher than expected levels in the following 5 years to 2017,” they wrote.

RA rates in the United States in 2017 were, as noted, above average, but they were not the highest. The United Kingdom achieved the RA trifecta of highest incidence (27.5 per 100,000), highest prevalence (471.8 per 100,000), and highest DALY rate (73 per 100,000) among the 195 countries in the study. At the other end of the three scales, Indonesia had the lowest incidence (5.6 per 100,000) and prevalence (91.1 per 100,000), and Sri Lanka had the lowest DALY rate (14.2 per 100,000), they said.

“Age-standardized prevalence and incidence rates are overall increasing globally. Increasing population awareness regarding RA, its risk factors and the importance of early diagnosis and treatment with disease-modifying agents is warranted to reduce the future burden of this condition,” the research team concluded.

GBD is funded by the Bill and Melinda Gates Foundation. The current analysis also was supported by Social Determinants of Health Research Center, Shahid Beheshti University of Medical Sciences in Tehran, Iran. The investigators did not declare any conflicts of interest.

rfranki@mdedge.com

SOURCE: Safiri S et al. Ann Rheum Dis. 2019 Sep 11. doi: 10.1136/annrheumdis-2019-215920.

The Food and Drug Administration has granted accelerated approval to a pembrolizumab (Keytruda) plus lenvatinib (Lenvima) combination for the treatment of patients with advanced endometrial carcinoma that is not microsatellite instability high or mismatch repair deficient, and who have disease progression following prior systemic therapy but are not candidates for curative surgery or radiation.

Olivier Le Moal/Getty Images

The approval was based on results of KEYNOTE-146, a single-arm, multicenter, open-label, multicohort trial with 108 patients with metastatic endometrial carcinoma; 94 of these were not microsatellite instability high or mismatch repair deficient. The objective response rate in those 94 patients was 38.3% (95% confidence interval, 29%-49%), with 10 complete responses and 26 partial responses. The median duration of response was not reached over the trial period, and 69% of those who responded had a response duration of at least 6 months.

The most common adverse events reported during the trial were fatigue, hypertension, musculoskeletal pain, diarrhea, decreased appetite, hypothyroidism, nausea, stomatitis, vomiting, decreased weight, abdominal pain, headache, constipation, urinary tract infection, dysphonia, hemorrhagic events, hypomagnesemia, palmar-plantar erythrodysesthesia, dyspnea, cough, and rash.

The recommended dosage is lenvatinib 20 mg orally once daily with pembrolizumab 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks, according to the FDA.

lfranki@mdedge.com

The Food and Drug Administration has granted accelerated approval to a pembrolizumab (Keytruda) plus lenvatinib (Lenvima) combination for the treatment of patients with advanced endometrial carcinoma that is not microsatellite instability high or mismatch repair deficient, and who have disease progression following prior systemic therapy but are not candidates for curative surgery or radiation.

Olivier Le Moal/Getty Images

The approval was based on results of KEYNOTE-146, a single-arm, multicenter, open-label, multicohort trial with 108 patients with metastatic endometrial carcinoma; 94 of these were not microsatellite instability high or mismatch repair deficient. The objective response rate in those 94 patients was 38.3% (95% confidence interval, 29%-49%), with 10 complete responses and 26 partial responses. The median duration of response was not reached over the trial period, and 69% of those who responded had a response duration of at least 6 months.

The most common adverse events reported during the trial were fatigue, hypertension, musculoskeletal pain, diarrhea, decreased appetite, hypothyroidism, nausea, stomatitis, vomiting, decreased weight, abdominal pain, headache, constipation, urinary tract infection, dysphonia, hemorrhagic events, hypomagnesemia, palmar-plantar erythrodysesthesia, dyspnea, cough, and rash.

The recommended dosage is lenvatinib 20 mg orally once daily with pembrolizumab 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks, according to the FDA.

lfranki@mdedge.com

The Food and Drug Administration has granted accelerated approval to a pembrolizumab (Keytruda) plus lenvatinib (Lenvima) combination for the treatment of patients with advanced endometrial carcinoma that is not microsatellite instability high or mismatch repair deficient, and who have disease progression following prior systemic therapy but are not candidates for curative surgery or radiation.

Olivier Le Moal/Getty Images

The approval was based on results of KEYNOTE-146, a single-arm, multicenter, open-label, multicohort trial with 108 patients with metastatic endometrial carcinoma; 94 of these were not microsatellite instability high or mismatch repair deficient. The objective response rate in those 94 patients was 38.3% (95% confidence interval, 29%-49%), with 10 complete responses and 26 partial responses. The median duration of response was not reached over the trial period, and 69% of those who responded had a response duration of at least 6 months.

The most common adverse events reported during the trial were fatigue, hypertension, musculoskeletal pain, diarrhea, decreased appetite, hypothyroidism, nausea, stomatitis, vomiting, decreased weight, abdominal pain, headache, constipation, urinary tract infection, dysphonia, hemorrhagic events, hypomagnesemia, palmar-plantar erythrodysesthesia, dyspnea, cough, and rash.

The recommended dosage is lenvatinib 20 mg orally once daily with pembrolizumab 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks, according to the FDA.

lfranki@mdedge.com

PARIS – Rivaroxaban monotherapy bested combination therapy with rivaroxaban and an antiplatelet agent for patients with atrial fibrillation and stable coronary artery disease, with significantly more deaths and bleeding events seen with combination therapy.

Catherine Hackett/MDedge News

The pronounced imbalance in all-cause and cardiovascular mortality (the hazard ratio favoring rivaroxaban monotherapy was 9.72) came as a surprise, and led to early cessation of the multisite Japanese trial, lead investigator Satoshi Yasuda, MD, said at the annual congress of the European Society of Cardiology.

Several previous clinical trials had studied a reduced antithrombotic regimen for patients with atrial fibrillation (AFib) after percutaneous coronary intervention (PCI), said Dr. Yasuda, professor of medicine at Tohoku University, Sendai, Japan. Current guidelines recommend triple therapy with an oral anticoagulant plus aspirin and a P2Y12 inhibitor for the shortest duration possible, with combination therapy of an anticoagulant plus a P2Y12 inhibitor for up to 12 months. Once the 1-year post-PCI mark is reached, current European and American guidelines or consensus documents recommend monotherapy with an oral anticoagulant if AFib persists and the patient has stable coronary artery disease (CAD), explained Dr. Yasuda. “However, this approach has yet to be supported by evidence from randomized, controlled trials,” he said, adding “substantial numbers of patients in this situation continue to be treated with combination therapy, which indicates a gap between guidelines and clinical practice.”

The Atrial Fibrillation and Ischemic events with Rivaroxaban in Patients With Stable Coronary Artery Disease Study (AFIRE), he said, was designed to address this practice gap, randomizing 2,200 individuals to receive monotherapy with rivaroxaban or combination therapy. A total of 1,973 patients completed follow-up.

Patients were included in the randomized, open-label, parallel-group trial if they had AFib and stable CAD and were more than 1 year out from revascularization, or if they had angiographically confirmed CAD that did not need revascularization. All 294 AFIRE study sites were in Japan.

The study’s primary endpoint for efficacy was a composite of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularization, and all-cause death.

Most of the patients (79%) were male, and the mean age was 74 years. About 70% of patients in each treatment arm had received prior PCI, and 11% had undergone previous coronary artery bypass grafting (CABG).

The monotherapy arm received rivaroxaban 10 or 15 mg once daily depending on renal status. Patients in the combination therapy arm received rivaroxaban, plus a single antiplatelet drug. This could be 81 or 100 mg aspirin daily, clopidogrel at 50 or 75 mg/day, or prasugrel at 2.5 or 3.5 mg/day.

On the recommendation of the data and safety monitoring committee, the trial was terminated about 3 months early because significantly more all-cause deaths were being seen in the combination therapy group, said Dr. Yasuda. In the end, patients were treated under the study protocol for a median 23 months and followed up for a median 24.1 months.

Kaplan-Meier estimates for the first occurrence of the composite efficacy endpoint showed that monotherapy had a rate of 4.14% per patient-year, while combination therapy had a rate of occurrence for the efficacy endpoint of 5.75% per patient-year.

These figures yielded a statistically significant hazard ratio (HR) of 9.72 favoring monotherapy (P less than .001) for the prespecified noninferiority endpoint. In a post hoc analysis, rivaroxaban monotherapy achieved superiority over dual therapy (P = .02).

Breaking down the composite efficacy endpoint into its constituents, deaths by any cause and cardiovascular deaths primarily drove the difference in treatment arms. Seventy-three patients in the combo therapy arm and 41 in the rivaroxaban arm died of any cause, and the cause of death was cardiovascular for 43 combination therapy patients and 26 monotherapy patients. This yielded HRs favoring rivaroxaban of 0.55 for all-cause mortality and 0.59 for cardiovascular deaths.

Hazard ratios for individual cardiovascular events were not statistically significantly different between treatment arms, except for hemorrhagic stroke, which was seen in 13 patients receiving dual therapy and 4 receiving rivaroxaban alone, for a hazard ratio of 0.30.

Rivaroxaban monotherapy also bested dual therapy in safety: The HR was 0.59 for the incidence of a major bleed on rivaroxaban versus combination therapy, using International Society on Thrombosis and Haemostasis–established criteria for major bleeding. In the dual therapy arm, 58 individuals experienced major bleeding – the study’s primary safety endpoint – compared with 35 in the monotherapy arm, for a hazard ratio of 0.59; nonmajor bleeding occurred in 198 dual therapy patients and 121 monotherapy patients, yielding a hazard ratio of 0.58.

The Kaplan-Meier estimate for major bleeding on monotherapy was 1.62% per patient-year, compared with 2.76% per patient-year for those on combination therapy. These findings, said Dr. Yasuda, were “generally” consistent across prespecified subgroups that included participant stratification by age, sex, and bleeding risk, among others.

Dr. Yasuda acknowledged the many limitations of the trial. First, early termination introduced the possibility of overestimating the benefit of rivaroxaban monotherapy. Indeed, said Dr. Yasuda, “the reductions in rate of ischemic events and death from any cause with rivaroxaban monotherapy were unanticipated and are difficult to explain.”

Furthermore, the open-label trial design could be a source of bias and the use of both aspirin and P2Y12 inhibitors for antiplatelet therapy “makes it uncertain whether the benefit of rivaroxaban monotherapy applies equally to the two combination regimens,” said Dr. Yasuda.

Rivaroxaban dosing in AFIRE was tailored to the Japanese study population, noted Dr. Yasuda. This means that the study is not immediately generalizable to non-Asian populations, needing replication before fully closing the knowledge gap about best long-term management of patients with AFib and stable CAD in the United States and Western Europe.

However, Dr. Yasuda pointed out, serum rivaroxaban levels in Japanese patients taking the 10- or 15-mg dose are generally similar to those seen in white patients taking a 20-mg rivaroxaban dose.

Freek Verheugt, MD, of Onze Lieve Vrouwe Gasthuis Hospital, Amsterdam, was the discussant for the presentation. He raised an additional concern: “East Asian patients are poor metabolizers of clopidogrel, which may have resulted also in underestimation of bleeding.” He cautioned that the AFIRE results may not be applicable to patients on a novel anticoagulant other than clopidogrel, or on vitamin K antagonists.

In his detailed critique of the AFIRE results, Dr. Verheugt cited the OAC ALONE trial, which used a similar study design and was also conducted in Japan. For OAC ALONE, Dr. Verheugt pointed out that “You can see ... that it was not harmful in this 700-patient study to stop aspirin therapy 1 year after an intervention.” However, he said, “the net clinical benefit is not very different, either” between treatment arms in the OAC ALONE trial. “Given the low number of patients and the low number of events, this trial was not conclusive whatsoever” he added, so AFIRE’s findings were needed.

The safety data from AFIRE, with a study population triple that of OAC ALONE, makes the safety argument for monotherapy “a very easy winner,” said Dr. Verheugt.

Dr. Verheugt was not mystified by the lower all-cause and cardiovascular death rate in the monotherapy group. “What are the mechanisms that if you stop antiplatelet therapy you have a better ischemic outcome? How come?” asked Dr. Verheugt.

“Very likely, it is the bleeding ... that you prevent if you stop antiplatelet therapy,” he said, adding that it’s known from previous studies in individuals with acute coronary syndromes and AFib that “bleeding is correlated with mortality, and that’s also proven here.”

Though Dr. Verheugt joined Dr. Yasuda in calling for replication of the results in a non-Asian population, he concurred that the AFIRE results validate current practice for anticoagulation in AFib with stable CAD. “Stopping at 1 year is safer than continuation and, most of all, it saves lives,” he said.

Full results of AFIRE were published online at the time of Dr. Yasuda’s presentation (N Engl J Med. 2019 Sep 2. doi: 10.1056/NEJMoa1904143).

The study was funded by the Japanese Cardiovascular Research Foundation. Dr. Yasuda reported financial relationships with Abbott, Bristol-Myers, Daiichi-Sankyo, and Takeda. Dr. Verheugt reported financial relationships with BayerHealthcare, BMS/Pfizer, Boehringer-Ingelheim, and Daiichi-Sankyo.

koakes@mdedge.com

SOURCE: Yasuda S. et al. ESC 2019, Hot Line Session 3, Abstract 3175.

PARIS – Rivaroxaban monotherapy bested combination therapy with rivaroxaban and an antiplatelet agent for patients with atrial fibrillation and stable coronary artery disease, with significantly more deaths and bleeding events seen with combination therapy.

Catherine Hackett/MDedge News

The pronounced imbalance in all-cause and cardiovascular mortality (the hazard ratio favoring rivaroxaban monotherapy was 9.72) came as a surprise, and led to early cessation of the multisite Japanese trial, lead investigator Satoshi Yasuda, MD, said at the annual congress of the European Society of Cardiology.

Several previous clinical trials had studied a reduced antithrombotic regimen for patients with atrial fibrillation (AFib) after percutaneous coronary intervention (PCI), said Dr. Yasuda, professor of medicine at Tohoku University, Sendai, Japan. Current guidelines recommend triple therapy with an oral anticoagulant plus aspirin and a P2Y12 inhibitor for the shortest duration possible, with combination therapy of an anticoagulant plus a P2Y12 inhibitor for up to 12 months. Once the 1-year post-PCI mark is reached, current European and American guidelines or consensus documents recommend monotherapy with an oral anticoagulant if AFib persists and the patient has stable coronary artery disease (CAD), explained Dr. Yasuda. “However, this approach has yet to be supported by evidence from randomized, controlled trials,” he said, adding “substantial numbers of patients in this situation continue to be treated with combination therapy, which indicates a gap between guidelines and clinical practice.”

The Atrial Fibrillation and Ischemic events with Rivaroxaban in Patients With Stable Coronary Artery Disease Study (AFIRE), he said, was designed to address this practice gap, randomizing 2,200 individuals to receive monotherapy with rivaroxaban or combination therapy. A total of 1,973 patients completed follow-up.

Patients were included in the randomized, open-label, parallel-group trial if they had AFib and stable CAD and were more than 1 year out from revascularization, or if they had angiographically confirmed CAD that did not need revascularization. All 294 AFIRE study sites were in Japan.

The study’s primary endpoint for efficacy was a composite of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularization, and all-cause death.

Most of the patients (79%) were male, and the mean age was 74 years. About 70% of patients in each treatment arm had received prior PCI, and 11% had undergone previous coronary artery bypass grafting (CABG).

The monotherapy arm received rivaroxaban 10 or 15 mg once daily depending on renal status. Patients in the combination therapy arm received rivaroxaban, plus a single antiplatelet drug. This could be 81 or 100 mg aspirin daily, clopidogrel at 50 or 75 mg/day, or prasugrel at 2.5 or 3.5 mg/day.

On the recommendation of the data and safety monitoring committee, the trial was terminated about 3 months early because significantly more all-cause deaths were being seen in the combination therapy group, said Dr. Yasuda. In the end, patients were treated under the study protocol for a median 23 months and followed up for a median 24.1 months.

Kaplan-Meier estimates for the first occurrence of the composite efficacy endpoint showed that monotherapy had a rate of 4.14% per patient-year, while combination therapy had a rate of occurrence for the efficacy endpoint of 5.75% per patient-year.

These figures yielded a statistically significant hazard ratio (HR) of 9.72 favoring monotherapy (P less than .001) for the prespecified noninferiority endpoint. In a post hoc analysis, rivaroxaban monotherapy achieved superiority over dual therapy (P = .02).

Breaking down the composite efficacy endpoint into its constituents, deaths by any cause and cardiovascular deaths primarily drove the difference in treatment arms. Seventy-three patients in the combo therapy arm and 41 in the rivaroxaban arm died of any cause, and the cause of death was cardiovascular for 43 combination therapy patients and 26 monotherapy patients. This yielded HRs favoring rivaroxaban of 0.55 for all-cause mortality and 0.59 for cardiovascular deaths.

Hazard ratios for individual cardiovascular events were not statistically significantly different between treatment arms, except for hemorrhagic stroke, which was seen in 13 patients receiving dual therapy and 4 receiving rivaroxaban alone, for a hazard ratio of 0.30.

Rivaroxaban monotherapy also bested dual therapy in safety: The HR was 0.59 for the incidence of a major bleed on rivaroxaban versus combination therapy, using International Society on Thrombosis and Haemostasis–established criteria for major bleeding. In the dual therapy arm, 58 individuals experienced major bleeding – the study’s primary safety endpoint – compared with 35 in the monotherapy arm, for a hazard ratio of 0.59; nonmajor bleeding occurred in 198 dual therapy patients and 121 monotherapy patients, yielding a hazard ratio of 0.58.

The Kaplan-Meier estimate for major bleeding on monotherapy was 1.62% per patient-year, compared with 2.76% per patient-year for those on combination therapy. These findings, said Dr. Yasuda, were “generally” consistent across prespecified subgroups that included participant stratification by age, sex, and bleeding risk, among others.

Dr. Yasuda acknowledged the many limitations of the trial. First, early termination introduced the possibility of overestimating the benefit of rivaroxaban monotherapy. Indeed, said Dr. Yasuda, “the reductions in rate of ischemic events and death from any cause with rivaroxaban monotherapy were unanticipated and are difficult to explain.”

Furthermore, the open-label trial design could be a source of bias and the use of both aspirin and P2Y12 inhibitors for antiplatelet therapy “makes it uncertain whether the benefit of rivaroxaban monotherapy applies equally to the two combination regimens,” said Dr. Yasuda.

Rivaroxaban dosing in AFIRE was tailored to the Japanese study population, noted Dr. Yasuda. This means that the study is not immediately generalizable to non-Asian populations, needing replication before fully closing the knowledge gap about best long-term management of patients with AFib and stable CAD in the United States and Western Europe.

However, Dr. Yasuda pointed out, serum rivaroxaban levels in Japanese patients taking the 10- or 15-mg dose are generally similar to those seen in white patients taking a 20-mg rivaroxaban dose.

Freek Verheugt, MD, of Onze Lieve Vrouwe Gasthuis Hospital, Amsterdam, was the discussant for the presentation. He raised an additional concern: “East Asian patients are poor metabolizers of clopidogrel, which may have resulted also in underestimation of bleeding.” He cautioned that the AFIRE results may not be applicable to patients on a novel anticoagulant other than clopidogrel, or on vitamin K antagonists.

In his detailed critique of the AFIRE results, Dr. Verheugt cited the OAC ALONE trial, which used a similar study design and was also conducted in Japan. For OAC ALONE, Dr. Verheugt pointed out that “You can see ... that it was not harmful in this 700-patient study to stop aspirin therapy 1 year after an intervention.” However, he said, “the net clinical benefit is not very different, either” between treatment arms in the OAC ALONE trial. “Given the low number of patients and the low number of events, this trial was not conclusive whatsoever” he added, so AFIRE’s findings were needed.

The safety data from AFIRE, with a study population triple that of OAC ALONE, makes the safety argument for monotherapy “a very easy winner,” said Dr. Verheugt.

Dr. Verheugt was not mystified by the lower all-cause and cardiovascular death rate in the monotherapy group. “What are the mechanisms that if you stop antiplatelet therapy you have a better ischemic outcome? How come?” asked Dr. Verheugt.

“Very likely, it is the bleeding ... that you prevent if you stop antiplatelet therapy,” he said, adding that it’s known from previous studies in individuals with acute coronary syndromes and AFib that “bleeding is correlated with mortality, and that’s also proven here.”

Though Dr. Verheugt joined Dr. Yasuda in calling for replication of the results in a non-Asian population, he concurred that the AFIRE results validate current practice for anticoagulation in AFib with stable CAD. “Stopping at 1 year is safer than continuation and, most of all, it saves lives,” he said.

Full results of AFIRE were published online at the time of Dr. Yasuda’s presentation (N Engl J Med. 2019 Sep 2. doi: 10.1056/NEJMoa1904143).

The study was funded by the Japanese Cardiovascular Research Foundation. Dr. Yasuda reported financial relationships with Abbott, Bristol-Myers, Daiichi-Sankyo, and Takeda. Dr. Verheugt reported financial relationships with BayerHealthcare, BMS/Pfizer, Boehringer-Ingelheim, and Daiichi-Sankyo.

koakes@mdedge.com

SOURCE: Yasuda S. et al. ESC 2019, Hot Line Session 3, Abstract 3175.

PARIS – Rivaroxaban monotherapy bested combination therapy with rivaroxaban and an antiplatelet agent for patients with atrial fibrillation and stable coronary artery disease, with significantly more deaths and bleeding events seen with combination therapy.

Catherine Hackett/MDedge News

The pronounced imbalance in all-cause and cardiovascular mortality (the hazard ratio favoring rivaroxaban monotherapy was 9.72) came as a surprise, and led to early cessation of the multisite Japanese trial, lead investigator Satoshi Yasuda, MD, said at the annual congress of the European Society of Cardiology.

Several previous clinical trials had studied a reduced antithrombotic regimen for patients with atrial fibrillation (AFib) after percutaneous coronary intervention (PCI), said Dr. Yasuda, professor of medicine at Tohoku University, Sendai, Japan. Current guidelines recommend triple therapy with an oral anticoagulant plus aspirin and a P2Y12 inhibitor for the shortest duration possible, with combination therapy of an anticoagulant plus a P2Y12 inhibitor for up to 12 months. Once the 1-year post-PCI mark is reached, current European and American guidelines or consensus documents recommend monotherapy with an oral anticoagulant if AFib persists and the patient has stable coronary artery disease (CAD), explained Dr. Yasuda. “However, this approach has yet to be supported by evidence from randomized, controlled trials,” he said, adding “substantial numbers of patients in this situation continue to be treated with combination therapy, which indicates a gap between guidelines and clinical practice.”

The Atrial Fibrillation and Ischemic events with Rivaroxaban in Patients With Stable Coronary Artery Disease Study (AFIRE), he said, was designed to address this practice gap, randomizing 2,200 individuals to receive monotherapy with rivaroxaban or combination therapy. A total of 1,973 patients completed follow-up.

Patients were included in the randomized, open-label, parallel-group trial if they had AFib and stable CAD and were more than 1 year out from revascularization, or if they had angiographically confirmed CAD that did not need revascularization. All 294 AFIRE study sites were in Japan.

The study’s primary endpoint for efficacy was a composite of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularization, and all-cause death.

Most of the patients (79%) were male, and the mean age was 74 years. About 70% of patients in each treatment arm had received prior PCI, and 11% had undergone previous coronary artery bypass grafting (CABG).

The monotherapy arm received rivaroxaban 10 or 15 mg once daily depending on renal status. Patients in the combination therapy arm received rivaroxaban, plus a single antiplatelet drug. This could be 81 or 100 mg aspirin daily, clopidogrel at 50 or 75 mg/day, or prasugrel at 2.5 or 3.5 mg/day.

On the recommendation of the data and safety monitoring committee, the trial was terminated about 3 months early because significantly more all-cause deaths were being seen in the combination therapy group, said Dr. Yasuda. In the end, patients were treated under the study protocol for a median 23 months and followed up for a median 24.1 months.

Kaplan-Meier estimates for the first occurrence of the composite efficacy endpoint showed that monotherapy had a rate of 4.14% per patient-year, while combination therapy had a rate of occurrence for the efficacy endpoint of 5.75% per patient-year.

These figures yielded a statistically significant hazard ratio (HR) of 9.72 favoring monotherapy (P less than .001) for the prespecified noninferiority endpoint. In a post hoc analysis, rivaroxaban monotherapy achieved superiority over dual therapy (P = .02).

Breaking down the composite efficacy endpoint into its constituents, deaths by any cause and cardiovascular deaths primarily drove the difference in treatment arms. Seventy-three patients in the combo therapy arm and 41 in the rivaroxaban arm died of any cause, and the cause of death was cardiovascular for 43 combination therapy patients and 26 monotherapy patients. This yielded HRs favoring rivaroxaban of 0.55 for all-cause mortality and 0.59 for cardiovascular deaths.

Hazard ratios for individual cardiovascular events were not statistically significantly different between treatment arms, except for hemorrhagic stroke, which was seen in 13 patients receiving dual therapy and 4 receiving rivaroxaban alone, for a hazard ratio of 0.30.

Rivaroxaban monotherapy also bested dual therapy in safety: The HR was 0.59 for the incidence of a major bleed on rivaroxaban versus combination therapy, using International Society on Thrombosis and Haemostasis–established criteria for major bleeding. In the dual therapy arm, 58 individuals experienced major bleeding – the study’s primary safety endpoint – compared with 35 in the monotherapy arm, for a hazard ratio of 0.59; nonmajor bleeding occurred in 198 dual therapy patients and 121 monotherapy patients, yielding a hazard ratio of 0.58.

The Kaplan-Meier estimate for major bleeding on monotherapy was 1.62% per patient-year, compared with 2.76% per patient-year for those on combination therapy. These findings, said Dr. Yasuda, were “generally” consistent across prespecified subgroups that included participant stratification by age, sex, and bleeding risk, among others.

Dr. Yasuda acknowledged the many limitations of the trial. First, early termination introduced the possibility of overestimating the benefit of rivaroxaban monotherapy. Indeed, said Dr. Yasuda, “the reductions in rate of ischemic events and death from any cause with rivaroxaban monotherapy were unanticipated and are difficult to explain.”

Furthermore, the open-label trial design could be a source of bias and the use of both aspirin and P2Y12 inhibitors for antiplatelet therapy “makes it uncertain whether the benefit of rivaroxaban monotherapy applies equally to the two combination regimens,” said Dr. Yasuda.

Rivaroxaban dosing in AFIRE was tailored to the Japanese study population, noted Dr. Yasuda. This means that the study is not immediately generalizable to non-Asian populations, needing replication before fully closing the knowledge gap about best long-term management of patients with AFib and stable CAD in the United States and Western Europe.

However, Dr. Yasuda pointed out, serum rivaroxaban levels in Japanese patients taking the 10- or 15-mg dose are generally similar to those seen in white patients taking a 20-mg rivaroxaban dose.

Freek Verheugt, MD, of Onze Lieve Vrouwe Gasthuis Hospital, Amsterdam, was the discussant for the presentation. He raised an additional concern: “East Asian patients are poor metabolizers of clopidogrel, which may have resulted also in underestimation of bleeding.” He cautioned that the AFIRE results may not be applicable to patients on a novel anticoagulant other than clopidogrel, or on vitamin K antagonists.

In his detailed critique of the AFIRE results, Dr. Verheugt cited the OAC ALONE trial, which used a similar study design and was also conducted in Japan. For OAC ALONE, Dr. Verheugt pointed out that “You can see ... that it was not harmful in this 700-patient study to stop aspirin therapy 1 year after an intervention.” However, he said, “the net clinical benefit is not very different, either” between treatment arms in the OAC ALONE trial. “Given the low number of patients and the low number of events, this trial was not conclusive whatsoever” he added, so AFIRE’s findings were needed.

The safety data from AFIRE, with a study population triple that of OAC ALONE, makes the safety argument for monotherapy “a very easy winner,” said Dr. Verheugt.

Dr. Verheugt was not mystified by the lower all-cause and cardiovascular death rate in the monotherapy group. “What are the mechanisms that if you stop antiplatelet therapy you have a better ischemic outcome? How come?” asked Dr. Verheugt.

“Very likely, it is the bleeding ... that you prevent if you stop antiplatelet therapy,” he said, adding that it’s known from previous studies in individuals with acute coronary syndromes and AFib that “bleeding is correlated with mortality, and that’s also proven here.”

Though Dr. Verheugt joined Dr. Yasuda in calling for replication of the results in a non-Asian population, he concurred that the AFIRE results validate current practice for anticoagulation in AFib with stable CAD. “Stopping at 1 year is safer than continuation and, most of all, it saves lives,” he said.

Full results of AFIRE were published online at the time of Dr. Yasuda’s presentation (N Engl J Med. 2019 Sep 2. doi: 10.1056/NEJMoa1904143).

The study was funded by the Japanese Cardiovascular Research Foundation. Dr. Yasuda reported financial relationships with Abbott, Bristol-Myers, Daiichi-Sankyo, and Takeda. Dr. Verheugt reported financial relationships with BayerHealthcare, BMS/Pfizer, Boehringer-Ingelheim, and Daiichi-Sankyo.

koakes@mdedge.com

SOURCE: Yasuda S. et al. ESC 2019, Hot Line Session 3, Abstract 3175.

PARIS – Prasugrel proved superior to ticagrelor in patients with acute coronary syndrome (ACS) in what was hailed as “a landmark study” presented at the annual congress of the European Society of Cardiology.

Bruce Jancin/MDedge News

The results of ISAR-REACT 5 (Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 5) were unequivocal: “In ACS patients with or without ST-segment elevation, treatment with prasugrel as compared with ticagrelor significantly reduced the composite rate of death, myocardial infarction, or stroke at 1 year without an increase in major bleeding,” declared first author Stephanie Schuepke, MD, a cardiologist at the German Heart Center in Munich.

The study outcome was totally unexpected. Indeed, the result didn’t merely turn heads, it no doubt caused numerous wrenched necks caused by strenuous double-takes on the part of interventional cardiologists at the congress. That’s because, even though both ticagrelor and prasugrel enjoy a class I recommendation for use in ACS in the ESC guidelines, it has been widely assumed – based on previous evidence plus the fact that ticagrelor is the more potent platelet inhibitor – that ticagrelor is the superior drug in this setting. It turns out, however, that those earlier studies weren’t germane to the issue directly addressed in ISAR-REACT 5, the first-ever direct head-to-head comparison of the two potent P2Y12 inhibitors in the setting of ACS with a planned invasive strategy.

“Obviously, very surprising results,” commented Roxana Mehran, MD, professor of medicine and director of interventional cardiology research and clinical trials at the Icahn School of Medicine at Mount Sinai, New York, who cochaired a press conference where Dr. Schuepke shared the study findings.

“We were surprised as well,” confessed Dr. Schuepke. “We assumed that ticagrelor is superior to prasugrel in terms of clinical outcomes in patients with ACS with a planned invasive strategy. But the results show us that the opposite is true.”

ISAR-REACT 5 was an open-label, investigator-initiated randomized trial conducted at 23 centers in Germany and Italy. It included 4,018 participants with ST-elevation segment MI (STEMI), without STEMI, or with unstable angina, all with scheduled coronary angiography. Participants were randomized to ticagrelor or prasugrel and were expected to remain on their assigned potent antiplatelet agent plus aspirin for 1 year of dual-antiplatelet therapy.

The primary outcome was the composite of death, MI, or stroke at 1 year of follow-up. This endpoint occurred in 9.3% of the ticagrelor group and 6.9% of patients in the prasugrel group, for a highly significant 36% increased relative risk in the ticagrelor-treated patients. Prasugrel had a numeric advantage in each of the individual components of the endpoint: the 1-year rate of all-cause mortality was 4.5% with ticagrelor versus 3.7% with prasugrel; for MI, the incidence was 4.8% with ticagrelor and 3.0% with prasugrel, a statistically significant difference; and for stroke, 1.1% versus 1.0%.

Major bleeding as defined by the Bleeding Academic Research Consortium scale occurred in 5.4% of patients in the ticagrelor arm, and was similar at 4.8% in the prasugrel group, Dr. Schuepke continued.

Definite or probable stent thrombosis occurred in 1.3% of the ticagrelor group and 1.0% of patients assigned to prasugrel.

The mechanism for prasugrel’s superior results is unclear, she said. Possibilities include the fact that it’s a once-daily drug, compared with twice-daily ticagrelor, which could affect adherence; a differential profile in terms of drug interactions; and prasugrel’s reversibility of action and capacity for step-down dosing in patients at high bleeding risk.

Discussant Gilles Montalescot, MD, PhD, called ISAR-REACT 5 a “fascinating” study. He elaborated: “It is a pragmatic study to answer a pragmatic question. It’s not a drug trial; really, it’s more a strategy trial, with a comparison of two drugs and two strategies.”

Bruce Jancin/MDedge News

In ISAR-REACT 5, ticagrelor was utilized in standard fashion: Patients, regardless of their ACS type, received a 180-mg loading dose as soon as possible after randomization, typically about 3 hours after presentation. That was also the protocol in the prasugrel arm, but only in patients with STEMI, who quickly got a 60-mg loading dose. In contrast, patients without STEMI or with unstable angina didn’t get a loading dose of prasugrel until they’d undergone coronary angiography and their coronary anatomy was known. That was the ISAR-REACT 5 strategy in light of an earlier study, which concluded that giving prasugrel prior to angiography in such patients led to increased bleeding without any improvement in clinical outcomes.

The essence of ISAR-REACT 5 lies in that difference in treatment strategies and the impact it had on outcomes. “The one-size-fits-all strategy – here, with ticagrelor – was inferior to an individualized strategy, here with prasugrel,” observed Dr. Montalescot, professor of cardiology at the University of Paris VI and director of the cardiac care unit at Paris-Salpetriere Hospital.

The study results were notably consistent, favoring prasugrel over ticagrelor numerically across the board regardless of whether a patient presented with STEMI, without STEMI, or with unstable angina. Particularly noteworthy was the finding that this was also true in terms of the individual components of the 1-year composite endpoint. Dr. Montalescot drew special attention to the large subset of patients who had presented with STEMI and thus received the same treatment strategy involving a loading dose of their assigned P2Y12 inhibitor prior to angiography. This allowed for a direct head-to-head comparison of the clinical efficacy of the two antiplatelet agents in STEMI patients. The clear winner here was prasugrel, as the composite event rate was 10.1% in the ticagrelor group, compared with 7.9% in the prasugrel group.

“ISAR-REACT 5 is a landmark study which is going to impact our practice and the next set of guidelines to come in 2020,” the interventional cardiologist predicted.

Dr. Schuepke reported having no financial conflicts regarding the ISAR-REACT 5 study, sponsored by the German Heart Center and the German Center for Cardiovascular Research.

Simultaneous with her presentation of ISAR-REACT 5, the study results were published online (N Engl J Med. 2019 Sep 1. doi: 10.1056/NEJMoa1908973).

bjancin@mdedge.com

PARIS – Prasugrel proved superior to ticagrelor in patients with acute coronary syndrome (ACS) in what was hailed as “a landmark study” presented at the annual congress of the European Society of Cardiology.

Bruce Jancin/MDedge News

The results of ISAR-REACT 5 (Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 5) were unequivocal: “In ACS patients with or without ST-segment elevation, treatment with prasugrel as compared with ticagrelor significantly reduced the composite rate of death, myocardial infarction, or stroke at 1 year without an increase in major bleeding,” declared first author Stephanie Schuepke, MD, a cardiologist at the German Heart Center in Munich.

The study outcome was totally unexpected. Indeed, the result didn’t merely turn heads, it no doubt caused numerous wrenched necks caused by strenuous double-takes on the part of interventional cardiologists at the congress. That’s because, even though both ticagrelor and prasugrel enjoy a class I recommendation for use in ACS in the ESC guidelines, it has been widely assumed – based on previous evidence plus the fact that ticagrelor is the more potent platelet inhibitor – that ticagrelor is the superior drug in this setting. It turns out, however, that those earlier studies weren’t germane to the issue directly addressed in ISAR-REACT 5, the first-ever direct head-to-head comparison of the two potent P2Y12 inhibitors in the setting of ACS with a planned invasive strategy.

“Obviously, very surprising results,” commented Roxana Mehran, MD, professor of medicine and director of interventional cardiology research and clinical trials at the Icahn School of Medicine at Mount Sinai, New York, who cochaired a press conference where Dr. Schuepke shared the study findings.

“We were surprised as well,” confessed Dr. Schuepke. “We assumed that ticagrelor is superior to prasugrel in terms of clinical outcomes in patients with ACS with a planned invasive strategy. But the results show us that the opposite is true.”

ISAR-REACT 5 was an open-label, investigator-initiated randomized trial conducted at 23 centers in Germany and Italy. It included 4,018 participants with ST-elevation segment MI (STEMI), without STEMI, or with unstable angina, all with scheduled coronary angiography. Participants were randomized to ticagrelor or prasugrel and were expected to remain on their assigned potent antiplatelet agent plus aspirin for 1 year of dual-antiplatelet therapy.

The primary outcome was the composite of death, MI, or stroke at 1 year of follow-up. This endpoint occurred in 9.3% of the ticagrelor group and 6.9% of patients in the prasugrel group, for a highly significant 36% increased relative risk in the ticagrelor-treated patients. Prasugrel had a numeric advantage in each of the individual components of the endpoint: the 1-year rate of all-cause mortality was 4.5% with ticagrelor versus 3.7% with prasugrel; for MI, the incidence was 4.8% with ticagrelor and 3.0% with prasugrel, a statistically significant difference; and for stroke, 1.1% versus 1.0%.

Major bleeding as defined by the Bleeding Academic Research Consortium scale occurred in 5.4% of patients in the ticagrelor arm, and was similar at 4.8% in the prasugrel group, Dr. Schuepke continued.

Definite or probable stent thrombosis occurred in 1.3% of the ticagrelor group and 1.0% of patients assigned to prasugrel.

The mechanism for prasugrel’s superior results is unclear, she said. Possibilities include the fact that it’s a once-daily drug, compared with twice-daily ticagrelor, which could affect adherence; a differential profile in terms of drug interactions; and prasugrel’s reversibility of action and capacity for step-down dosing in patients at high bleeding risk.

Discussant Gilles Montalescot, MD, PhD, called ISAR-REACT 5 a “fascinating” study. He elaborated: “It is a pragmatic study to answer a pragmatic question. It’s not a drug trial; really, it’s more a strategy trial, with a comparison of two drugs and two strategies.”

Bruce Jancin/MDedge News

In ISAR-REACT 5, ticagrelor was utilized in standard fashion: Patients, regardless of their ACS type, received a 180-mg loading dose as soon as possible after randomization, typically about 3 hours after presentation. That was also the protocol in the prasugrel arm, but only in patients with STEMI, who quickly got a 60-mg loading dose. In contrast, patients without STEMI or with unstable angina didn’t get a loading dose of prasugrel until they’d undergone coronary angiography and their coronary anatomy was known. That was the ISAR-REACT 5 strategy in light of an earlier study, which concluded that giving prasugrel prior to angiography in such patients led to increased bleeding without any improvement in clinical outcomes.

The essence of ISAR-REACT 5 lies in that difference in treatment strategies and the impact it had on outcomes. “The one-size-fits-all strategy – here, with ticagrelor – was inferior to an individualized strategy, here with prasugrel,” observed Dr. Montalescot, professor of cardiology at the University of Paris VI and director of the cardiac care unit at Paris-Salpetriere Hospital.

The study results were notably consistent, favoring prasugrel over ticagrelor numerically across the board regardless of whether a patient presented with STEMI, without STEMI, or with unstable angina. Particularly noteworthy was the finding that this was also true in terms of the individual components of the 1-year composite endpoint. Dr. Montalescot drew special attention to the large subset of patients who had presented with STEMI and thus received the same treatment strategy involving a loading dose of their assigned P2Y12 inhibitor prior to angiography. This allowed for a direct head-to-head comparison of the clinical efficacy of the two antiplatelet agents in STEMI patients. The clear winner here was prasugrel, as the composite event rate was 10.1% in the ticagrelor group, compared with 7.9% in the prasugrel group.

“ISAR-REACT 5 is a landmark study which is going to impact our practice and the next set of guidelines to come in 2020,” the interventional cardiologist predicted.

Dr. Schuepke reported having no financial conflicts regarding the ISAR-REACT 5 study, sponsored by the German Heart Center and the German Center for Cardiovascular Research.

Simultaneous with her presentation of ISAR-REACT 5, the study results were published online (N Engl J Med. 2019 Sep 1. doi: 10.1056/NEJMoa1908973).

bjancin@mdedge.com

PARIS – Prasugrel proved superior to ticagrelor in patients with acute coronary syndrome (ACS) in what was hailed as “a landmark study” presented at the annual congress of the European Society of Cardiology.

Bruce Jancin/MDedge News

The results of ISAR-REACT 5 (Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 5) were unequivocal: “In ACS patients with or without ST-segment elevation, treatment with prasugrel as compared with ticagrelor significantly reduced the composite rate of death, myocardial infarction, or stroke at 1 year without an increase in major bleeding,” declared first author Stephanie Schuepke, MD, a cardiologist at the German Heart Center in Munich.

The study outcome was totally unexpected. Indeed, the result didn’t merely turn heads, it no doubt caused numerous wrenched necks caused by strenuous double-takes on the part of interventional cardiologists at the congress. That’s because, even though both ticagrelor and prasugrel enjoy a class I recommendation for use in ACS in the ESC guidelines, it has been widely assumed – based on previous evidence plus the fact that ticagrelor is the more potent platelet inhibitor – that ticagrelor is the superior drug in this setting. It turns out, however, that those earlier studies weren’t germane to the issue directly addressed in ISAR-REACT 5, the first-ever direct head-to-head comparison of the two potent P2Y12 inhibitors in the setting of ACS with a planned invasive strategy.

“Obviously, very surprising results,” commented Roxana Mehran, MD, professor of medicine and director of interventional cardiology research and clinical trials at the Icahn School of Medicine at Mount Sinai, New York, who cochaired a press conference where Dr. Schuepke shared the study findings.

“We were surprised as well,” confessed Dr. Schuepke. “We assumed that ticagrelor is superior to prasugrel in terms of clinical outcomes in patients with ACS with a planned invasive strategy. But the results show us that the opposite is true.”

ISAR-REACT 5 was an open-label, investigator-initiated randomized trial conducted at 23 centers in Germany and Italy. It included 4,018 participants with ST-elevation segment MI (STEMI), without STEMI, or with unstable angina, all with scheduled coronary angiography. Participants were randomized to ticagrelor or prasugrel and were expected to remain on their assigned potent antiplatelet agent plus aspirin for 1 year of dual-antiplatelet therapy.

The primary outcome was the composite of death, MI, or stroke at 1 year of follow-up. This endpoint occurred in 9.3% of the ticagrelor group and 6.9% of patients in the prasugrel group, for a highly significant 36% increased relative risk in the ticagrelor-treated patients. Prasugrel had a numeric advantage in each of the individual components of the endpoint: the 1-year rate of all-cause mortality was 4.5% with ticagrelor versus 3.7% with prasugrel; for MI, the incidence was 4.8% with ticagrelor and 3.0% with prasugrel, a statistically significant difference; and for stroke, 1.1% versus 1.0%.

Major bleeding as defined by the Bleeding Academic Research Consortium scale occurred in 5.4% of patients in the ticagrelor arm, and was similar at 4.8% in the prasugrel group, Dr. Schuepke continued.

Definite or probable stent thrombosis occurred in 1.3% of the ticagrelor group and 1.0% of patients assigned to prasugrel.

The mechanism for prasugrel’s superior results is unclear, she said. Possibilities include the fact that it’s a once-daily drug, compared with twice-daily ticagrelor, which could affect adherence; a differential profile in terms of drug interactions; and prasugrel’s reversibility of action and capacity for step-down dosing in patients at high bleeding risk.

Discussant Gilles Montalescot, MD, PhD, called ISAR-REACT 5 a “fascinating” study. He elaborated: “It is a pragmatic study to answer a pragmatic question. It’s not a drug trial; really, it’s more a strategy trial, with a comparison of two drugs and two strategies.”

Bruce Jancin/MDedge News

In ISAR-REACT 5, ticagrelor was utilized in standard fashion: Patients, regardless of their ACS type, received a 180-mg loading dose as soon as possible after randomization, typically about 3 hours after presentation. That was also the protocol in the prasugrel arm, but only in patients with STEMI, who quickly got a 60-mg loading dose. In contrast, patients without STEMI or with unstable angina didn’t get a loading dose of prasugrel until they’d undergone coronary angiography and their coronary anatomy was known. That was the ISAR-REACT 5 strategy in light of an earlier study, which concluded that giving prasugrel prior to angiography in such patients led to increased bleeding without any improvement in clinical outcomes.

The essence of ISAR-REACT 5 lies in that difference in treatment strategies and the impact it had on outcomes. “The one-size-fits-all strategy – here, with ticagrelor – was inferior to an individualized strategy, here with prasugrel,” observed Dr. Montalescot, professor of cardiology at the University of Paris VI and director of the cardiac care unit at Paris-Salpetriere Hospital.

The study results were notably consistent, favoring prasugrel over ticagrelor numerically across the board regardless of whether a patient presented with STEMI, without STEMI, or with unstable angina. Particularly noteworthy was the finding that this was also true in terms of the individual components of the 1-year composite endpoint. Dr. Montalescot drew special attention to the large subset of patients who had presented with STEMI and thus received the same treatment strategy involving a loading dose of their assigned P2Y12 inhibitor prior to angiography. This allowed for a direct head-to-head comparison of the clinical efficacy of the two antiplatelet agents in STEMI patients. The clear winner here was prasugrel, as the composite event rate was 10.1% in the ticagrelor group, compared with 7.9% in the prasugrel group.

“ISAR-REACT 5 is a landmark study which is going to impact our practice and the next set of guidelines to come in 2020,” the interventional cardiologist predicted.

Dr. Schuepke reported having no financial conflicts regarding the ISAR-REACT 5 study, sponsored by the German Heart Center and the German Center for Cardiovascular Research.

Simultaneous with her presentation of ISAR-REACT 5, the study results were published online (N Engl J Med. 2019 Sep 1. doi: 10.1056/NEJMoa1908973).

bjancin@mdedge.com

The good news: AYA survival improvement was at least as large as in younger children and older adults comparing deaths in two time periods, 1988-2000 and 2001-2014, in a California Cancer Registry.

The bad news: There was no statistically significant difference in survival between time periods for patients with bone and soft tissue sarcoma.

The good news: AYA survival improvement was at least as large as in younger children and older adults comparing deaths in two time periods, 1988-2000 and 2001-2014, in a California Cancer Registry.

The bad news: There was no statistically significant difference in survival between time periods for patients with bone and soft tissue sarcoma.

The good news: AYA survival improvement was at least as large as in younger children and older adults comparing deaths in two time periods, 1988-2000 and 2001-2014, in a California Cancer Registry.

The bad news: There was no statistically significant difference in survival between time periods for patients with bone and soft tissue sarcoma.

A federal effort to reduce health care expenditures has left many older Medicare recipients experiencing the sticker shock of “observation status.” Patients who are not sick enough to meet inpatient admission criteria, however, still require hospitalization, and may be placed under Medicare observation care.

Seniors can get frustrated, confused, and anxious as their status can be changed while they are in the hospital, and they may receive large medical bills after they are discharged. The Centers for Medicare & Medicaid Services’ “3-day rule” mandates that Medicare will not pay for skilled nursing facility care unless the patient is admitted as an “inpatient” for at least 3 days. Observation days do not count towards this 3-day hospital stay.

There has been an increase in outpatient services over the years since 2006. The 2018 State of Hospital Medicine Report (SoHM) highlights the percentage of discharges based on hospitalists’ billed Current Procedural Terminology codes. Codes 99217 (observation discharge) and 99238-99239 (inpatient discharge) were used to calculate the percentages. 80.7% of adult medicine hospitalist discharges were coded using inpatient discharge codes, while 19.3% of patients were discharged with observation discharge codes.

In the 2016 SoHM report, the ratio was 76.0% inpatient and 21.1% observation codes and in the 2014 report we saw 80.3% inpatient and 16.1% observation discharges (see table 1). But in both of those surveys, same-day admission/discharge codes were also separately reported, which did not occur in 2018. That makes year-over-year comparison of the data challenging.

Interestingly, the 2017 CMS data on Evaluation and Management Codes by Specialty for the first time included separate data for hospitalists, based on hospitalists who credentialed with Medicare using the new C6 specialty code. Based on that data, when looking only at inpatient (99238-99239) and observation (99217) codes, 83% of the discharges were inpatient and 17% were observation.

Physicians feel the pressure of strained patient-physician relationships as a consequence of patients feeling the brunt of the financing gap related to observation status. Patients often feel they were not warned adequately about the financial ramifications of observation status. Even if Medicare beneficiaries have received the Medicare Outpatient Observation Notice, outlined by the Notice of Observation Treatment and Implication for Care Eligibility Act, they have no rights to appeal.

Currently Medicare beneficiaries admitted as inpatients only incur a Part A deductible; they are not liable for tests, procedures, and nursing care. On the other hand, in observation status all services are billed separately. For Medicare Part B services (which covers observation care) patients must pay 20% of services after the Part B deductible, which could result in a huge financial burden. Costs for skilled nursing facilities, when they are not covered by Medicare Part A, because of the 3-day rule, can easily go up to $20,000 or more. Medicare beneficiaries have no cap on costs for an observation stay. In some cases, hospitals have to apply a condition code 44 and retroactively change the stay to observation status.

I attended the 2019 Society of Hospital Medicine Annual Conference in Washington. Hospitalists from all parts of the country advocated on Capitol Hill against the “observation bill,” and “meet and greets” with congressional representatives increased their opposition to the bill. These efforts may work in favor of protecting patients from surprise medical bills. Hospital medicine physicians are on the front lines for providing health care in the hospital setting; they have demanded a fix to this legislative loophole which brings high out of pocket costs to our nation’s most vulnerable seniors. The observation status “2-midnight rule” utilized by CMS has increased financial barriers and decreased access to postacute care, affecting the provision of high-quality care for patients.

My hospital has a utilization review committee which reviews all cases to determine the appropriateness of an inpatient versus an observation designation. (An interesting question is whether the financial resources used to support this additional staff could be better assigned to provide high-quality care.) Distribution of these patients is determined on very specific criteria as outlined by Medicare. Observation is basically considered a billing method implemented by payers to decrease dollars paid to acute care hospitals for inpatient care. It pertains to admission status, not to the level of care provided in the hospital. Unfortunately, it is felt that no two payers define observation the same way. A few examples of common observation diagnoses are chest pain, abdominal pain, syncope, and migraine headache; in other words, patients with diagnoses where it is suspected that a less than 24-hour stay in the hospital could be sufficient.

Observation care is increasing and can sometimes contribute to work flow impediments and frustrations in hospitalists; thus, hospitalists are demanding reform. It has been proposed that observation could be eliminated altogether by creating a payment blend of inpatient/outpatient rates. Another option could be to assign lower Diagnosis Related Group coding to lower acuity disease processes, instead of separate observation reimbursement.

Patients and doctors lament that “Once you are in the hospital, you are admitted!” I don’t know the right answer that would solve the observation versus inpatient dilemma, but it is intriguing to consider changes in policy that might focus on the complete elimination of observation status.
 

Dr. Puri is a hospitalist at Lahey Hospital and Medical Center in Burlington, Mass.

A federal effort to reduce health care expenditures has left many older Medicare recipients experiencing the sticker shock of “observation status.” Patients who are not sick enough to meet inpatient admission criteria, however, still require hospitalization, and may be placed under Medicare observation care.

Seniors can get frustrated, confused, and anxious as their status can be changed while they are in the hospital, and they may receive large medical bills after they are discharged. The Centers for Medicare & Medicaid Services’ “3-day rule” mandates that Medicare will not pay for skilled nursing facility care unless the patient is admitted as an “inpatient” for at least 3 days. Observation days do not count towards this 3-day hospital stay.

There has been an increase in outpatient services over the years since 2006. The 2018 State of Hospital Medicine Report (SoHM) highlights the percentage of discharges based on hospitalists’ billed Current Procedural Terminology codes. Codes 99217 (observation discharge) and 99238-99239 (inpatient discharge) were used to calculate the percentages. 80.7% of adult medicine hospitalist discharges were coded using inpatient discharge codes, while 19.3% of patients were discharged with observation discharge codes.

In the 2016 SoHM report, the ratio was 76.0% inpatient and 21.1% observation codes and in the 2014 report we saw 80.3% inpatient and 16.1% observation discharges (see table 1). But in both of those surveys, same-day admission/discharge codes were also separately reported, which did not occur in 2018. That makes year-over-year comparison of the data challenging.

Interestingly, the 2017 CMS data on Evaluation and Management Codes by Specialty for the first time included separate data for hospitalists, based on hospitalists who credentialed with Medicare using the new C6 specialty code. Based on that data, when looking only at inpatient (99238-99239) and observation (99217) codes, 83% of the discharges were inpatient and 17% were observation.

Physicians feel the pressure of strained patient-physician relationships as a consequence of patients feeling the brunt of the financing gap related to observation status. Patients often feel they were not warned adequately about the financial ramifications of observation status. Even if Medicare beneficiaries have received the Medicare Outpatient Observation Notice, outlined by the Notice of Observation Treatment and Implication for Care Eligibility Act, they have no rights to appeal.

Currently Medicare beneficiaries admitted as inpatients only incur a Part A deductible; they are not liable for tests, procedures, and nursing care. On the other hand, in observation status all services are billed separately. For Medicare Part B services (which covers observation care) patients must pay 20% of services after the Part B deductible, which could result in a huge financial burden. Costs for skilled nursing facilities, when they are not covered by Medicare Part A, because of the 3-day rule, can easily go up to $20,000 or more. Medicare beneficiaries have no cap on costs for an observation stay. In some cases, hospitals have to apply a condition code 44 and retroactively change the stay to observation status.

I attended the 2019 Society of Hospital Medicine Annual Conference in Washington. Hospitalists from all parts of the country advocated on Capitol Hill against the “observation bill,” and “meet and greets” with congressional representatives increased their opposition to the bill. These efforts may work in favor of protecting patients from surprise medical bills. Hospital medicine physicians are on the front lines for providing health care in the hospital setting; they have demanded a fix to this legislative loophole which brings high out of pocket costs to our nation’s most vulnerable seniors. The observation status “2-midnight rule” utilized by CMS has increased financial barriers and decreased access to postacute care, affecting the provision of high-quality care for patients.

My hospital has a utilization review committee which reviews all cases to determine the appropriateness of an inpatient versus an observation designation. (An interesting question is whether the financial resources used to support this additional staff could be better assigned to provide high-quality care.) Distribution of these patients is determined on very specific criteria as outlined by Medicare. Observation is basically considered a billing method implemented by payers to decrease dollars paid to acute care hospitals for inpatient care. It pertains to admission status, not to the level of care provided in the hospital. Unfortunately, it is felt that no two payers define observation the same way. A few examples of common observation diagnoses are chest pain, abdominal pain, syncope, and migraine headache; in other words, patients with diagnoses where it is suspected that a less than 24-hour stay in the hospital could be sufficient.

Observation care is increasing and can sometimes contribute to work flow impediments and frustrations in hospitalists; thus, hospitalists are demanding reform. It has been proposed that observation could be eliminated altogether by creating a payment blend of inpatient/outpatient rates. Another option could be to assign lower Diagnosis Related Group coding to lower acuity disease processes, instead of separate observation reimbursement.

Patients and doctors lament that “Once you are in the hospital, you are admitted!” I don’t know the right answer that would solve the observation versus inpatient dilemma, but it is intriguing to consider changes in policy that might focus on the complete elimination of observation status.
 

Dr. Puri is a hospitalist at Lahey Hospital and Medical Center in Burlington, Mass.

A federal effort to reduce health care expenditures has left many older Medicare recipients experiencing the sticker shock of “observation status.” Patients who are not sick enough to meet inpatient admission criteria, however, still require hospitalization, and may be placed under Medicare observation care.

Seniors can get frustrated, confused, and anxious as their status can be changed while they are in the hospital, and they may receive large medical bills after they are discharged. The Centers for Medicare & Medicaid Services’ “3-day rule” mandates that Medicare will not pay for skilled nursing facility care unless the patient is admitted as an “inpatient” for at least 3 days. Observation days do not count towards this 3-day hospital stay.

There has been an increase in outpatient services over the years since 2006. The 2018 State of Hospital Medicine Report (SoHM) highlights the percentage of discharges based on hospitalists’ billed Current Procedural Terminology codes. Codes 99217 (observation discharge) and 99238-99239 (inpatient discharge) were used to calculate the percentages. 80.7% of adult medicine hospitalist discharges were coded using inpatient discharge codes, while 19.3% of patients were discharged with observation discharge codes.

In the 2016 SoHM report, the ratio was 76.0% inpatient and 21.1% observation codes and in the 2014 report we saw 80.3% inpatient and 16.1% observation discharges (see table 1). But in both of those surveys, same-day admission/discharge codes were also separately reported, which did not occur in 2018. That makes year-over-year comparison of the data challenging.

Interestingly, the 2017 CMS data on Evaluation and Management Codes by Specialty for the first time included separate data for hospitalists, based on hospitalists who credentialed with Medicare using the new C6 specialty code. Based on that data, when looking only at inpatient (99238-99239) and observation (99217) codes, 83% of the discharges were inpatient and 17% were observation.

Physicians feel the pressure of strained patient-physician relationships as a consequence of patients feeling the brunt of the financing gap related to observation status. Patients often feel they were not warned adequately about the financial ramifications of observation status. Even if Medicare beneficiaries have received the Medicare Outpatient Observation Notice, outlined by the Notice of Observation Treatment and Implication for Care Eligibility Act, they have no rights to appeal.

Currently Medicare beneficiaries admitted as inpatients only incur a Part A deductible; they are not liable for tests, procedures, and nursing care. On the other hand, in observation status all services are billed separately. For Medicare Part B services (which covers observation care) patients must pay 20% of services after the Part B deductible, which could result in a huge financial burden. Costs for skilled nursing facilities, when they are not covered by Medicare Part A, because of the 3-day rule, can easily go up to $20,000 or more. Medicare beneficiaries have no cap on costs for an observation stay. In some cases, hospitals have to apply a condition code 44 and retroactively change the stay to observation status.

I attended the 2019 Society of Hospital Medicine Annual Conference in Washington. Hospitalists from all parts of the country advocated on Capitol Hill against the “observation bill,” and “meet and greets” with congressional representatives increased their opposition to the bill. These efforts may work in favor of protecting patients from surprise medical bills. Hospital medicine physicians are on the front lines for providing health care in the hospital setting; they have demanded a fix to this legislative loophole which brings high out of pocket costs to our nation’s most vulnerable seniors. The observation status “2-midnight rule” utilized by CMS has increased financial barriers and decreased access to postacute care, affecting the provision of high-quality care for patients.

My hospital has a utilization review committee which reviews all cases to determine the appropriateness of an inpatient versus an observation designation. (An interesting question is whether the financial resources used to support this additional staff could be better assigned to provide high-quality care.) Distribution of these patients is determined on very specific criteria as outlined by Medicare. Observation is basically considered a billing method implemented by payers to decrease dollars paid to acute care hospitals for inpatient care. It pertains to admission status, not to the level of care provided in the hospital. Unfortunately, it is felt that no two payers define observation the same way. A few examples of common observation diagnoses are chest pain, abdominal pain, syncope, and migraine headache; in other words, patients with diagnoses where it is suspected that a less than 24-hour stay in the hospital could be sufficient.

Observation care is increasing and can sometimes contribute to work flow impediments and frustrations in hospitalists; thus, hospitalists are demanding reform. It has been proposed that observation could be eliminated altogether by creating a payment blend of inpatient/outpatient rates. Another option could be to assign lower Diagnosis Related Group coding to lower acuity disease processes, instead of separate observation reimbursement.

Patients and doctors lament that “Once you are in the hospital, you are admitted!” I don’t know the right answer that would solve the observation versus inpatient dilemma, but it is intriguing to consider changes in policy that might focus on the complete elimination of observation status.
 

Dr. Puri is a hospitalist at Lahey Hospital and Medical Center in Burlington, Mass.