Introduction

The treatment of benign gallbladder disease has changed substantially in the past decade, but this represents only a snapshot in the evolutionary history of the management of this organ. What began as a problem managed exclusively by open cholecystectomy (CCY) transitioned into a race toward minimally invasive approaches in the 1980s, with advances from gastroenterology, surgery, and radiology.

The opening strides were made in 1980 with the first description of percutaneous cholecystostomy (PC) by Dr. R.W. Radder.¹ Shortly thereafter, in 1984, Dr. Richard Kozarek first reported the feasibility of selective cystic duct cannulation during endoscopic retrograde cholangiopancreatography (ERCP).² Subsequent stenting for the treatment of acute cholecystitis (endoscopic transpapillary gallbladder drainage, ET-GBD) was then reported by Tamada et. al. in 1991.³ Not to be outdone, the first laparoscopic cholecystectomy (LC) was completed by Dr. Med Erich Mühe of Germany in 1985.⁴ More recently, with the expansion of interventional endoscopic ultrasound (EUS), the first transmural EUS-guided gallbladder drainage (EUS-GBD) was described by Dr. Baron and Dr. Topazian in 2007.⁵

Techniques & Tips

ET-GBD

• During ERCP, after successful cannulation of the bile duct, attempted wire cannulation of the cystic duct is performed.

A cholangiogram, which clearly delineates the insertion of the cystic duct into the main bile duct, can enhance cannulation success. Rotatable fluoroscopy can facilitate identification.

• After anatomy is clear, wire access is often best achieved using a sphincterotome or stone retrieval (occlusion) balloon.

The balloon, once inflated, can be pulled downward to establish traction on the main bile duct, which can straighten the approach.

• After superficial wire engagement into the cystic duct, the accessory used can be slowly advanced into the cystic duct to stabilize the catheter and then navigate the valves of Heister to reach the gallbladder lumen.

Use of a sphincterotome, which directs toward the patient’s right (most often direction of cystic duct takeoff), is helpful. Angled guidewires are preferable. We often use a 0.035-inch, 260-cm angled hydrophilic wire (GLIDEWIRE; Terumo, Somerset, NJ) to overcome this challenging portion of ET-GBD.

If despite the above maneuvers the guidewire has failed to enter the cystic duct, cholangioscopy can be used to identify the orifice and/or stabilize deep wire cannulation. This is often cumbersome, time consuming, does not always produce success, and requires additional expertise.

• If a stone is encountered that cannot be extracted or traversed by a guidewire, cholangioscopy with electrohydraulic lithotripsy can be pursued.
• After the guidewire has entered the gallbladder, a 5 French or 7 French plastic double pigtail stent is placed. Typical lengths are 9-15 cm.

Some authors prefer to use two side-by-side plastic stents.¹² This has been shown retrospectively to enhance the long term clinical success of ET-GBD but with additional technical difficulty.

• This stent can remain in place indefinitely and need not be exchanged, though it should be removed just prior to CCY if pursued. Alternatively, the surgeon can be alerted to its presence and, if comfortable, it can be removed intraoperatively.

EUS-GBD

• Use of fluoroscopy is optional but can enhance technical success in selected situations.
• Conversion, or internalization, of PC is reasonable and can enhance patient quality of life.¹³
• If the gallbladder wall is not in close apposition to the duodenal (or gastric) wall, consider measuring the distance.

We preferentially use 10-mm diameter by 10-mm saddle length LAMS for EUS-GBD, unless the above distance warrants use of a 15-mm by 15-mm LAMS (AXIOS, Boston Scientific, Marlborough, MA). If the distance is greater than 15 mm, consider searching for an alternative site, using a traditional biliary fully covered self-expandable metal stent (FCSEMS) for longer length, or converting to ET-GBD. Smaller diameter (8 mm) with an 8-mm saddle length can be used as well. The optimal diameter is unknown and also dependent on whether transluminal endoscopic diagnosis or therapy is a consideration.

• If there is difficulty locating the gallbladder, it may be decompressed or small (particularly if PC or a partial CCY has already been performed).

If a cholecystostomy tube is in place, instillation of sterile water via the tube can sometimes improve the target for LAMS placement, though caution should be made to not over-distend the gallbladder. ERCP with placement of a nasobiliary tube into the gallbladder can also serve this purpose and has been previously described.¹⁴

The gallbladder can be punctured with a 19-gauge FNA needle to instill sterile water and distend the gallbladder with the added benefit of being able to pass a guidewire, which may enhance procedural safety in difficult cases. However, success of this technique is contingent on fluid remaining within the gallbladder and not transiting out via the cystic duct. Expedient exchange of the FNA needle for the LAMS device may be necessary.

• Attempt to confirm location within the duodenum prior to puncture, as gastric origins can pose unique ramifications (i.e. potential for partial gastric outlet obstruction, obstruction of LAMS with food debris, etc.).

It can be easy to mistake an unintentional pre-pyloric position for a position within the duodenum since the working channel is behind (proximal to) the echoprobe.

• Turning off Doppler flow prior to advancement of the cautery enhanced LAMS can reduce obscurement of views on entry into the gallbladder. Lack of certainty about entry or misdeployment after presumed entry herald the most challenging aspect of EUS-GBD.

Utilization of a previously placed guidewire or advancement of one preloaded into the LAMS can aid in both enhancing confidence in location and assist with salvage maneuvers, if needed.

• After successful deployment of the LAMS we routinely place a double pigtail plastic stent through it (typically 7 French by 4 cm) to maintain patency. This may also prevent bleeding from the LAMS flange abrading the wall of either lumen.
• We routinely exchange the LAMS for two double pigtail plastic stents (typically 7 French by 4 cm) 4 weeks after initial placement especially when there is a more than modest residual stone burden (data in press). These plastic stents can remain in place indefinitely.

This exchange can be deferred if the patient is not expected to survive until the one-year anniversary of LAMS deployment. After one year the LAMS plastic covering may degrade and pose additional problems.¹⁵

LAMS Misdeployment Salvage Tips

• Salvage techniques can vary from simple to complex.
• If a wire is in place, it can be used to balloon or catheter dilate the tract and place a FCSEMS traversing the gallbladder and duodenal/gastric lumens. A similar approach can be used if the LAMS deployed on only one side (gallbladder or duodenum/stomach) and the other flange is within the peritoneum.
• The most challenging scenario to salvage is if the LAMS is misdeployed or becomes dislodged and no wire is present. This is why the use of a guidewire, even if preloaded into the LAMS and placement is freehand, is essential for EUS-GBD. A potential technique is to balloon dilate the duodenal/gastric defect and drive the endoscope into the peritoneum to reconnect that lumen to the gallbladder defect or LAMS, depending on the site of misdeployment. Doing so requires a high degree of commitment and skill and should not be done casually.
• If uncertainty remains or if misdeployment has occurred and salvage attempts have failed, consider closure of the duodenal/gastric defect and conversion to ET-GBD.

This may both treat the initial procedural indication and assist with what is essentially a large bile leak, which might also require percutaneous therapy for non-surgical management.

• For endoscopists with limited experience at salvage techniques, it is reasonable for the threshold for conversion to be low, assuming experience with and confidence in ET-GBD is high.
• If salvage is successful but ambiguity remains, consider obtaining a cholangiogram via the LAMS to confirm positioning and absence of leak.

Adverse Events

Both ET-GBD and EUS-GBD should be performed by an endoscopist comfortable with their techniques and the management of their adverse events (AEs). Rates for EUS-GBD AEs in patients at high risk for LC were reported in one international multicenter registry to be 15.3% with a 30-day mortality of 9.2%, with a significant predictor of AE being endoscopist experience less than 25 procedures.¹⁶ A meta-analysis also found an overall AE rate of 18.31%, with rates for perforation and stent related AEs (i.e. migration, occlusion, pneumoperitoneum) being 6.71% and 8.16%, respectively.¹⁷ For this reason, we recommend that patients with cholecystitis who are deemed to be poor surgical candidates be transferred to a tertiary referral center with expertise in these approaches. Rates of AEs for ET-GBD are similar to that for standard ERCP, with reported ranges of 5%-10.3%.¹⁰
 

Comparisons Between Techniques

The decision on which technique to utilize for endoscopic management of cholecystitis or symptomatic cholelithiasis depends first and foremost on the expertise and comfort level of the endoscopist. Given the additional training that an advanced endoscopist needs to perform EUS-GBD, combined with the perhaps slightly higher AE rate and permanency of endoscopic cholecystostomy, it is reasonable to proceed with a trial of ET-GBD if confidence is insufficient. However, ET-GBD can certainly be more technically challenging and less effective than EUS-GBD, with lower reported technical and clinical success rates (technical 85.3% vs 93.0%, clinical 95.2% vs 97.3%).¹⁸ Despite this, the rate of recurrence of cholecystitis is similar between ET-GBD and EUS-GBD (4.6% vs 4.2%).¹⁹ As stated above in the Techniques & Tips section, some authors utilize two plastic stents for ET-GBD for this purpose, though with increased technical difficulty. It is important to remember that these numbers, when paired with AE rates, represent the achievements of expert endoscopists.

Discussion with your surgery team is important when deciding modality. If the patient is felt to be a potential candidate for CCY, and EUS-GBD is not being used as a destination therapy, the surgeon may prefer ET-GBD. EUS-GBD may enhance the difficulty of CCY, though at least one study demonstrated that this was no different than PC with similar rates of conversion from LC to open CCY.²⁰ This conversation is most critical for patients who are potential liver transplant candidates. For patients where this is not a consideration there is some evidence to suggest equivalency between LC and EUS-GBD, though certainly EUS-GBD has not yet supplanted LC as the treatment of choice.²¹

While there may eventually be a shift towards EUS-GBD instead of LC in certain patient groups, what is clearer are the advantages of EUS-GBD over PC. One recent meta-analysis revealed that EUS-GBD has significantly favorable odds of overall adverse events (OR 0.43, 95% CI 0.18-1.00), shorter hospital stay (2.76 less days, 95% CI 0.31-5.20 less days), reinterventions (OR 0.15, 95% CI 0.02-0.98), and unplanned readmissions (OR 0.14, 95% CI 0.03-0.70) compared to PC.²² Beyond the data, though, are the emotional and psychological impacts an external drain can have on a patient.
 

Conclusion

When expertise is available, endoscopic treatment of benign gallbladder disease has a definite role but should be undertaken only by those with the experience and skill to safely do so. Decision to proceed, especially with EUS-GBD, should be accompanied by conversation and collaboration with surgical teams. If a patient is under consideration for PC instead of LC, it may be worthwhile to seek consultation with a local center with expertise in EUS-GBD or ET-GBD. The adoption of these techniques is part of the paradigm shift, seen broadly throughout medicine, towards minimally invasive interventions, particularly in advanced endoscopy.
 

Dr. Gilman (X @a_gilman) and Dr. Baron (X @EndoTx) are with the University of North Carolina, Chapel Hill, Division of Gastroenterology & Hepatology. Dr. Gilman has no relevant financial disclosures. Dr. Baron is a consultant and speaker for Ambu, Boston Scientific, Cook Endoscopy, Medtronic, Olympus America, and W.L. Gore.

References

1. Radder RW. Ultrasonically guided percutaneous catheter drainage for gallbladder empyema. Diagn Imaging. 1980;49:330-333.

2. Kozarek RA. Selective cannulation of the cystic duct at time of ERCP. J Clin Gastroenterol. 1984;6:37-40.

3. Tamada K et al. Efficacy of endoscopic retrograde cholecystoendoprosthesis (ERCCE) for cholecystitis. Endoscopy. 1991;23:2-3.

4. Reynolds W. The first laparoscopic cholecystectomy. JSLS. 2001;5:89-94.

5. Baron TH, Topazian MD. Endoscopic transduodenal drainage of the gallbladder: Implications for endoluminal treatment of gallbladder disease. Gastrointest Endosc. 2007 Apr;65(4):735-7. doi: 10.1016/j.gie.2006.07.041.

6. Irani SS et al. Endoscopic ultrasound-guided transluminal gallbladder drainage in patients with acute cholecystitis: A prospective multicenter trial. Ann Surg. 2023 Sep 1;278(3):e556-e562. doi: 10.1097/SLA.0000000000005784.

7. Shen Y et al. Endoscopic ultrasound-guided cholecystostomy for resection of gallbladder polyps with lumen-apposing metal stent. Medicine (Baltimore). 2020 Oct 23;99(43):e22903. doi: 10.1097/MD.0000000000022903.

8. Pang H et al. Endoscopic ultrasound-guided gallbladder endoscopic mucosal resection: A pilot porcine study. Minim Invasive Ther Allied Technol. 2023 Feb;32(1):24-32. doi: 10.1080/13645706.2022.2153228.

9. Imai H et al. EUS-guided gallbladder drainage for rescue treatment of malignant distal biliary obstruction after unsuccessful ERCP. Gastrointest Endosc. 2016 Jul;84(1):147-51. doi: 10.1016/j.gie.2015.12.024.

10. Saumoy M et al. Endoscopic therapies for gallbladder drainage. Gastrointest Endosc. 2021 Oct;94(4):671-84. doi: 10.1016/j.gie.2021.05.031.

11. Van der Merwe SW et al. Therapeutic endoscopic ultrasound: European Society of Gastrointestinal Endoscopy (ESGE) Guideline. Endoscopy. 2022 Feb;54(2):185-205. doi: 10.1055/a-1717-1391.

12. Storm AC et al. Transpapillary gallbladder stent placement for long-term therapy of acute cholecystitis. Gastrointest Endosc. 2021 Oct;94(4):742-8 e1. doi: 10.1016/j.gie.2021.03.025.

13. James TW, Baron TH. Converting percutaneous gallbladder drainage to internal drainage using EUS-guided therapy: A review of current practices and procedures. Endosc Ultrasound. 2018 Mar-Apr;7(2):93-6. doi: 10.4103/eus.eus_110_17.

14. James TW, Baron TH. Transpapillary nasocystic tube placement to allow gallbladder distention for EUS-guided cholecystoduodenostomy. VideoGIE. 2019 Dec;4(12):561-2. doi: 10.1016/j.vgie.2019.08.009.

15. Gilman AJ, Baron TH. Delamination of a lumen-apposing metal stent with tissue ingrowth and stent-in-stent removal. Gastrointest Endosc. 2023 Sep;98(3):451-3. doi: 10.1016/j.gie.2023.04.2087.

16. Teoh AY et al. Outcomes of an international multicenter registry on EUS-guided gallbladder drainage in patients at high risk for cholecystectomy. Endosc Int Open. 2019 Aug;7(8):E964-E973. doi: 10.1055/a-0915-2098.

17. Kalva NR et al. Efficacy and safety of lumen apposing self-expandable metal stents for EUS guided cholecystostomy: A meta-analysis and systematic review. Can J Gastroenterol Hepatol. 2018;2018:7070961. doi: 10.1155/2018/7070961.

18. Khan MA et al. Efficacy and safety of endoscopic gallbladder drainage in acute cholecystitis: Is it better than percutaneous gallbladder drainage? Gastrointest Endosc. 2017 Jan;85(1):76-87 e3. doi: 10.1016/j.gie.2016.06.032.

19. Mohan BP et al. Endoscopic ultrasound-guided gallbladder drainage, transpapillary drainage, or percutaneous drainage in high risk acute cholecystitis patients: a systematic review and comparative meta-analysis. Endoscopy. 2020 Feb;52(2):96-106. doi: 10.1055/a-1020-3932.

20. Jang JW et al. Endoscopic ultrasound-guided transmural and percutaneous transhepatic gallbladder drainage are comparable for acute cholecystitis. Gastroenterology. 2012 Apr;142(4):805-11. doi: 10.1053/j.gastro.2011.12.051.

21. Teoh AYB et al. EUS-guided gallbladder drainage versus laparoscopic cholecystectomy for acute cholecystitis: a propensity score analysis with 1-year follow-up data. Gastrointest Endosc. 2021 Mar;93(3):577-83. doi: 10.1016/j.gie.2020.06.066.

22. Luk SW et al. Endoscopic ultrasound-guided gallbladder drainage versus percutaneous cholecystostomy for high risk surgical patients with acute cholecystitis: a systematic review and meta-analysis. Endoscopy. 2019 Aug;51(8):722-32. doi: 10.1055/a-0929-6603.

Introduction

The treatment of benign gallbladder disease has changed substantially in the past decade, but this represents only a snapshot in the evolutionary history of the management of this organ. What began as a problem managed exclusively by open cholecystectomy (CCY) transitioned into a race toward minimally invasive approaches in the 1980s, with advances from gastroenterology, surgery, and radiology.

The opening strides were made in 1980 with the first description of percutaneous cholecystostomy (PC) by Dr. R.W. Radder.¹ Shortly thereafter, in 1984, Dr. Richard Kozarek first reported the feasibility of selective cystic duct cannulation during endoscopic retrograde cholangiopancreatography (ERCP).² Subsequent stenting for the treatment of acute cholecystitis (endoscopic transpapillary gallbladder drainage, ET-GBD) was then reported by Tamada et. al. in 1991.³ Not to be outdone, the first laparoscopic cholecystectomy (LC) was completed by Dr. Med Erich Mühe of Germany in 1985.⁴ More recently, with the expansion of interventional endoscopic ultrasound (EUS), the first transmural EUS-guided gallbladder drainage (EUS-GBD) was described by Dr. Baron and Dr. Topazian in 2007.⁵

Techniques & Tips

ET-GBD

• During ERCP, after successful cannulation of the bile duct, attempted wire cannulation of the cystic duct is performed.

A cholangiogram, which clearly delineates the insertion of the cystic duct into the main bile duct, can enhance cannulation success. Rotatable fluoroscopy can facilitate identification.

• After anatomy is clear, wire access is often best achieved using a sphincterotome or stone retrieval (occlusion) balloon.

The balloon, once inflated, can be pulled downward to establish traction on the main bile duct, which can straighten the approach.

• After superficial wire engagement into the cystic duct, the accessory used can be slowly advanced into the cystic duct to stabilize the catheter and then navigate the valves of Heister to reach the gallbladder lumen.

Use of a sphincterotome, which directs toward the patient’s right (most often direction of cystic duct takeoff), is helpful. Angled guidewires are preferable. We often use a 0.035-inch, 260-cm angled hydrophilic wire (GLIDEWIRE; Terumo, Somerset, NJ) to overcome this challenging portion of ET-GBD.

If despite the above maneuvers the guidewire has failed to enter the cystic duct, cholangioscopy can be used to identify the orifice and/or stabilize deep wire cannulation. This is often cumbersome, time consuming, does not always produce success, and requires additional expertise.

• If a stone is encountered that cannot be extracted or traversed by a guidewire, cholangioscopy with electrohydraulic lithotripsy can be pursued.
• After the guidewire has entered the gallbladder, a 5 French or 7 French plastic double pigtail stent is placed. Typical lengths are 9-15 cm.

Some authors prefer to use two side-by-side plastic stents.¹² This has been shown retrospectively to enhance the long term clinical success of ET-GBD but with additional technical difficulty.

• This stent can remain in place indefinitely and need not be exchanged, though it should be removed just prior to CCY if pursued. Alternatively, the surgeon can be alerted to its presence and, if comfortable, it can be removed intraoperatively.

EUS-GBD

• Use of fluoroscopy is optional but can enhance technical success in selected situations.
• Conversion, or internalization, of PC is reasonable and can enhance patient quality of life.¹³
• If the gallbladder wall is not in close apposition to the duodenal (or gastric) wall, consider measuring the distance.

We preferentially use 10-mm diameter by 10-mm saddle length LAMS for EUS-GBD, unless the above distance warrants use of a 15-mm by 15-mm LAMS (AXIOS, Boston Scientific, Marlborough, MA). If the distance is greater than 15 mm, consider searching for an alternative site, using a traditional biliary fully covered self-expandable metal stent (FCSEMS) for longer length, or converting to ET-GBD. Smaller diameter (8 mm) with an 8-mm saddle length can be used as well. The optimal diameter is unknown and also dependent on whether transluminal endoscopic diagnosis or therapy is a consideration.

• If there is difficulty locating the gallbladder, it may be decompressed or small (particularly if PC or a partial CCY has already been performed).

If a cholecystostomy tube is in place, instillation of sterile water via the tube can sometimes improve the target for LAMS placement, though caution should be made to not over-distend the gallbladder. ERCP with placement of a nasobiliary tube into the gallbladder can also serve this purpose and has been previously described.¹⁴

The gallbladder can be punctured with a 19-gauge FNA needle to instill sterile water and distend the gallbladder with the added benefit of being able to pass a guidewire, which may enhance procedural safety in difficult cases. However, success of this technique is contingent on fluid remaining within the gallbladder and not transiting out via the cystic duct. Expedient exchange of the FNA needle for the LAMS device may be necessary.

• Attempt to confirm location within the duodenum prior to puncture, as gastric origins can pose unique ramifications (i.e. potential for partial gastric outlet obstruction, obstruction of LAMS with food debris, etc.).

It can be easy to mistake an unintentional pre-pyloric position for a position within the duodenum since the working channel is behind (proximal to) the echoprobe.

• Turning off Doppler flow prior to advancement of the cautery enhanced LAMS can reduce obscurement of views on entry into the gallbladder. Lack of certainty about entry or misdeployment after presumed entry herald the most challenging aspect of EUS-GBD.

Utilization of a previously placed guidewire or advancement of one preloaded into the LAMS can aid in both enhancing confidence in location and assist with salvage maneuvers, if needed.

• After successful deployment of the LAMS we routinely place a double pigtail plastic stent through it (typically 7 French by 4 cm) to maintain patency. This may also prevent bleeding from the LAMS flange abrading the wall of either lumen.
• We routinely exchange the LAMS for two double pigtail plastic stents (typically 7 French by 4 cm) 4 weeks after initial placement especially when there is a more than modest residual stone burden (data in press). These plastic stents can remain in place indefinitely.

This exchange can be deferred if the patient is not expected to survive until the one-year anniversary of LAMS deployment. After one year the LAMS plastic covering may degrade and pose additional problems.¹⁵

LAMS Misdeployment Salvage Tips

• Salvage techniques can vary from simple to complex.
• If a wire is in place, it can be used to balloon or catheter dilate the tract and place a FCSEMS traversing the gallbladder and duodenal/gastric lumens. A similar approach can be used if the LAMS deployed on only one side (gallbladder or duodenum/stomach) and the other flange is within the peritoneum.
• The most challenging scenario to salvage is if the LAMS is misdeployed or becomes dislodged and no wire is present. This is why the use of a guidewire, even if preloaded into the LAMS and placement is freehand, is essential for EUS-GBD. A potential technique is to balloon dilate the duodenal/gastric defect and drive the endoscope into the peritoneum to reconnect that lumen to the gallbladder defect or LAMS, depending on the site of misdeployment. Doing so requires a high degree of commitment and skill and should not be done casually.
• If uncertainty remains or if misdeployment has occurred and salvage attempts have failed, consider closure of the duodenal/gastric defect and conversion to ET-GBD.

This may both treat the initial procedural indication and assist with what is essentially a large bile leak, which might also require percutaneous therapy for non-surgical management.

• For endoscopists with limited experience at salvage techniques, it is reasonable for the threshold for conversion to be low, assuming experience with and confidence in ET-GBD is high.
• If salvage is successful but ambiguity remains, consider obtaining a cholangiogram via the LAMS to confirm positioning and absence of leak.

Adverse Events

Both ET-GBD and EUS-GBD should be performed by an endoscopist comfortable with their techniques and the management of their adverse events (AEs). Rates for EUS-GBD AEs in patients at high risk for LC were reported in one international multicenter registry to be 15.3% with a 30-day mortality of 9.2%, with a significant predictor of AE being endoscopist experience less than 25 procedures.¹⁶ A meta-analysis also found an overall AE rate of 18.31%, with rates for perforation and stent related AEs (i.e. migration, occlusion, pneumoperitoneum) being 6.71% and 8.16%, respectively.¹⁷ For this reason, we recommend that patients with cholecystitis who are deemed to be poor surgical candidates be transferred to a tertiary referral center with expertise in these approaches. Rates of AEs for ET-GBD are similar to that for standard ERCP, with reported ranges of 5%-10.3%.¹⁰
 

Comparisons Between Techniques

The decision on which technique to utilize for endoscopic management of cholecystitis or symptomatic cholelithiasis depends first and foremost on the expertise and comfort level of the endoscopist. Given the additional training that an advanced endoscopist needs to perform EUS-GBD, combined with the perhaps slightly higher AE rate and permanency of endoscopic cholecystostomy, it is reasonable to proceed with a trial of ET-GBD if confidence is insufficient. However, ET-GBD can certainly be more technically challenging and less effective than EUS-GBD, with lower reported technical and clinical success rates (technical 85.3% vs 93.0%, clinical 95.2% vs 97.3%).¹⁸ Despite this, the rate of recurrence of cholecystitis is similar between ET-GBD and EUS-GBD (4.6% vs 4.2%).¹⁹ As stated above in the Techniques & Tips section, some authors utilize two plastic stents for ET-GBD for this purpose, though with increased technical difficulty. It is important to remember that these numbers, when paired with AE rates, represent the achievements of expert endoscopists.

Discussion with your surgery team is important when deciding modality. If the patient is felt to be a potential candidate for CCY, and EUS-GBD is not being used as a destination therapy, the surgeon may prefer ET-GBD. EUS-GBD may enhance the difficulty of CCY, though at least one study demonstrated that this was no different than PC with similar rates of conversion from LC to open CCY.²⁰ This conversation is most critical for patients who are potential liver transplant candidates. For patients where this is not a consideration there is some evidence to suggest equivalency between LC and EUS-GBD, though certainly EUS-GBD has not yet supplanted LC as the treatment of choice.²¹

While there may eventually be a shift towards EUS-GBD instead of LC in certain patient groups, what is clearer are the advantages of EUS-GBD over PC. One recent meta-analysis revealed that EUS-GBD has significantly favorable odds of overall adverse events (OR 0.43, 95% CI 0.18-1.00), shorter hospital stay (2.76 less days, 95% CI 0.31-5.20 less days), reinterventions (OR 0.15, 95% CI 0.02-0.98), and unplanned readmissions (OR 0.14, 95% CI 0.03-0.70) compared to PC.²² Beyond the data, though, are the emotional and psychological impacts an external drain can have on a patient.
 

Conclusion

When expertise is available, endoscopic treatment of benign gallbladder disease has a definite role but should be undertaken only by those with the experience and skill to safely do so. Decision to proceed, especially with EUS-GBD, should be accompanied by conversation and collaboration with surgical teams. If a patient is under consideration for PC instead of LC, it may be worthwhile to seek consultation with a local center with expertise in EUS-GBD or ET-GBD. The adoption of these techniques is part of the paradigm shift, seen broadly throughout medicine, towards minimally invasive interventions, particularly in advanced endoscopy.
 

Dr. Gilman (X @a_gilman) and Dr. Baron (X @EndoTx) are with the University of North Carolina, Chapel Hill, Division of Gastroenterology & Hepatology. Dr. Gilman has no relevant financial disclosures. Dr. Baron is a consultant and speaker for Ambu, Boston Scientific, Cook Endoscopy, Medtronic, Olympus America, and W.L. Gore.

References

1. Radder RW. Ultrasonically guided percutaneous catheter drainage for gallbladder empyema. Diagn Imaging. 1980;49:330-333.

2. Kozarek RA. Selective cannulation of the cystic duct at time of ERCP. J Clin Gastroenterol. 1984;6:37-40.

3. Tamada K et al. Efficacy of endoscopic retrograde cholecystoendoprosthesis (ERCCE) for cholecystitis. Endoscopy. 1991;23:2-3.

4. Reynolds W. The first laparoscopic cholecystectomy. JSLS. 2001;5:89-94.

5. Baron TH, Topazian MD. Endoscopic transduodenal drainage of the gallbladder: Implications for endoluminal treatment of gallbladder disease. Gastrointest Endosc. 2007 Apr;65(4):735-7. doi: 10.1016/j.gie.2006.07.041.

6. Irani SS et al. Endoscopic ultrasound-guided transluminal gallbladder drainage in patients with acute cholecystitis: A prospective multicenter trial. Ann Surg. 2023 Sep 1;278(3):e556-e562. doi: 10.1097/SLA.0000000000005784.

7. Shen Y et al. Endoscopic ultrasound-guided cholecystostomy for resection of gallbladder polyps with lumen-apposing metal stent. Medicine (Baltimore). 2020 Oct 23;99(43):e22903. doi: 10.1097/MD.0000000000022903.

8. Pang H et al. Endoscopic ultrasound-guided gallbladder endoscopic mucosal resection: A pilot porcine study. Minim Invasive Ther Allied Technol. 2023 Feb;32(1):24-32. doi: 10.1080/13645706.2022.2153228.

9. Imai H et al. EUS-guided gallbladder drainage for rescue treatment of malignant distal biliary obstruction after unsuccessful ERCP. Gastrointest Endosc. 2016 Jul;84(1):147-51. doi: 10.1016/j.gie.2015.12.024.

10. Saumoy M et al. Endoscopic therapies for gallbladder drainage. Gastrointest Endosc. 2021 Oct;94(4):671-84. doi: 10.1016/j.gie.2021.05.031.

11. Van der Merwe SW et al. Therapeutic endoscopic ultrasound: European Society of Gastrointestinal Endoscopy (ESGE) Guideline. Endoscopy. 2022 Feb;54(2):185-205. doi: 10.1055/a-1717-1391.

12. Storm AC et al. Transpapillary gallbladder stent placement for long-term therapy of acute cholecystitis. Gastrointest Endosc. 2021 Oct;94(4):742-8 e1. doi: 10.1016/j.gie.2021.03.025.

13. James TW, Baron TH. Converting percutaneous gallbladder drainage to internal drainage using EUS-guided therapy: A review of current practices and procedures. Endosc Ultrasound. 2018 Mar-Apr;7(2):93-6. doi: 10.4103/eus.eus_110_17.

14. James TW, Baron TH. Transpapillary nasocystic tube placement to allow gallbladder distention for EUS-guided cholecystoduodenostomy. VideoGIE. 2019 Dec;4(12):561-2. doi: 10.1016/j.vgie.2019.08.009.

15. Gilman AJ, Baron TH. Delamination of a lumen-apposing metal stent with tissue ingrowth and stent-in-stent removal. Gastrointest Endosc. 2023 Sep;98(3):451-3. doi: 10.1016/j.gie.2023.04.2087.

16. Teoh AY et al. Outcomes of an international multicenter registry on EUS-guided gallbladder drainage in patients at high risk for cholecystectomy. Endosc Int Open. 2019 Aug;7(8):E964-E973. doi: 10.1055/a-0915-2098.

17. Kalva NR et al. Efficacy and safety of lumen apposing self-expandable metal stents for EUS guided cholecystostomy: A meta-analysis and systematic review. Can J Gastroenterol Hepatol. 2018;2018:7070961. doi: 10.1155/2018/7070961.

18. Khan MA et al. Efficacy and safety of endoscopic gallbladder drainage in acute cholecystitis: Is it better than percutaneous gallbladder drainage? Gastrointest Endosc. 2017 Jan;85(1):76-87 e3. doi: 10.1016/j.gie.2016.06.032.

19. Mohan BP et al. Endoscopic ultrasound-guided gallbladder drainage, transpapillary drainage, or percutaneous drainage in high risk acute cholecystitis patients: a systematic review and comparative meta-analysis. Endoscopy. 2020 Feb;52(2):96-106. doi: 10.1055/a-1020-3932.

20. Jang JW et al. Endoscopic ultrasound-guided transmural and percutaneous transhepatic gallbladder drainage are comparable for acute cholecystitis. Gastroenterology. 2012 Apr;142(4):805-11. doi: 10.1053/j.gastro.2011.12.051.

21. Teoh AYB et al. EUS-guided gallbladder drainage versus laparoscopic cholecystectomy for acute cholecystitis: a propensity score analysis with 1-year follow-up data. Gastrointest Endosc. 2021 Mar;93(3):577-83. doi: 10.1016/j.gie.2020.06.066.

22. Luk SW et al. Endoscopic ultrasound-guided gallbladder drainage versus percutaneous cholecystostomy for high risk surgical patients with acute cholecystitis: a systematic review and meta-analysis. Endoscopy. 2019 Aug;51(8):722-32. doi: 10.1055/a-0929-6603.

Introduction

The treatment of benign gallbladder disease has changed substantially in the past decade, but this represents only a snapshot in the evolutionary history of the management of this organ. What began as a problem managed exclusively by open cholecystectomy (CCY) transitioned into a race toward minimally invasive approaches in the 1980s, with advances from gastroenterology, surgery, and radiology.

The opening strides were made in 1980 with the first description of percutaneous cholecystostomy (PC) by Dr. R.W. Radder.¹ Shortly thereafter, in 1984, Dr. Richard Kozarek first reported the feasibility of selective cystic duct cannulation during endoscopic retrograde cholangiopancreatography (ERCP).² Subsequent stenting for the treatment of acute cholecystitis (endoscopic transpapillary gallbladder drainage, ET-GBD) was then reported by Tamada et. al. in 1991.³ Not to be outdone, the first laparoscopic cholecystectomy (LC) was completed by Dr. Med Erich Mühe of Germany in 1985.⁴ More recently, with the expansion of interventional endoscopic ultrasound (EUS), the first transmural EUS-guided gallbladder drainage (EUS-GBD) was described by Dr. Baron and Dr. Topazian in 2007.⁵

Techniques & Tips

ET-GBD

• During ERCP, after successful cannulation of the bile duct, attempted wire cannulation of the cystic duct is performed.

A cholangiogram, which clearly delineates the insertion of the cystic duct into the main bile duct, can enhance cannulation success. Rotatable fluoroscopy can facilitate identification.

• After anatomy is clear, wire access is often best achieved using a sphincterotome or stone retrieval (occlusion) balloon.

The balloon, once inflated, can be pulled downward to establish traction on the main bile duct, which can straighten the approach.

• After superficial wire engagement into the cystic duct, the accessory used can be slowly advanced into the cystic duct to stabilize the catheter and then navigate the valves of Heister to reach the gallbladder lumen.

Use of a sphincterotome, which directs toward the patient’s right (most often direction of cystic duct takeoff), is helpful. Angled guidewires are preferable. We often use a 0.035-inch, 260-cm angled hydrophilic wire (GLIDEWIRE; Terumo, Somerset, NJ) to overcome this challenging portion of ET-GBD.

If despite the above maneuvers the guidewire has failed to enter the cystic duct, cholangioscopy can be used to identify the orifice and/or stabilize deep wire cannulation. This is often cumbersome, time consuming, does not always produce success, and requires additional expertise.

• If a stone is encountered that cannot be extracted or traversed by a guidewire, cholangioscopy with electrohydraulic lithotripsy can be pursued.
• After the guidewire has entered the gallbladder, a 5 French or 7 French plastic double pigtail stent is placed. Typical lengths are 9-15 cm.

Some authors prefer to use two side-by-side plastic stents.¹² This has been shown retrospectively to enhance the long term clinical success of ET-GBD but with additional technical difficulty.

• This stent can remain in place indefinitely and need not be exchanged, though it should be removed just prior to CCY if pursued. Alternatively, the surgeon can be alerted to its presence and, if comfortable, it can be removed intraoperatively.

EUS-GBD

• Use of fluoroscopy is optional but can enhance technical success in selected situations.
• Conversion, or internalization, of PC is reasonable and can enhance patient quality of life.¹³
• If the gallbladder wall is not in close apposition to the duodenal (or gastric) wall, consider measuring the distance.

We preferentially use 10-mm diameter by 10-mm saddle length LAMS for EUS-GBD, unless the above distance warrants use of a 15-mm by 15-mm LAMS (AXIOS, Boston Scientific, Marlborough, MA). If the distance is greater than 15 mm, consider searching for an alternative site, using a traditional biliary fully covered self-expandable metal stent (FCSEMS) for longer length, or converting to ET-GBD. Smaller diameter (8 mm) with an 8-mm saddle length can be used as well. The optimal diameter is unknown and also dependent on whether transluminal endoscopic diagnosis or therapy is a consideration.

• If there is difficulty locating the gallbladder, it may be decompressed or small (particularly if PC or a partial CCY has already been performed).

If a cholecystostomy tube is in place, instillation of sterile water via the tube can sometimes improve the target for LAMS placement, though caution should be made to not over-distend the gallbladder. ERCP with placement of a nasobiliary tube into the gallbladder can also serve this purpose and has been previously described.¹⁴

The gallbladder can be punctured with a 19-gauge FNA needle to instill sterile water and distend the gallbladder with the added benefit of being able to pass a guidewire, which may enhance procedural safety in difficult cases. However, success of this technique is contingent on fluid remaining within the gallbladder and not transiting out via the cystic duct. Expedient exchange of the FNA needle for the LAMS device may be necessary.

• Attempt to confirm location within the duodenum prior to puncture, as gastric origins can pose unique ramifications (i.e. potential for partial gastric outlet obstruction, obstruction of LAMS with food debris, etc.).

It can be easy to mistake an unintentional pre-pyloric position for a position within the duodenum since the working channel is behind (proximal to) the echoprobe.

• Turning off Doppler flow prior to advancement of the cautery enhanced LAMS can reduce obscurement of views on entry into the gallbladder. Lack of certainty about entry or misdeployment after presumed entry herald the most challenging aspect of EUS-GBD.

Utilization of a previously placed guidewire or advancement of one preloaded into the LAMS can aid in both enhancing confidence in location and assist with salvage maneuvers, if needed.

• After successful deployment of the LAMS we routinely place a double pigtail plastic stent through it (typically 7 French by 4 cm) to maintain patency. This may also prevent bleeding from the LAMS flange abrading the wall of either lumen.
• We routinely exchange the LAMS for two double pigtail plastic stents (typically 7 French by 4 cm) 4 weeks after initial placement especially when there is a more than modest residual stone burden (data in press). These plastic stents can remain in place indefinitely.

This exchange can be deferred if the patient is not expected to survive until the one-year anniversary of LAMS deployment. After one year the LAMS plastic covering may degrade and pose additional problems.¹⁵

LAMS Misdeployment Salvage Tips

• Salvage techniques can vary from simple to complex.
• If a wire is in place, it can be used to balloon or catheter dilate the tract and place a FCSEMS traversing the gallbladder and duodenal/gastric lumens. A similar approach can be used if the LAMS deployed on only one side (gallbladder or duodenum/stomach) and the other flange is within the peritoneum.
• The most challenging scenario to salvage is if the LAMS is misdeployed or becomes dislodged and no wire is present. This is why the use of a guidewire, even if preloaded into the LAMS and placement is freehand, is essential for EUS-GBD. A potential technique is to balloon dilate the duodenal/gastric defect and drive the endoscope into the peritoneum to reconnect that lumen to the gallbladder defect or LAMS, depending on the site of misdeployment. Doing so requires a high degree of commitment and skill and should not be done casually.
• If uncertainty remains or if misdeployment has occurred and salvage attempts have failed, consider closure of the duodenal/gastric defect and conversion to ET-GBD.

This may both treat the initial procedural indication and assist with what is essentially a large bile leak, which might also require percutaneous therapy for non-surgical management.

• For endoscopists with limited experience at salvage techniques, it is reasonable for the threshold for conversion to be low, assuming experience with and confidence in ET-GBD is high.
• If salvage is successful but ambiguity remains, consider obtaining a cholangiogram via the LAMS to confirm positioning and absence of leak.

Adverse Events

Both ET-GBD and EUS-GBD should be performed by an endoscopist comfortable with their techniques and the management of their adverse events (AEs). Rates for EUS-GBD AEs in patients at high risk for LC were reported in one international multicenter registry to be 15.3% with a 30-day mortality of 9.2%, with a significant predictor of AE being endoscopist experience less than 25 procedures.¹⁶ A meta-analysis also found an overall AE rate of 18.31%, with rates for perforation and stent related AEs (i.e. migration, occlusion, pneumoperitoneum) being 6.71% and 8.16%, respectively.¹⁷ For this reason, we recommend that patients with cholecystitis who are deemed to be poor surgical candidates be transferred to a tertiary referral center with expertise in these approaches. Rates of AEs for ET-GBD are similar to that for standard ERCP, with reported ranges of 5%-10.3%.¹⁰
 

Comparisons Between Techniques

The decision on which technique to utilize for endoscopic management of cholecystitis or symptomatic cholelithiasis depends first and foremost on the expertise and comfort level of the endoscopist. Given the additional training that an advanced endoscopist needs to perform EUS-GBD, combined with the perhaps slightly higher AE rate and permanency of endoscopic cholecystostomy, it is reasonable to proceed with a trial of ET-GBD if confidence is insufficient. However, ET-GBD can certainly be more technically challenging and less effective than EUS-GBD, with lower reported technical and clinical success rates (technical 85.3% vs 93.0%, clinical 95.2% vs 97.3%).¹⁸ Despite this, the rate of recurrence of cholecystitis is similar between ET-GBD and EUS-GBD (4.6% vs 4.2%).¹⁹ As stated above in the Techniques & Tips section, some authors utilize two plastic stents for ET-GBD for this purpose, though with increased technical difficulty. It is important to remember that these numbers, when paired with AE rates, represent the achievements of expert endoscopists.

Discussion with your surgery team is important when deciding modality. If the patient is felt to be a potential candidate for CCY, and EUS-GBD is not being used as a destination therapy, the surgeon may prefer ET-GBD. EUS-GBD may enhance the difficulty of CCY, though at least one study demonstrated that this was no different than PC with similar rates of conversion from LC to open CCY.²⁰ This conversation is most critical for patients who are potential liver transplant candidates. For patients where this is not a consideration there is some evidence to suggest equivalency between LC and EUS-GBD, though certainly EUS-GBD has not yet supplanted LC as the treatment of choice.²¹

While there may eventually be a shift towards EUS-GBD instead of LC in certain patient groups, what is clearer are the advantages of EUS-GBD over PC. One recent meta-analysis revealed that EUS-GBD has significantly favorable odds of overall adverse events (OR 0.43, 95% CI 0.18-1.00), shorter hospital stay (2.76 less days, 95% CI 0.31-5.20 less days), reinterventions (OR 0.15, 95% CI 0.02-0.98), and unplanned readmissions (OR 0.14, 95% CI 0.03-0.70) compared to PC.²² Beyond the data, though, are the emotional and psychological impacts an external drain can have on a patient.
 

Conclusion

When expertise is available, endoscopic treatment of benign gallbladder disease has a definite role but should be undertaken only by those with the experience and skill to safely do so. Decision to proceed, especially with EUS-GBD, should be accompanied by conversation and collaboration with surgical teams. If a patient is under consideration for PC instead of LC, it may be worthwhile to seek consultation with a local center with expertise in EUS-GBD or ET-GBD. The adoption of these techniques is part of the paradigm shift, seen broadly throughout medicine, towards minimally invasive interventions, particularly in advanced endoscopy.
 

Dr. Gilman (X @a_gilman) and Dr. Baron (X @EndoTx) are with the University of North Carolina, Chapel Hill, Division of Gastroenterology & Hepatology. Dr. Gilman has no relevant financial disclosures. Dr. Baron is a consultant and speaker for Ambu, Boston Scientific, Cook Endoscopy, Medtronic, Olympus America, and W.L. Gore.

References

1. Radder RW. Ultrasonically guided percutaneous catheter drainage for gallbladder empyema. Diagn Imaging. 1980;49:330-333.

2. Kozarek RA. Selective cannulation of the cystic duct at time of ERCP. J Clin Gastroenterol. 1984;6:37-40.

3. Tamada K et al. Efficacy of endoscopic retrograde cholecystoendoprosthesis (ERCCE) for cholecystitis. Endoscopy. 1991;23:2-3.

4. Reynolds W. The first laparoscopic cholecystectomy. JSLS. 2001;5:89-94.

5. Baron TH, Topazian MD. Endoscopic transduodenal drainage of the gallbladder: Implications for endoluminal treatment of gallbladder disease. Gastrointest Endosc. 2007 Apr;65(4):735-7. doi: 10.1016/j.gie.2006.07.041.

6. Irani SS et al. Endoscopic ultrasound-guided transluminal gallbladder drainage in patients with acute cholecystitis: A prospective multicenter trial. Ann Surg. 2023 Sep 1;278(3):e556-e562. doi: 10.1097/SLA.0000000000005784.

7. Shen Y et al. Endoscopic ultrasound-guided cholecystostomy for resection of gallbladder polyps with lumen-apposing metal stent. Medicine (Baltimore). 2020 Oct 23;99(43):e22903. doi: 10.1097/MD.0000000000022903.

8. Pang H et al. Endoscopic ultrasound-guided gallbladder endoscopic mucosal resection: A pilot porcine study. Minim Invasive Ther Allied Technol. 2023 Feb;32(1):24-32. doi: 10.1080/13645706.2022.2153228.

9. Imai H et al. EUS-guided gallbladder drainage for rescue treatment of malignant distal biliary obstruction after unsuccessful ERCP. Gastrointest Endosc. 2016 Jul;84(1):147-51. doi: 10.1016/j.gie.2015.12.024.

10. Saumoy M et al. Endoscopic therapies for gallbladder drainage. Gastrointest Endosc. 2021 Oct;94(4):671-84. doi: 10.1016/j.gie.2021.05.031.

11. Van der Merwe SW et al. Therapeutic endoscopic ultrasound: European Society of Gastrointestinal Endoscopy (ESGE) Guideline. Endoscopy. 2022 Feb;54(2):185-205. doi: 10.1055/a-1717-1391.

12. Storm AC et al. Transpapillary gallbladder stent placement for long-term therapy of acute cholecystitis. Gastrointest Endosc. 2021 Oct;94(4):742-8 e1. doi: 10.1016/j.gie.2021.03.025.

13. James TW, Baron TH. Converting percutaneous gallbladder drainage to internal drainage using EUS-guided therapy: A review of current practices and procedures. Endosc Ultrasound. 2018 Mar-Apr;7(2):93-6. doi: 10.4103/eus.eus_110_17.

14. James TW, Baron TH. Transpapillary nasocystic tube placement to allow gallbladder distention for EUS-guided cholecystoduodenostomy. VideoGIE. 2019 Dec;4(12):561-2. doi: 10.1016/j.vgie.2019.08.009.

15. Gilman AJ, Baron TH. Delamination of a lumen-apposing metal stent with tissue ingrowth and stent-in-stent removal. Gastrointest Endosc. 2023 Sep;98(3):451-3. doi: 10.1016/j.gie.2023.04.2087.

16. Teoh AY et al. Outcomes of an international multicenter registry on EUS-guided gallbladder drainage in patients at high risk for cholecystectomy. Endosc Int Open. 2019 Aug;7(8):E964-E973. doi: 10.1055/a-0915-2098.

17. Kalva NR et al. Efficacy and safety of lumen apposing self-expandable metal stents for EUS guided cholecystostomy: A meta-analysis and systematic review. Can J Gastroenterol Hepatol. 2018;2018:7070961. doi: 10.1155/2018/7070961.

18. Khan MA et al. Efficacy and safety of endoscopic gallbladder drainage in acute cholecystitis: Is it better than percutaneous gallbladder drainage? Gastrointest Endosc. 2017 Jan;85(1):76-87 e3. doi: 10.1016/j.gie.2016.06.032.

19. Mohan BP et al. Endoscopic ultrasound-guided gallbladder drainage, transpapillary drainage, or percutaneous drainage in high risk acute cholecystitis patients: a systematic review and comparative meta-analysis. Endoscopy. 2020 Feb;52(2):96-106. doi: 10.1055/a-1020-3932.

20. Jang JW et al. Endoscopic ultrasound-guided transmural and percutaneous transhepatic gallbladder drainage are comparable for acute cholecystitis. Gastroenterology. 2012 Apr;142(4):805-11. doi: 10.1053/j.gastro.2011.12.051.

21. Teoh AYB et al. EUS-guided gallbladder drainage versus laparoscopic cholecystectomy for acute cholecystitis: a propensity score analysis with 1-year follow-up data. Gastrointest Endosc. 2021 Mar;93(3):577-83. doi: 10.1016/j.gie.2020.06.066.

22. Luk SW et al. Endoscopic ultrasound-guided gallbladder drainage versus percutaneous cholecystostomy for high risk surgical patients with acute cholecystitis: a systematic review and meta-analysis. Endoscopy. 2019 Aug;51(8):722-32. doi: 10.1055/a-0929-6603.

Faced with an opportunity to advocate for patients, Rajeev Jain, MD, AGAF, is never afraid to speak up. He recently spoke out publicly against a major payer’s new advance notification process for colonoscopy and endoscopy procedures, cautioning it was a glidepath toward far-reaching prior authorization requirements.

UnitedHealthcare plans to collect a larger scope of data for this new policy, “which I fear will disrupt and deny patients’ access to lifesaving care,” Dr. Jain, a gastroenterologist with Texas Digestive Disease Consultants and a member of the American Gastroenterological Association’s (AGA) Prior Authorization Reform Task Force, wrote in an opinion piece in the Dallas Morning News.

Insurance coverage should be fair to the end goal of taking good care of patients, said Dr. Jain. “And if they’re putting processes in place, which are solely to be an impediment to excellent care, then that’s not right.”

Through his extensive participation in AGA panels and other influential groups, Dr. Jain has sought to improve clinical practice and reduce physician burnout. As Director and now Chair of the Board of Directors” of the American Board of Internal Medicine, Dr. Jain participated in conversations to make the maintenance of certification (MOC) process more accessible and less burdensome for doctors.

People spent a lot of time studying for ABIM’s 10-year MOC exam, sometimes even taking a course to help them pass. Now, there’s an option in all specialties to take a 30-question exam every quarter.

On average, it takes someone roughly 2 minutes to answer each question on this short exam. “Per quarter, you’re roughly spending an hour to do that instead of taking a big 10-year exam, where people were spending money and missing work,” said Dr. Jain. This modality enables physicians to meet credentialing requirements “in a way that it meets many of the desires of our practitioners,” he added.

Dr. Jain expounded on his work to advocate for patients and physicians in an interview.



Q: I’d like to discuss your opinion piece on UnitedHealthcare’s advanced notification process. Where does that policy stand now? I’m wondering if your opinion piece led to any changes.

Dr. Jain: There’s not a metric I can use to measure its success. But I will tell you this: I’ve had numerous patients mention to me, “Hey, I saw your article in the Dallas Morning News. That was great.” And that would lead to a conversation.



Q: Why do you think UHC’s policy was a tool for prior authorization?

Dr. Jain: Imagine you go to see a gastroenterologist in clinic, and the GI believes you need a procedure for certain symptoms or abnormal laboratory tests or imaging. It’s not a screening procedure. It’s a diagnostic procedure. Now, the insurance company is going to say, “Well, we can’t schedule that until you do a preauthorization.”

That could take a day. It could take a week. It could take longer. And now, the patient has lost that moment where they can get this settled. It’s not just the schedule for the patient. They’re going to get anesthesia, be it conscious sedation or deeper sedation, and they’re going to need a ride home. They have to coordinate things with family members or friends. Those little logistics add up to a lot of times why patients cancel or don’t show up or don’t follow through, because we couldn’t get it scheduled at that moment.

I feel like we are trying to attack this problem from many different angles, and my opinion piece was one of those tactics. The patients and the rank-and-file gastroenterologists appreciate the AGA being at the forefront of this issue.

Lightning Round:

Favorite type of music?

1980s alternative

Favorite movie genre?

Comedy



Cat person or dog person?

Dog



Favorite sport:

College football



What song do you have to sing along with when you hear it?

“I Ran,” by a Flock of Seagulls

Faced with an opportunity to advocate for patients, Rajeev Jain, MD, AGAF, is never afraid to speak up. He recently spoke out publicly against a major payer’s new advance notification process for colonoscopy and endoscopy procedures, cautioning it was a glidepath toward far-reaching prior authorization requirements.

UnitedHealthcare plans to collect a larger scope of data for this new policy, “which I fear will disrupt and deny patients’ access to lifesaving care,” Dr. Jain, a gastroenterologist with Texas Digestive Disease Consultants and a member of the American Gastroenterological Association’s (AGA) Prior Authorization Reform Task Force, wrote in an opinion piece in the Dallas Morning News.

Insurance coverage should be fair to the end goal of taking good care of patients, said Dr. Jain. “And if they’re putting processes in place, which are solely to be an impediment to excellent care, then that’s not right.”

Through his extensive participation in AGA panels and other influential groups, Dr. Jain has sought to improve clinical practice and reduce physician burnout. As Director and now Chair of the Board of Directors” of the American Board of Internal Medicine, Dr. Jain participated in conversations to make the maintenance of certification (MOC) process more accessible and less burdensome for doctors.

People spent a lot of time studying for ABIM’s 10-year MOC exam, sometimes even taking a course to help them pass. Now, there’s an option in all specialties to take a 30-question exam every quarter.

On average, it takes someone roughly 2 minutes to answer each question on this short exam. “Per quarter, you’re roughly spending an hour to do that instead of taking a big 10-year exam, where people were spending money and missing work,” said Dr. Jain. This modality enables physicians to meet credentialing requirements “in a way that it meets many of the desires of our practitioners,” he added.

Dr. Jain expounded on his work to advocate for patients and physicians in an interview.



Q: I’d like to discuss your opinion piece on UnitedHealthcare’s advanced notification process. Where does that policy stand now? I’m wondering if your opinion piece led to any changes.

Dr. Jain: There’s not a metric I can use to measure its success. But I will tell you this: I’ve had numerous patients mention to me, “Hey, I saw your article in the Dallas Morning News. That was great.” And that would lead to a conversation.



Q: Why do you think UHC’s policy was a tool for prior authorization?

Dr. Jain: Imagine you go to see a gastroenterologist in clinic, and the GI believes you need a procedure for certain symptoms or abnormal laboratory tests or imaging. It’s not a screening procedure. It’s a diagnostic procedure. Now, the insurance company is going to say, “Well, we can’t schedule that until you do a preauthorization.”

That could take a day. It could take a week. It could take longer. And now, the patient has lost that moment where they can get this settled. It’s not just the schedule for the patient. They’re going to get anesthesia, be it conscious sedation or deeper sedation, and they’re going to need a ride home. They have to coordinate things with family members or friends. Those little logistics add up to a lot of times why patients cancel or don’t show up or don’t follow through, because we couldn’t get it scheduled at that moment.

I feel like we are trying to attack this problem from many different angles, and my opinion piece was one of those tactics. The patients and the rank-and-file gastroenterologists appreciate the AGA being at the forefront of this issue.

Lightning Round:

Favorite type of music?

1980s alternative

Favorite movie genre?

Comedy



Cat person or dog person?

Dog



Favorite sport:

College football



What song do you have to sing along with when you hear it?

“I Ran,” by a Flock of Seagulls

Faced with an opportunity to advocate for patients, Rajeev Jain, MD, AGAF, is never afraid to speak up. He recently spoke out publicly against a major payer’s new advance notification process for colonoscopy and endoscopy procedures, cautioning it was a glidepath toward far-reaching prior authorization requirements.

UnitedHealthcare plans to collect a larger scope of data for this new policy, “which I fear will disrupt and deny patients’ access to lifesaving care,” Dr. Jain, a gastroenterologist with Texas Digestive Disease Consultants and a member of the American Gastroenterological Association’s (AGA) Prior Authorization Reform Task Force, wrote in an opinion piece in the Dallas Morning News.

Insurance coverage should be fair to the end goal of taking good care of patients, said Dr. Jain. “And if they’re putting processes in place, which are solely to be an impediment to excellent care, then that’s not right.”

Through his extensive participation in AGA panels and other influential groups, Dr. Jain has sought to improve clinical practice and reduce physician burnout. As Director and now Chair of the Board of Directors” of the American Board of Internal Medicine, Dr. Jain participated in conversations to make the maintenance of certification (MOC) process more accessible and less burdensome for doctors.

People spent a lot of time studying for ABIM’s 10-year MOC exam, sometimes even taking a course to help them pass. Now, there’s an option in all specialties to take a 30-question exam every quarter.

On average, it takes someone roughly 2 minutes to answer each question on this short exam. “Per quarter, you’re roughly spending an hour to do that instead of taking a big 10-year exam, where people were spending money and missing work,” said Dr. Jain. This modality enables physicians to meet credentialing requirements “in a way that it meets many of the desires of our practitioners,” he added.

Dr. Jain expounded on his work to advocate for patients and physicians in an interview.



Q: I’d like to discuss your opinion piece on UnitedHealthcare’s advanced notification process. Where does that policy stand now? I’m wondering if your opinion piece led to any changes.

Dr. Jain: There’s not a metric I can use to measure its success. But I will tell you this: I’ve had numerous patients mention to me, “Hey, I saw your article in the Dallas Morning News. That was great.” And that would lead to a conversation.



Q: Why do you think UHC’s policy was a tool for prior authorization?

Dr. Jain: Imagine you go to see a gastroenterologist in clinic, and the GI believes you need a procedure for certain symptoms or abnormal laboratory tests or imaging. It’s not a screening procedure. It’s a diagnostic procedure. Now, the insurance company is going to say, “Well, we can’t schedule that until you do a preauthorization.”

That could take a day. It could take a week. It could take longer. And now, the patient has lost that moment where they can get this settled. It’s not just the schedule for the patient. They’re going to get anesthesia, be it conscious sedation or deeper sedation, and they’re going to need a ride home. They have to coordinate things with family members or friends. Those little logistics add up to a lot of times why patients cancel or don’t show up or don’t follow through, because we couldn’t get it scheduled at that moment.

I feel like we are trying to attack this problem from many different angles, and my opinion piece was one of those tactics. The patients and the rank-and-file gastroenterologists appreciate the AGA being at the forefront of this issue.

Lightning Round:

Favorite type of music?

1980s alternative

Favorite movie genre?

Comedy



Cat person or dog person?

Dog



Favorite sport:

College football



What song do you have to sing along with when you hear it?

“I Ran,” by a Flock of Seagulls

TOPLINE:

Individuals who frequently used one or more coping strategies to stay awake while driving are significantly more likely to be diagnosed with obstructive sleep apnea (OSA) than are those who don’t use such coping strategies, new research showed.

METHODOLOGY:

• Investigators analyzed data on 119 participants with an Epworth Sleepiness Score (ESS) of > 10 who were being considered for a continuous positive airway pressure (CPAP) trial or who drove regularly.
• A total of 105 healthy volunteers with an ESS score of < 10 with no symptoms of OSA were recruited as controls.
• All participants completed questionnaires about how sleepiness affected their driving.

TAKEAWAY:

• Participants with OSA were more likely to feel sleepy while driving than controls (P = .0002).
• Participants with OSA were significantly more likely than were controls to use at least one coping strategy “frequently” vs control participants (43.7% vs 10.5%; P ≤ .0001).
• Strategies included rolling down the window, drinking tea or coffee, or listening to music at a high volume.
• Participants with OSA were significantly more likely to have either reported an accident or have been involved in an accident irrespective of any insurance claims in the last year than controls (16.8% vs 2.85%; P ≤ .0013).

IN PRACTICE:

“Our research suggests that untreated OSA patients often use coping strategies that could be surrogate markers of sleepiness,” lead author Akshay Dwarakanath, MD, said in a press release. “Asking about these strategies in the clinic may help doctors identifying patients who are at risk of driving incidents and to advise appropriately.”

SOURCE:

Akshay Dwarakanath, MD, of St. James University Hospital in Leeds, England, led the study, which was published online on January 17, 2024, in ERJ Open Research.

LIMITATIONS:

Investigators only evaluated patients with OSA with symptoms severe enough to warrant a CPAP trial and who needed to be assessed to determine if they should be allowed to continue to drive. Participant reporting and recall bias was another potential limitation.

DISCLOSURES:

There was no information available about study funding, and study authors had no disclosures.

A version of this article appeared on Medscape.com.

TOPLINE:

Individuals who frequently used one or more coping strategies to stay awake while driving are significantly more likely to be diagnosed with obstructive sleep apnea (OSA) than are those who don’t use such coping strategies, new research showed.

METHODOLOGY:

• Investigators analyzed data on 119 participants with an Epworth Sleepiness Score (ESS) of > 10 who were being considered for a continuous positive airway pressure (CPAP) trial or who drove regularly.
• A total of 105 healthy volunteers with an ESS score of < 10 with no symptoms of OSA were recruited as controls.
• All participants completed questionnaires about how sleepiness affected their driving.

TAKEAWAY:

• Participants with OSA were more likely to feel sleepy while driving than controls (P = .0002).
• Participants with OSA were significantly more likely than were controls to use at least one coping strategy “frequently” vs control participants (43.7% vs 10.5%; P ≤ .0001).
• Strategies included rolling down the window, drinking tea or coffee, or listening to music at a high volume.
• Participants with OSA were significantly more likely to have either reported an accident or have been involved in an accident irrespective of any insurance claims in the last year than controls (16.8% vs 2.85%; P ≤ .0013).

IN PRACTICE:

“Our research suggests that untreated OSA patients often use coping strategies that could be surrogate markers of sleepiness,” lead author Akshay Dwarakanath, MD, said in a press release. “Asking about these strategies in the clinic may help doctors identifying patients who are at risk of driving incidents and to advise appropriately.”

SOURCE:

Akshay Dwarakanath, MD, of St. James University Hospital in Leeds, England, led the study, which was published online on January 17, 2024, in ERJ Open Research.

LIMITATIONS:

Investigators only evaluated patients with OSA with symptoms severe enough to warrant a CPAP trial and who needed to be assessed to determine if they should be allowed to continue to drive. Participant reporting and recall bias was another potential limitation.

DISCLOSURES:

There was no information available about study funding, and study authors had no disclosures.

A version of this article appeared on Medscape.com.

TOPLINE:

Individuals who frequently used one or more coping strategies to stay awake while driving are significantly more likely to be diagnosed with obstructive sleep apnea (OSA) than are those who don’t use such coping strategies, new research showed.

METHODOLOGY:

• Investigators analyzed data on 119 participants with an Epworth Sleepiness Score (ESS) of > 10 who were being considered for a continuous positive airway pressure (CPAP) trial or who drove regularly.
• A total of 105 healthy volunteers with an ESS score of < 10 with no symptoms of OSA were recruited as controls.
• All participants completed questionnaires about how sleepiness affected their driving.

TAKEAWAY:

• Participants with OSA were more likely to feel sleepy while driving than controls (P = .0002).
• Participants with OSA were significantly more likely than were controls to use at least one coping strategy “frequently” vs control participants (43.7% vs 10.5%; P ≤ .0001).
• Strategies included rolling down the window, drinking tea or coffee, or listening to music at a high volume.
• Participants with OSA were significantly more likely to have either reported an accident or have been involved in an accident irrespective of any insurance claims in the last year than controls (16.8% vs 2.85%; P ≤ .0013).

IN PRACTICE:

“Our research suggests that untreated OSA patients often use coping strategies that could be surrogate markers of sleepiness,” lead author Akshay Dwarakanath, MD, said in a press release. “Asking about these strategies in the clinic may help doctors identifying patients who are at risk of driving incidents and to advise appropriately.”

SOURCE:

Akshay Dwarakanath, MD, of St. James University Hospital in Leeds, England, led the study, which was published online on January 17, 2024, in ERJ Open Research.

LIMITATIONS:

Investigators only evaluated patients with OSA with symptoms severe enough to warrant a CPAP trial and who needed to be assessed to determine if they should be allowed to continue to drive. Participant reporting and recall bias was another potential limitation.

DISCLOSURES:

There was no information available about study funding, and study authors had no disclosures.

A version of this article appeared on Medscape.com.

TOPLINE:

Legalization of recreational and medical cannabis is not associated with a reduction in opioid prescriptions or overall opioid overdose mortality, a new study suggested. However, investigators did find that recreational cannabis laws may be tied to a potential reduction in synthetic opioid deaths.

METHODOLOGY:

• Investigators analyzed state-level data from the US Centers for Disease Control and Prevention and other databases (2006-2020) on the number of opioid prescriptions (per 100,000 persons).
• Prescription opioids included buprenorphine (except products to treat opioid use disorder), codeine, fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxycodone, oxymorphone, propoxyphene, tapentadol, and tramadol.
• Researchers used regression analyses to account for poverty rates and real gross domestic product and a generalized difference-in-differences method that accounted for staggered implementation of cannabis laws.

TAKEAWAY:

• During the full study period, 13 states legalized recreational cannabis and 23 legalized medical cannabis.
• No statistically significant association was found between recreational cannabis laws and opioid prescriptions (3.08 fewer prescriptions per 100 persons; P = .17) or overall opioid overdose mortality (3.05 fewer deaths per 100,000; P = .24).
• The changes in outcomes associated with medical cannabis laws were larger in magnitude than those for recreational cannabis laws but also not statistically significant (3.54 additional prescriptions per 100 persons; P = .17 and 3.09 additional deaths per 100,000; P = .07).
• A potential reduction was found in synthetic opioid deaths associated specifically with states that had recreational cannabis laws (4.9 fewer deaths per 100,000; P = .04), but there were no differences in overdose deaths with other opioids.

IN PRACTICE:

“These results contrast with recent studies that suggested that recreational and medical cannabis legalization are associated with reductions in opioid prescriptions and medical cannabis legalization is associated with an increase in opioid mortality,” the authors wrote.

SOURCE:

Hai V. Nguyen, PhD, of the School of Pharmacy, Memorial University of Newfoundland, St. John’s, Canada, was the lead and corresponding author of the study. It was published online on January 19, 2024, in JAMA Health Forum.

A version of this article appeared on Medscape.com.

TOPLINE:

Legalization of recreational and medical cannabis is not associated with a reduction in opioid prescriptions or overall opioid overdose mortality, a new study suggested. However, investigators did find that recreational cannabis laws may be tied to a potential reduction in synthetic opioid deaths.

METHODOLOGY:

• Investigators analyzed state-level data from the US Centers for Disease Control and Prevention and other databases (2006-2020) on the number of opioid prescriptions (per 100,000 persons).
• Prescription opioids included buprenorphine (except products to treat opioid use disorder), codeine, fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxycodone, oxymorphone, propoxyphene, tapentadol, and tramadol.
• Researchers used regression analyses to account for poverty rates and real gross domestic product and a generalized difference-in-differences method that accounted for staggered implementation of cannabis laws.

TAKEAWAY:

• During the full study period, 13 states legalized recreational cannabis and 23 legalized medical cannabis.
• No statistically significant association was found between recreational cannabis laws and opioid prescriptions (3.08 fewer prescriptions per 100 persons; P = .17) or overall opioid overdose mortality (3.05 fewer deaths per 100,000; P = .24).
• The changes in outcomes associated with medical cannabis laws were larger in magnitude than those for recreational cannabis laws but also not statistically significant (3.54 additional prescriptions per 100 persons; P = .17 and 3.09 additional deaths per 100,000; P = .07).
• A potential reduction was found in synthetic opioid deaths associated specifically with states that had recreational cannabis laws (4.9 fewer deaths per 100,000; P = .04), but there were no differences in overdose deaths with other opioids.

IN PRACTICE:

“These results contrast with recent studies that suggested that recreational and medical cannabis legalization are associated with reductions in opioid prescriptions and medical cannabis legalization is associated with an increase in opioid mortality,” the authors wrote.

SOURCE:

Hai V. Nguyen, PhD, of the School of Pharmacy, Memorial University of Newfoundland, St. John’s, Canada, was the lead and corresponding author of the study. It was published online on January 19, 2024, in JAMA Health Forum.

A version of this article appeared on Medscape.com.

TOPLINE:

Legalization of recreational and medical cannabis is not associated with a reduction in opioid prescriptions or overall opioid overdose mortality, a new study suggested. However, investigators did find that recreational cannabis laws may be tied to a potential reduction in synthetic opioid deaths.

METHODOLOGY:

• Investigators analyzed state-level data from the US Centers for Disease Control and Prevention and other databases (2006-2020) on the number of opioid prescriptions (per 100,000 persons).
• Prescription opioids included buprenorphine (except products to treat opioid use disorder), codeine, fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxycodone, oxymorphone, propoxyphene, tapentadol, and tramadol.
• Researchers used regression analyses to account for poverty rates and real gross domestic product and a generalized difference-in-differences method that accounted for staggered implementation of cannabis laws.

TAKEAWAY:

• During the full study period, 13 states legalized recreational cannabis and 23 legalized medical cannabis.
• No statistically significant association was found between recreational cannabis laws and opioid prescriptions (3.08 fewer prescriptions per 100 persons; P = .17) or overall opioid overdose mortality (3.05 fewer deaths per 100,000; P = .24).
• The changes in outcomes associated with medical cannabis laws were larger in magnitude than those for recreational cannabis laws but also not statistically significant (3.54 additional prescriptions per 100 persons; P = .17 and 3.09 additional deaths per 100,000; P = .07).
• A potential reduction was found in synthetic opioid deaths associated specifically with states that had recreational cannabis laws (4.9 fewer deaths per 100,000; P = .04), but there were no differences in overdose deaths with other opioids.

IN PRACTICE:

“These results contrast with recent studies that suggested that recreational and medical cannabis legalization are associated with reductions in opioid prescriptions and medical cannabis legalization is associated with an increase in opioid mortality,” the authors wrote.

SOURCE:

Hai V. Nguyen, PhD, of the School of Pharmacy, Memorial University of Newfoundland, St. John’s, Canada, was the lead and corresponding author of the study. It was published online on January 19, 2024, in JAMA Health Forum.

A version of this article appeared on Medscape.com.

Men with metastatic castration-resistant prostate cancer (mCRPC) that had progressed despite treatment with novel hormonal therapy had a slight but statistically significant improvement in progression-free survival (PFS) with a combination of a targeted agent and immunotherapy compared with a second-line novel hormonal therapy.

The combination of the tyrosine kinase inhibitor (TKI), cabozantinib (Cabometyx), and the immune checkpoint inhibitor (ICI), atezolizumab (Tecentriq), was associated with a median PFS of 6.3 months vs 4.2 months for patients assigned to second hormonal therapy with either abiraterone (Zytiga) and prednisone, or enzalutamide (Xtandi) in the CONTACT-02 trial, Neeraj Agarwal, MD, reported at the ASCO Genitourinary Cancers Symposium. 

“CONTACT 2 is the first phase 3 trial of the TKI/ICI combination to show statistically significant improvement in PFS in patients with mCRPC,” said Dr. Agarwal, of the Huntsman Cancer Institute at the University of Utah in Salt Lake City.

­­The data support the combination of cabozantinib and atezolizumab as a potential new treatment option for patients with mCRPC that has progressed on novel hormonal therapy, he said.
 

Study Design Questioned

That opinion, however, was not shared by Kim N. Chi, MD, of the University of British Columbia in Vancouver, BC, Canada, the invited discussant.

Dr. Chi acknowledged that the study results as presented were positive, but also pointed to several limitations, including the small difference between the treatment groups in radiographic progression-free survival (rPFS).

“I would say the rPFS benefit is modest, and in the absence of other improvements the difference in the median rPFS is equivalent from one scan to the next in the scanning cycle. I would argue about the clinical significance of that,” he said.

He also noted that there was no improvement in the investigational arm in patient-reported outcomes, and that pain progression and quality-of-life deterioration occurred within 2 to 4 months, which is “quite quick.”

Additionally, he questioned the choice of an androgen receptor pathway inhibitor (ARPI) switch as the control arm of the study.

“I’d also argue that ARPI switch is not the best standard of care for this patient population with measurable disease and 40% visceral metastases; there are better options,” he said.

For example, in phase 3 trials, docetaxel and cabazitaxel (Jevtana) have consistently demonstrated radiographic PFS of 8 to 9 months. In addition, lutetium-177–PSMA-617, a radioligand therapy that delivers beta-particle radiation to PSMA-expressing cells and the tumor microenvironment, has also been shown to have PFS and overall survival benefits, he said.

“Irrespective of regulatory decisions, I personally could not recommend this at this time, given the data that we’ve seen and the better options that are available for this patient population,” Dr. Chi said.
 

Real-World Practice

“Kim Chi offered a pretty fair critique and summary of the control arm, but in real world practice, ARPI switch, from abi [abiraterone] to enza [enzalutamide] or enza to abi continues to be used in routine clinical practice for various reasons,” Xin Gao, MD, a genitourinary oncologist at Mass General Cancer Center in Boston, said in an interview.

“There are patients who can’t tolerate chemotherapy or don’t want chemotherapy, and we do know also that there are patients who can benefit from an ARPI switch, especially some patients with more indolent disease,” said Dr. Gao, who attended the presentation but was not involved in the study.

He noted that some patients being switched from abiraterone to enzalutamide have clinical responses, and that the ARPIs are generally more tolerable than chemotherapy.

In addition, CONTACT-02 is one of a series of trials in which ARPI switch was used as the control arm, and many of these trials were initiated before there were data confirming the superior efficacy of some newer therapeutic options, Dr. Gao noted.

He agreed, however that there is growing evidence to show that ARPI switch may not be the optimal choice for patients with more measurable disease, especially visceral metastases, and other more aggressive forms of mCRPC.
 

CONTACT-02 Details

Investigators in the phase 3 study screened 866 men with mCRPC and after stratification by liver metastases, prior docetaxel use for castration-sensitive prostate cancer, and disease stage for which the first novel hormonal therapy was given. About 500 patients (507) were randomized to receive either oral cabozantinib 40 mg daily plus intravenous atezolizumab 1200 mg every 3 weeks or second hormonal therapy with either abiraterone 1000 mg with oral prednisone 5 mg twice daily, or oral enzalutamide 160 mg daily.

After a median follow-up of 14.3 months in the PFS intention-to-treat population, the median ­PFS by blinded central review was 6.3 months with cabozantinib/atezolizumab and 4.2 months with second hormonal therapy. This translated into a hazard ratio of 0.64 (P = .0002). The results were similar for a PFS analysis according to Prostate Cancer Working Group 3 criteria.

The combination was also associated with modest improvements in PFS in prespecified subgroups, including patients who had liver or bone metastases and those who had previously received docetaxel.

There were no significant differences in overall survival at the time of data cutoff. Overall survival data were not mature and will be reported at a later date.

Disease control rates, a composite of complete and partial responses and stable disease, were 73% with the combination and 55% with second hormonal therapy (P value not shown).
 

Safety Data

The safety analysis indicated that patients found the ARPI switch easier to tolerate than the combination.

Adverse events leading to dose reductions occurred in 40% of patients on the combination, vs 3% of patients on second hormonal therapy, and treatment-related adverse events leading to discontinuation occurred in 13% and 2%, respectively.

Grade 3 or 4 adverse events occurred in 48% of patients assigned to the combination vs. 23% of patients assigned to the ARPI switch.

In all, 8% of patients on the combination and 12% on second hormonal therapy died on study, but none of the deaths were deemed to be treatment related.­­

CONTACT-02 was sponsored by Exelixis in partnerships with Ipsen and Takeda.

Dr. Agarwal disclosed institutional research funding from Exelixis, Roche, Takeda, and others, and travel expenses from Pfizer. Dr. Chi disclosed honoraria, a consulting/advisory role and institutional research funding with Roche and others. Dr. Gao has served as a consultant or advisor to several companies, not including the sponsors of the study, and has served as principal investigator at his institution, which has received research funding from Exelixis, Takeda, and others.

Men with metastatic castration-resistant prostate cancer (mCRPC) that had progressed despite treatment with novel hormonal therapy had a slight but statistically significant improvement in progression-free survival (PFS) with a combination of a targeted agent and immunotherapy compared with a second-line novel hormonal therapy.

The combination of the tyrosine kinase inhibitor (TKI), cabozantinib (Cabometyx), and the immune checkpoint inhibitor (ICI), atezolizumab (Tecentriq), was associated with a median PFS of 6.3 months vs 4.2 months for patients assigned to second hormonal therapy with either abiraterone (Zytiga) and prednisone, or enzalutamide (Xtandi) in the CONTACT-02 trial, Neeraj Agarwal, MD, reported at the ASCO Genitourinary Cancers Symposium. 

“CONTACT 2 is the first phase 3 trial of the TKI/ICI combination to show statistically significant improvement in PFS in patients with mCRPC,” said Dr. Agarwal, of the Huntsman Cancer Institute at the University of Utah in Salt Lake City.

­­The data support the combination of cabozantinib and atezolizumab as a potential new treatment option for patients with mCRPC that has progressed on novel hormonal therapy, he said.
 

Study Design Questioned

That opinion, however, was not shared by Kim N. Chi, MD, of the University of British Columbia in Vancouver, BC, Canada, the invited discussant.

Dr. Chi acknowledged that the study results as presented were positive, but also pointed to several limitations, including the small difference between the treatment groups in radiographic progression-free survival (rPFS).

“I would say the rPFS benefit is modest, and in the absence of other improvements the difference in the median rPFS is equivalent from one scan to the next in the scanning cycle. I would argue about the clinical significance of that,” he said.

He also noted that there was no improvement in the investigational arm in patient-reported outcomes, and that pain progression and quality-of-life deterioration occurred within 2 to 4 months, which is “quite quick.”

Additionally, he questioned the choice of an androgen receptor pathway inhibitor (ARPI) switch as the control arm of the study.

“I’d also argue that ARPI switch is not the best standard of care for this patient population with measurable disease and 40% visceral metastases; there are better options,” he said.

For example, in phase 3 trials, docetaxel and cabazitaxel (Jevtana) have consistently demonstrated radiographic PFS of 8 to 9 months. In addition, lutetium-177–PSMA-617, a radioligand therapy that delivers beta-particle radiation to PSMA-expressing cells and the tumor microenvironment, has also been shown to have PFS and overall survival benefits, he said.

“Irrespective of regulatory decisions, I personally could not recommend this at this time, given the data that we’ve seen and the better options that are available for this patient population,” Dr. Chi said.
 

Real-World Practice

“Kim Chi offered a pretty fair critique and summary of the control arm, but in real world practice, ARPI switch, from abi [abiraterone] to enza [enzalutamide] or enza to abi continues to be used in routine clinical practice for various reasons,” Xin Gao, MD, a genitourinary oncologist at Mass General Cancer Center in Boston, said in an interview.

“There are patients who can’t tolerate chemotherapy or don’t want chemotherapy, and we do know also that there are patients who can benefit from an ARPI switch, especially some patients with more indolent disease,” said Dr. Gao, who attended the presentation but was not involved in the study.

He noted that some patients being switched from abiraterone to enzalutamide have clinical responses, and that the ARPIs are generally more tolerable than chemotherapy.

In addition, CONTACT-02 is one of a series of trials in which ARPI switch was used as the control arm, and many of these trials were initiated before there were data confirming the superior efficacy of some newer therapeutic options, Dr. Gao noted.

He agreed, however that there is growing evidence to show that ARPI switch may not be the optimal choice for patients with more measurable disease, especially visceral metastases, and other more aggressive forms of mCRPC.
 

CONTACT-02 Details

Investigators in the phase 3 study screened 866 men with mCRPC and after stratification by liver metastases, prior docetaxel use for castration-sensitive prostate cancer, and disease stage for which the first novel hormonal therapy was given. About 500 patients (507) were randomized to receive either oral cabozantinib 40 mg daily plus intravenous atezolizumab 1200 mg every 3 weeks or second hormonal therapy with either abiraterone 1000 mg with oral prednisone 5 mg twice daily, or oral enzalutamide 160 mg daily.

After a median follow-up of 14.3 months in the PFS intention-to-treat population, the median ­PFS by blinded central review was 6.3 months with cabozantinib/atezolizumab and 4.2 months with second hormonal therapy. This translated into a hazard ratio of 0.64 (P = .0002). The results were similar for a PFS analysis according to Prostate Cancer Working Group 3 criteria.

The combination was also associated with modest improvements in PFS in prespecified subgroups, including patients who had liver or bone metastases and those who had previously received docetaxel.

There were no significant differences in overall survival at the time of data cutoff. Overall survival data were not mature and will be reported at a later date.

Disease control rates, a composite of complete and partial responses and stable disease, were 73% with the combination and 55% with second hormonal therapy (P value not shown).
 

Safety Data

The safety analysis indicated that patients found the ARPI switch easier to tolerate than the combination.

Adverse events leading to dose reductions occurred in 40% of patients on the combination, vs 3% of patients on second hormonal therapy, and treatment-related adverse events leading to discontinuation occurred in 13% and 2%, respectively.

Grade 3 or 4 adverse events occurred in 48% of patients assigned to the combination vs. 23% of patients assigned to the ARPI switch.

In all, 8% of patients on the combination and 12% on second hormonal therapy died on study, but none of the deaths were deemed to be treatment related.­­

CONTACT-02 was sponsored by Exelixis in partnerships with Ipsen and Takeda.

Dr. Agarwal disclosed institutional research funding from Exelixis, Roche, Takeda, and others, and travel expenses from Pfizer. Dr. Chi disclosed honoraria, a consulting/advisory role and institutional research funding with Roche and others. Dr. Gao has served as a consultant or advisor to several companies, not including the sponsors of the study, and has served as principal investigator at his institution, which has received research funding from Exelixis, Takeda, and others.

Men with metastatic castration-resistant prostate cancer (mCRPC) that had progressed despite treatment with novel hormonal therapy had a slight but statistically significant improvement in progression-free survival (PFS) with a combination of a targeted agent and immunotherapy compared with a second-line novel hormonal therapy.

The combination of the tyrosine kinase inhibitor (TKI), cabozantinib (Cabometyx), and the immune checkpoint inhibitor (ICI), atezolizumab (Tecentriq), was associated with a median PFS of 6.3 months vs 4.2 months for patients assigned to second hormonal therapy with either abiraterone (Zytiga) and prednisone, or enzalutamide (Xtandi) in the CONTACT-02 trial, Neeraj Agarwal, MD, reported at the ASCO Genitourinary Cancers Symposium. 

“CONTACT 2 is the first phase 3 trial of the TKI/ICI combination to show statistically significant improvement in PFS in patients with mCRPC,” said Dr. Agarwal, of the Huntsman Cancer Institute at the University of Utah in Salt Lake City.

­­The data support the combination of cabozantinib and atezolizumab as a potential new treatment option for patients with mCRPC that has progressed on novel hormonal therapy, he said.
 

Study Design Questioned

That opinion, however, was not shared by Kim N. Chi, MD, of the University of British Columbia in Vancouver, BC, Canada, the invited discussant.

Dr. Chi acknowledged that the study results as presented were positive, but also pointed to several limitations, including the small difference between the treatment groups in radiographic progression-free survival (rPFS).

“I would say the rPFS benefit is modest, and in the absence of other improvements the difference in the median rPFS is equivalent from one scan to the next in the scanning cycle. I would argue about the clinical significance of that,” he said.

He also noted that there was no improvement in the investigational arm in patient-reported outcomes, and that pain progression and quality-of-life deterioration occurred within 2 to 4 months, which is “quite quick.”

Additionally, he questioned the choice of an androgen receptor pathway inhibitor (ARPI) switch as the control arm of the study.

“I’d also argue that ARPI switch is not the best standard of care for this patient population with measurable disease and 40% visceral metastases; there are better options,” he said.

For example, in phase 3 trials, docetaxel and cabazitaxel (Jevtana) have consistently demonstrated radiographic PFS of 8 to 9 months. In addition, lutetium-177–PSMA-617, a radioligand therapy that delivers beta-particle radiation to PSMA-expressing cells and the tumor microenvironment, has also been shown to have PFS and overall survival benefits, he said.

“Irrespective of regulatory decisions, I personally could not recommend this at this time, given the data that we’ve seen and the better options that are available for this patient population,” Dr. Chi said.
 

Real-World Practice

“Kim Chi offered a pretty fair critique and summary of the control arm, but in real world practice, ARPI switch, from abi [abiraterone] to enza [enzalutamide] or enza to abi continues to be used in routine clinical practice for various reasons,” Xin Gao, MD, a genitourinary oncologist at Mass General Cancer Center in Boston, said in an interview.

“There are patients who can’t tolerate chemotherapy or don’t want chemotherapy, and we do know also that there are patients who can benefit from an ARPI switch, especially some patients with more indolent disease,” said Dr. Gao, who attended the presentation but was not involved in the study.

He noted that some patients being switched from abiraterone to enzalutamide have clinical responses, and that the ARPIs are generally more tolerable than chemotherapy.

In addition, CONTACT-02 is one of a series of trials in which ARPI switch was used as the control arm, and many of these trials were initiated before there were data confirming the superior efficacy of some newer therapeutic options, Dr. Gao noted.

He agreed, however that there is growing evidence to show that ARPI switch may not be the optimal choice for patients with more measurable disease, especially visceral metastases, and other more aggressive forms of mCRPC.
 

CONTACT-02 Details

Investigators in the phase 3 study screened 866 men with mCRPC and after stratification by liver metastases, prior docetaxel use for castration-sensitive prostate cancer, and disease stage for which the first novel hormonal therapy was given. About 500 patients (507) were randomized to receive either oral cabozantinib 40 mg daily plus intravenous atezolizumab 1200 mg every 3 weeks or second hormonal therapy with either abiraterone 1000 mg with oral prednisone 5 mg twice daily, or oral enzalutamide 160 mg daily.

After a median follow-up of 14.3 months in the PFS intention-to-treat population, the median ­PFS by blinded central review was 6.3 months with cabozantinib/atezolizumab and 4.2 months with second hormonal therapy. This translated into a hazard ratio of 0.64 (P = .0002). The results were similar for a PFS analysis according to Prostate Cancer Working Group 3 criteria.

The combination was also associated with modest improvements in PFS in prespecified subgroups, including patients who had liver or bone metastases and those who had previously received docetaxel.

There were no significant differences in overall survival at the time of data cutoff. Overall survival data were not mature and will be reported at a later date.

Disease control rates, a composite of complete and partial responses and stable disease, were 73% with the combination and 55% with second hormonal therapy (P value not shown).
 

Safety Data

The safety analysis indicated that patients found the ARPI switch easier to tolerate than the combination.

Adverse events leading to dose reductions occurred in 40% of patients on the combination, vs 3% of patients on second hormonal therapy, and treatment-related adverse events leading to discontinuation occurred in 13% and 2%, respectively.

Grade 3 or 4 adverse events occurred in 48% of patients assigned to the combination vs. 23% of patients assigned to the ARPI switch.

In all, 8% of patients on the combination and 12% on second hormonal therapy died on study, but none of the deaths were deemed to be treatment related.­­

CONTACT-02 was sponsored by Exelixis in partnerships with Ipsen and Takeda.

Dr. Agarwal disclosed institutional research funding from Exelixis, Roche, Takeda, and others, and travel expenses from Pfizer. Dr. Chi disclosed honoraria, a consulting/advisory role and institutional research funding with Roche and others. Dr. Gao has served as a consultant or advisor to several companies, not including the sponsors of the study, and has served as principal investigator at his institution, which has received research funding from Exelixis, Takeda, and others.

Characteristics

Rhipicephalus ticks belong to the Ixodidae family of hard-bodied ticks. They are large and teardrop shaped with an inornate scutum (hard dorsal plate) and relatively short mouthparts attached at a hexagonal basis capitulum (base of the head to which mouthparts are attached)(Figure).¹ Widely spaced eyes and festoons also are present. The first pair of coxae—attachment base for the first pair of legs—are characteristically bifid; males have a pair of sclerotized adanal plates on the ventral surface adjacent to the anus as well as accessory adanal shields.²Rhipicephalus (formerly Boophilus) microplus (the so-called cattle tick) is a newly added species; it lacks posterior festoons, and the anal groove is absent.³

Almost all Rhipicephalus ticks, except for R microplus, are 3-host ticks in which a single blood meal is consumed from a vertebrate host at each active life stage—larva, nymph, and adult—to complete development.^4,5 In contrast to most ixodid ticks, which are exophilic (living outside of human habitation), the Rhipicephalus sanguineus sensu lato species (the brown dog tick) is highly endophilic (adapted to indoor living) and often can be found hidden in cracks and crevices of walls in homes and peridomestic structures.⁶ It is predominately monotropic (all developmental stages feed on the same host species) and has a strong host preference for dogs, though it occasionally feeds on other hosts (eg, humans).⁷ Although most common in tropical and subtropical climates, they can be found anywhere there are dogs due to their ability to colonize indoor dwellings.⁸ In contrast, R microplus ticks have a predilection for cattle and livestock rather than humans, posing a notable concern to livestock worldwide. Infestation results in transmission of disease-causing pathogens, such as Babesia and Anaplasma species, which costs the cattle industry billions of dollars annually.⁹

Clinical Manifestations and Treatment

Tick bites usually manifest as intensely pruritic, erythematous papules at the site of tick attachment due to a local type IV hypersensitivity reaction to antigens in the tick’s saliva. This reaction can be long-lasting. In addition to pruritic papules following a bite, an attached tick can be mistaken for a skin neoplasm or nevus. Given that ticks are small, especially during the larval stage, dermoscopy may be helpful in making a diagnosis.¹⁰ Symptomatic relief usually can be achieved with topical antipruritics or oral antihistamines.

Of public health concern, brown dog ticks are important vectors of Rickettsia rickettsii (the causative organism of Rocky Mountain spotted fever [RMSF]) in the Western hemisphere, and Rickettsia conorii (the causative organism of Mediterranean spotted fever [MSF][also known as Boutonneuse fever]) in the Eastern hemisphere.¹¹ Bites by ticks carrying rickettsial disease classically manifest with early symptoms of fever, headache, and myalgia, followed by a rash or by a localized eschar or tache noire (a black, necrotic, scabbed lesion) that represents direct endothelial invasion and vascular damage by Rickettsia.¹² Rocky Mountain spotted fever and MSF are more prevalent during summer, likely due, in part, to the combination of increased outdoor activity and a higher rate of tick-questing (host-seeking) behavior in warmer climates.^4,7

Rocky Mountain Spotted Fever—Dermacentor variabilis is the primary vector of RMSF in the southeastern United States; Dermacentor andersoni is the major vector of RMSF in Rocky Mountain states. Rhipicephalus sanguineus sensu lato is an important vector of RMSF in the southwestern United States, Mexico, and Central America.^11,13

Early symptoms of RMSF are nonspecific and can include fever, headache, arthralgia, myalgia, and malaise. Gastrointestinal tract symptoms (eg, nausea, vomiting, anorexia) may occur; notable abdominal pain occurs in some patients, particularly children. A characteristic petechial rash occurs in as many as 90% of patients, typically at the third to fifth day of illness, and classically begins on the wrists and ankles, with progression to the palms and soles before spreading centripetally to the arms, legs, and trunk.¹⁴ An eschar at the inoculation site is uncommon in RMSF; when present, it is more suggestive of MSF.¹⁵

The classic triad of fever, headache, and rash is present in 3% of patients during the first 3 days after a tick bite and in 60% to 70% within 2 weeks.¹⁶ A rash often is absent when patients first seek medical attention and may not develop (absent in 9% to 12% of cases; so-called spotless RMSF). Therefore, absence of rash should not be a reason to withhold treatment.¹⁶ Empiric treatment with doxycycline should be started promptly for all suspected cases of RMSF because of the rapid progression of disease and an increased risk for morbidity and mortality with delayed diagnosis.

Patients do not become antibody positive until 7 to 10 days after symptoms begin; therefore, treatment should not be delayed while awaiting serologic test results. The case fatality rate in the United States is estimated to be 5% to 10% overall and as high as 40% to 50% among patients who are not treated until day 8 or 9 of illness.¹⁷

Cutaneous complications include skin necrosis and gangrene due to continuous tissue damage in severe cases.¹⁶ Severe infection also may manifest with signs of multiorgan system damage, including altered mental status, cerebral edema, meningismus, transient deafness, myocarditis, pulmonary hemorrhage and edema, conjunctivitis, retinal abnormalities, and acute renal failure.^14,16 Risk factors for more severe illness include delayed treatment, age 40 years or older or younger than 10 years, and underlying medical conditions such as alcoholic liver disease and glucose-6-phosphate dehydrogenase deficiency. However, even some healthy young patients die of this disease.¹⁷

Mediterranean Spotted Fever—Rhipicephalus sanguineus sensu lato is the primary vector of MSF, which is prevalent in areas adjacent to the Mediterranean Sea, including southern Europe, Africa, and Central Asia; Sicily is the most highly affected region.¹⁸ Findings with MSF are nearly identical to those of RMSF, except that tache noire is more common, present in as many as 70% of cases at the site of the inoculating tick bite, and MSF typically follows a less severe clinical course.¹² Similar to other rickettsial diseases, the pathogenesis of MSF involves direct injury to vascular endothelial cells, causing a vasculitis that is responsible for the clinical abnormalities observed.

Patients with severe MSF experience complications similar to severe RMSF, including neurologic manifestations and multiorgan damage.¹⁸ Risk factors include advanced age, immunocompromised state, cardiac disease, chronic alcoholism, diabetes mellitus, glucose-6-phosphate dehydrogenase deficiency, respiratory insufficiency, and delayed treatment.¹⁸

Treatment—For all spotted fever group rickettsial infections, doxycycline is the treatment of choice for all patients, including children and pregnant women. Treatment should be started without delay; recommended dosages are 100 mg twice daily for children weighing more than 45 kg and adults, and 2.2 mg/kg twice daily for children weighing 45 kg or less.¹²

Rhipicephalus tick bites rarely can result in paralysis; however, Dermacentor ticks are responsible for most cases of tick-related paralysis in North America. Other pathogens proven or reputed to be transmitted by Rhipicephalus sanguineus sensu lato with zoonotic potential include but are not limited to Rickettsia massiliae, Coxiella burnetti, Anaplasma platys, Leishmania infantum, and Crimean-Congo hemorrhagic fever virus (Nairovirus).¹⁹

Environmental Treatment and Prevention

The most effective way to prevent tick-borne illness is avoidance of tick bites. Primary prevention methods include vector control, use of repellents (eg, N,N-diethyl-meta-toluamide [DEET]), picaridin, permethrin), avoidance of areas with a high tick burden, use of protective clothing, and detection and removal of ticks as soon as possible.

Environmental and veterinary controls also are important methods of tick-bite prevention. A veterinarian can recommend a variety of agents for dogs and cats that prevent attachment of ticks. Environmental controls include synthetic or natural product-based chemical acaricides and nonchemical methods, such as landscape management (eg, sealing cracks and crevices in homes and controlling tall grasses, weeds, and leaf debris) to minimize potential tick habitat.²⁰ Secondary prevention includes antibiotics for prophylaxis or for treatment of tick-borne disease, when indicated.

Numerous tick repellents are available commercially; others are being studied. DEET, the most widely used topical repellent, has a broad spectrum of activity against many tick species.²¹ In addition, DEET has a well-known safety and toxicity profile, with rare adverse effects, and is safe for use in pregnant women and children older than 2 years. Alternative repellents, such as those containing picaridin, ethyl butylacetylaminopropionate (IR3535 [Merck]), oil of lemon eucalyptus, and 2-undecanone can be effective; some show efficacy comparable to that of DEET.²² Permethrin, a synthetic pyrethroid, is a highly efficacious tick repellent and insecticide, especially when used in conjunction with a topical repellent such as DEET. Unlike topically applied repellents, permethrin spray is applied to fabric (eg, clothing, shoes, bed nets, camping gear), not to skin.

Indiscriminate use of acaricides worldwide has led to increasing selection of acaricide resistance in Rhipicephalus tick species, which is especially true with the use of acaricides in controlling R microplus livestock infestations; several tick populations now show resistance to all major classes of these compounds.^23-25 For that reason, there has been an increasing effort to develop new chemical and nonchemical approaches to tick control that are more environmentally sustainable and strategies to minimize development and progression of resistance such as rotation of acaricides; reducing the frequency of their application; use of pesticide mixtures, synergists, or both; and increasing use of nonacaricidal methods of control.²⁶

Prompt removal of ticks is important for preventing the transmission of tick-borne disease. Proper removal involves rubbing the tick in a circular motion with a moist gauze pad or using fine-tipped tweezers to grasp the tick as close to the skin surface as possible and pulling upward with a steady pressure.^17,27 It is important not to jerk, twist, squeeze, smash, or burn the tick, as this can result in insufficient removal of mouthparts or spread contaminated tick fluids to mucous membranes, increasing the risk for infection. Application of petroleum jelly or nail polish to aid in tick removal have not been shown to be effective and are not recommended.^16,28

Characteristics

Rhipicephalus ticks belong to the Ixodidae family of hard-bodied ticks. They are large and teardrop shaped with an inornate scutum (hard dorsal plate) and relatively short mouthparts attached at a hexagonal basis capitulum (base of the head to which mouthparts are attached)(Figure).¹ Widely spaced eyes and festoons also are present. The first pair of coxae—attachment base for the first pair of legs—are characteristically bifid; males have a pair of sclerotized adanal plates on the ventral surface adjacent to the anus as well as accessory adanal shields.²Rhipicephalus (formerly Boophilus) microplus (the so-called cattle tick) is a newly added species; it lacks posterior festoons, and the anal groove is absent.³

Almost all Rhipicephalus ticks, except for R microplus, are 3-host ticks in which a single blood meal is consumed from a vertebrate host at each active life stage—larva, nymph, and adult—to complete development.^4,5 In contrast to most ixodid ticks, which are exophilic (living outside of human habitation), the Rhipicephalus sanguineus sensu lato species (the brown dog tick) is highly endophilic (adapted to indoor living) and often can be found hidden in cracks and crevices of walls in homes and peridomestic structures.⁶ It is predominately monotropic (all developmental stages feed on the same host species) and has a strong host preference for dogs, though it occasionally feeds on other hosts (eg, humans).⁷ Although most common in tropical and subtropical climates, they can be found anywhere there are dogs due to their ability to colonize indoor dwellings.⁸ In contrast, R microplus ticks have a predilection for cattle and livestock rather than humans, posing a notable concern to livestock worldwide. Infestation results in transmission of disease-causing pathogens, such as Babesia and Anaplasma species, which costs the cattle industry billions of dollars annually.⁹

Clinical Manifestations and Treatment

Tick bites usually manifest as intensely pruritic, erythematous papules at the site of tick attachment due to a local type IV hypersensitivity reaction to antigens in the tick’s saliva. This reaction can be long-lasting. In addition to pruritic papules following a bite, an attached tick can be mistaken for a skin neoplasm or nevus. Given that ticks are small, especially during the larval stage, dermoscopy may be helpful in making a diagnosis.¹⁰ Symptomatic relief usually can be achieved with topical antipruritics or oral antihistamines.

Of public health concern, brown dog ticks are important vectors of Rickettsia rickettsii (the causative organism of Rocky Mountain spotted fever [RMSF]) in the Western hemisphere, and Rickettsia conorii (the causative organism of Mediterranean spotted fever [MSF][also known as Boutonneuse fever]) in the Eastern hemisphere.¹¹ Bites by ticks carrying rickettsial disease classically manifest with early symptoms of fever, headache, and myalgia, followed by a rash or by a localized eschar or tache noire (a black, necrotic, scabbed lesion) that represents direct endothelial invasion and vascular damage by Rickettsia.¹² Rocky Mountain spotted fever and MSF are more prevalent during summer, likely due, in part, to the combination of increased outdoor activity and a higher rate of tick-questing (host-seeking) behavior in warmer climates.^4,7

Rocky Mountain Spotted Fever—Dermacentor variabilis is the primary vector of RMSF in the southeastern United States; Dermacentor andersoni is the major vector of RMSF in Rocky Mountain states. Rhipicephalus sanguineus sensu lato is an important vector of RMSF in the southwestern United States, Mexico, and Central America.^11,13

Early symptoms of RMSF are nonspecific and can include fever, headache, arthralgia, myalgia, and malaise. Gastrointestinal tract symptoms (eg, nausea, vomiting, anorexia) may occur; notable abdominal pain occurs in some patients, particularly children. A characteristic petechial rash occurs in as many as 90% of patients, typically at the third to fifth day of illness, and classically begins on the wrists and ankles, with progression to the palms and soles before spreading centripetally to the arms, legs, and trunk.¹⁴ An eschar at the inoculation site is uncommon in RMSF; when present, it is more suggestive of MSF.¹⁵

The classic triad of fever, headache, and rash is present in 3% of patients during the first 3 days after a tick bite and in 60% to 70% within 2 weeks.¹⁶ A rash often is absent when patients first seek medical attention and may not develop (absent in 9% to 12% of cases; so-called spotless RMSF). Therefore, absence of rash should not be a reason to withhold treatment.¹⁶ Empiric treatment with doxycycline should be started promptly for all suspected cases of RMSF because of the rapid progression of disease and an increased risk for morbidity and mortality with delayed diagnosis.

Patients do not become antibody positive until 7 to 10 days after symptoms begin; therefore, treatment should not be delayed while awaiting serologic test results. The case fatality rate in the United States is estimated to be 5% to 10% overall and as high as 40% to 50% among patients who are not treated until day 8 or 9 of illness.¹⁷

Cutaneous complications include skin necrosis and gangrene due to continuous tissue damage in severe cases.¹⁶ Severe infection also may manifest with signs of multiorgan system damage, including altered mental status, cerebral edema, meningismus, transient deafness, myocarditis, pulmonary hemorrhage and edema, conjunctivitis, retinal abnormalities, and acute renal failure.^14,16 Risk factors for more severe illness include delayed treatment, age 40 years or older or younger than 10 years, and underlying medical conditions such as alcoholic liver disease and glucose-6-phosphate dehydrogenase deficiency. However, even some healthy young patients die of this disease.¹⁷

Mediterranean Spotted Fever—Rhipicephalus sanguineus sensu lato is the primary vector of MSF, which is prevalent in areas adjacent to the Mediterranean Sea, including southern Europe, Africa, and Central Asia; Sicily is the most highly affected region.¹⁸ Findings with MSF are nearly identical to those of RMSF, except that tache noire is more common, present in as many as 70% of cases at the site of the inoculating tick bite, and MSF typically follows a less severe clinical course.¹² Similar to other rickettsial diseases, the pathogenesis of MSF involves direct injury to vascular endothelial cells, causing a vasculitis that is responsible for the clinical abnormalities observed.

Patients with severe MSF experience complications similar to severe RMSF, including neurologic manifestations and multiorgan damage.¹⁸ Risk factors include advanced age, immunocompromised state, cardiac disease, chronic alcoholism, diabetes mellitus, glucose-6-phosphate dehydrogenase deficiency, respiratory insufficiency, and delayed treatment.¹⁸

Treatment—For all spotted fever group rickettsial infections, doxycycline is the treatment of choice for all patients, including children and pregnant women. Treatment should be started without delay; recommended dosages are 100 mg twice daily for children weighing more than 45 kg and adults, and 2.2 mg/kg twice daily for children weighing 45 kg or less.¹²

Rhipicephalus tick bites rarely can result in paralysis; however, Dermacentor ticks are responsible for most cases of tick-related paralysis in North America. Other pathogens proven or reputed to be transmitted by Rhipicephalus sanguineus sensu lato with zoonotic potential include but are not limited to Rickettsia massiliae, Coxiella burnetti, Anaplasma platys, Leishmania infantum, and Crimean-Congo hemorrhagic fever virus (Nairovirus).¹⁹

Environmental Treatment and Prevention

The most effective way to prevent tick-borne illness is avoidance of tick bites. Primary prevention methods include vector control, use of repellents (eg, N,N-diethyl-meta-toluamide [DEET]), picaridin, permethrin), avoidance of areas with a high tick burden, use of protective clothing, and detection and removal of ticks as soon as possible.

Environmental and veterinary controls also are important methods of tick-bite prevention. A veterinarian can recommend a variety of agents for dogs and cats that prevent attachment of ticks. Environmental controls include synthetic or natural product-based chemical acaricides and nonchemical methods, such as landscape management (eg, sealing cracks and crevices in homes and controlling tall grasses, weeds, and leaf debris) to minimize potential tick habitat.²⁰ Secondary prevention includes antibiotics for prophylaxis or for treatment of tick-borne disease, when indicated.

Numerous tick repellents are available commercially; others are being studied. DEET, the most widely used topical repellent, has a broad spectrum of activity against many tick species.²¹ In addition, DEET has a well-known safety and toxicity profile, with rare adverse effects, and is safe for use in pregnant women and children older than 2 years. Alternative repellents, such as those containing picaridin, ethyl butylacetylaminopropionate (IR3535 [Merck]), oil of lemon eucalyptus, and 2-undecanone can be effective; some show efficacy comparable to that of DEET.²² Permethrin, a synthetic pyrethroid, is a highly efficacious tick repellent and insecticide, especially when used in conjunction with a topical repellent such as DEET. Unlike topically applied repellents, permethrin spray is applied to fabric (eg, clothing, shoes, bed nets, camping gear), not to skin.

Indiscriminate use of acaricides worldwide has led to increasing selection of acaricide resistance in Rhipicephalus tick species, which is especially true with the use of acaricides in controlling R microplus livestock infestations; several tick populations now show resistance to all major classes of these compounds.^23-25 For that reason, there has been an increasing effort to develop new chemical and nonchemical approaches to tick control that are more environmentally sustainable and strategies to minimize development and progression of resistance such as rotation of acaricides; reducing the frequency of their application; use of pesticide mixtures, synergists, or both; and increasing use of nonacaricidal methods of control.²⁶

Prompt removal of ticks is important for preventing the transmission of tick-borne disease. Proper removal involves rubbing the tick in a circular motion with a moist gauze pad or using fine-tipped tweezers to grasp the tick as close to the skin surface as possible and pulling upward with a steady pressure.^17,27 It is important not to jerk, twist, squeeze, smash, or burn the tick, as this can result in insufficient removal of mouthparts or spread contaminated tick fluids to mucous membranes, increasing the risk for infection. Application of petroleum jelly or nail polish to aid in tick removal have not been shown to be effective and are not recommended.^16,28

Characteristics

Rhipicephalus ticks belong to the Ixodidae family of hard-bodied ticks. They are large and teardrop shaped with an inornate scutum (hard dorsal plate) and relatively short mouthparts attached at a hexagonal basis capitulum (base of the head to which mouthparts are attached)(Figure).¹ Widely spaced eyes and festoons also are present. The first pair of coxae—attachment base for the first pair of legs—are characteristically bifid; males have a pair of sclerotized adanal plates on the ventral surface adjacent to the anus as well as accessory adanal shields.²Rhipicephalus (formerly Boophilus) microplus (the so-called cattle tick) is a newly added species; it lacks posterior festoons, and the anal groove is absent.³

Almost all Rhipicephalus ticks, except for R microplus, are 3-host ticks in which a single blood meal is consumed from a vertebrate host at each active life stage—larva, nymph, and adult—to complete development.^4,5 In contrast to most ixodid ticks, which are exophilic (living outside of human habitation), the Rhipicephalus sanguineus sensu lato species (the brown dog tick) is highly endophilic (adapted to indoor living) and often can be found hidden in cracks and crevices of walls in homes and peridomestic structures.⁶ It is predominately monotropic (all developmental stages feed on the same host species) and has a strong host preference for dogs, though it occasionally feeds on other hosts (eg, humans).⁷ Although most common in tropical and subtropical climates, they can be found anywhere there are dogs due to their ability to colonize indoor dwellings.⁸ In contrast, R microplus ticks have a predilection for cattle and livestock rather than humans, posing a notable concern to livestock worldwide. Infestation results in transmission of disease-causing pathogens, such as Babesia and Anaplasma species, which costs the cattle industry billions of dollars annually.⁹

Clinical Manifestations and Treatment

Tick bites usually manifest as intensely pruritic, erythematous papules at the site of tick attachment due to a local type IV hypersensitivity reaction to antigens in the tick’s saliva. This reaction can be long-lasting. In addition to pruritic papules following a bite, an attached tick can be mistaken for a skin neoplasm or nevus. Given that ticks are small, especially during the larval stage, dermoscopy may be helpful in making a diagnosis.¹⁰ Symptomatic relief usually can be achieved with topical antipruritics or oral antihistamines.

Of public health concern, brown dog ticks are important vectors of Rickettsia rickettsii (the causative organism of Rocky Mountain spotted fever [RMSF]) in the Western hemisphere, and Rickettsia conorii (the causative organism of Mediterranean spotted fever [MSF][also known as Boutonneuse fever]) in the Eastern hemisphere.¹¹ Bites by ticks carrying rickettsial disease classically manifest with early symptoms of fever, headache, and myalgia, followed by a rash or by a localized eschar or tache noire (a black, necrotic, scabbed lesion) that represents direct endothelial invasion and vascular damage by Rickettsia.¹² Rocky Mountain spotted fever and MSF are more prevalent during summer, likely due, in part, to the combination of increased outdoor activity and a higher rate of tick-questing (host-seeking) behavior in warmer climates.^4,7

Rocky Mountain Spotted Fever—Dermacentor variabilis is the primary vector of RMSF in the southeastern United States; Dermacentor andersoni is the major vector of RMSF in Rocky Mountain states. Rhipicephalus sanguineus sensu lato is an important vector of RMSF in the southwestern United States, Mexico, and Central America.^11,13

Early symptoms of RMSF are nonspecific and can include fever, headache, arthralgia, myalgia, and malaise. Gastrointestinal tract symptoms (eg, nausea, vomiting, anorexia) may occur; notable abdominal pain occurs in some patients, particularly children. A characteristic petechial rash occurs in as many as 90% of patients, typically at the third to fifth day of illness, and classically begins on the wrists and ankles, with progression to the palms and soles before spreading centripetally to the arms, legs, and trunk.¹⁴ An eschar at the inoculation site is uncommon in RMSF; when present, it is more suggestive of MSF.¹⁵

The classic triad of fever, headache, and rash is present in 3% of patients during the first 3 days after a tick bite and in 60% to 70% within 2 weeks.¹⁶ A rash often is absent when patients first seek medical attention and may not develop (absent in 9% to 12% of cases; so-called spotless RMSF). Therefore, absence of rash should not be a reason to withhold treatment.¹⁶ Empiric treatment with doxycycline should be started promptly for all suspected cases of RMSF because of the rapid progression of disease and an increased risk for morbidity and mortality with delayed diagnosis.

Patients do not become antibody positive until 7 to 10 days after symptoms begin; therefore, treatment should not be delayed while awaiting serologic test results. The case fatality rate in the United States is estimated to be 5% to 10% overall and as high as 40% to 50% among patients who are not treated until day 8 or 9 of illness.¹⁷

Cutaneous complications include skin necrosis and gangrene due to continuous tissue damage in severe cases.¹⁶ Severe infection also may manifest with signs of multiorgan system damage, including altered mental status, cerebral edema, meningismus, transient deafness, myocarditis, pulmonary hemorrhage and edema, conjunctivitis, retinal abnormalities, and acute renal failure.^14,16 Risk factors for more severe illness include delayed treatment, age 40 years or older or younger than 10 years, and underlying medical conditions such as alcoholic liver disease and glucose-6-phosphate dehydrogenase deficiency. However, even some healthy young patients die of this disease.¹⁷

Mediterranean Spotted Fever—Rhipicephalus sanguineus sensu lato is the primary vector of MSF, which is prevalent in areas adjacent to the Mediterranean Sea, including southern Europe, Africa, and Central Asia; Sicily is the most highly affected region.¹⁸ Findings with MSF are nearly identical to those of RMSF, except that tache noire is more common, present in as many as 70% of cases at the site of the inoculating tick bite, and MSF typically follows a less severe clinical course.¹² Similar to other rickettsial diseases, the pathogenesis of MSF involves direct injury to vascular endothelial cells, causing a vasculitis that is responsible for the clinical abnormalities observed.

Patients with severe MSF experience complications similar to severe RMSF, including neurologic manifestations and multiorgan damage.¹⁸ Risk factors include advanced age, immunocompromised state, cardiac disease, chronic alcoholism, diabetes mellitus, glucose-6-phosphate dehydrogenase deficiency, respiratory insufficiency, and delayed treatment.¹⁸

Treatment—For all spotted fever group rickettsial infections, doxycycline is the treatment of choice for all patients, including children and pregnant women. Treatment should be started without delay; recommended dosages are 100 mg twice daily for children weighing more than 45 kg and adults, and 2.2 mg/kg twice daily for children weighing 45 kg or less.¹²

Rhipicephalus tick bites rarely can result in paralysis; however, Dermacentor ticks are responsible for most cases of tick-related paralysis in North America. Other pathogens proven or reputed to be transmitted by Rhipicephalus sanguineus sensu lato with zoonotic potential include but are not limited to Rickettsia massiliae, Coxiella burnetti, Anaplasma platys, Leishmania infantum, and Crimean-Congo hemorrhagic fever virus (Nairovirus).¹⁹

Environmental Treatment and Prevention

The most effective way to prevent tick-borne illness is avoidance of tick bites. Primary prevention methods include vector control, use of repellents (eg, N,N-diethyl-meta-toluamide [DEET]), picaridin, permethrin), avoidance of areas with a high tick burden, use of protective clothing, and detection and removal of ticks as soon as possible.

Environmental and veterinary controls also are important methods of tick-bite prevention. A veterinarian can recommend a variety of agents for dogs and cats that prevent attachment of ticks. Environmental controls include synthetic or natural product-based chemical acaricides and nonchemical methods, such as landscape management (eg, sealing cracks and crevices in homes and controlling tall grasses, weeds, and leaf debris) to minimize potential tick habitat.²⁰ Secondary prevention includes antibiotics for prophylaxis or for treatment of tick-borne disease, when indicated.

Numerous tick repellents are available commercially; others are being studied. DEET, the most widely used topical repellent, has a broad spectrum of activity against many tick species.²¹ In addition, DEET has a well-known safety and toxicity profile, with rare adverse effects, and is safe for use in pregnant women and children older than 2 years. Alternative repellents, such as those containing picaridin, ethyl butylacetylaminopropionate (IR3535 [Merck]), oil of lemon eucalyptus, and 2-undecanone can be effective; some show efficacy comparable to that of DEET.²² Permethrin, a synthetic pyrethroid, is a highly efficacious tick repellent and insecticide, especially when used in conjunction with a topical repellent such as DEET. Unlike topically applied repellents, permethrin spray is applied to fabric (eg, clothing, shoes, bed nets, camping gear), not to skin.

Indiscriminate use of acaricides worldwide has led to increasing selection of acaricide resistance in Rhipicephalus tick species, which is especially true with the use of acaricides in controlling R microplus livestock infestations; several tick populations now show resistance to all major classes of these compounds.^23-25 For that reason, there has been an increasing effort to develop new chemical and nonchemical approaches to tick control that are more environmentally sustainable and strategies to minimize development and progression of resistance such as rotation of acaricides; reducing the frequency of their application; use of pesticide mixtures, synergists, or both; and increasing use of nonacaricidal methods of control.²⁶

Prompt removal of ticks is important for preventing the transmission of tick-borne disease. Proper removal involves rubbing the tick in a circular motion with a moist gauze pad or using fine-tipped tweezers to grasp the tick as close to the skin surface as possible and pulling upward with a steady pressure.^17,27 It is important not to jerk, twist, squeeze, smash, or burn the tick, as this can result in insufficient removal of mouthparts or spread contaminated tick fluids to mucous membranes, increasing the risk for infection. Application of petroleum jelly or nail polish to aid in tick removal have not been shown to be effective and are not recommended.^16,28

To curb alcohol-associated liver disease (ALD), alcohol consumption should be avoided among those with underlying obesity, chronic hepatitis C infection, hepatitis B virus infection, or a history of gastric bypass, according to a new clinical guideline from the American College of Gastroenterology.

In addition, health systems need to overcome barriers to treating alcohol use disorder (AUD) and commit to creating a multidisciplinary care model with behavioral interventions and pharmacotherapy for patients.

Experts were convened to develop these guidelines because it was “imperative to provide an up-to-date, evidence-based blueprint for how to care for patients, as well as guide prevention and research efforts in the field of ALD for the coming years,” said the first author, Loretta Jophlin, MD, PhD, assistant professor of medicine in gastroenterology, hepatology, and nutrition and medical director of liver transplantation at the University of Louisville in Kentucky.

“In recent years, perhaps fueled by the COVID-19 pandemic, alcohol use has been normalized in an increasing number of situations,” she said. “Drinking was normalized as a coping mechanism to deal with many of the sorrows we experienced during the pandemic, including loss of purposeful work and social isolation, and many more people are struggling with AUD. So many aspects of our culture have been inundated by the presence of alcohol use, and we need to work hard to denormalize this, first focusing on at-risk populations.”

The guideline was published in the January issue of the American Journal of Gastroenterology.
 

Updating ALD Recommendations

With ALD as the most common cause of advanced hepatic disease and a frequent indicator of eventual liver transplantation, the rising incidence of alcohol use during the past decade has led to rapid growth in ALD-related healthcare burdens, the guideline authors wrote.

In particular, those with ALD tend to present at an advanced stage and progress faster, which can lead to progressive fibrosis, cirrhosis, and hepatocellular carcinoma. This can include alcohol-associated hepatitis (AH), which often presents with a rapid onset or worsening of jaundice and can lead to acute or chronic liver failure.

To update the guideline, Dr. Jophlin and colleagues analyzed data based on a patient-intervention-comparison-outcome format, resulting in 34 key concepts or statements and 21 recommendations.

Among them, the authors recommended screening and treating AUD with the goal of helping patients who have not yet developed significant liver injury and preventing progression to advanced stages of ALD, particularly among at-risk groups who have had an increasing prevalence of severe AUD, including women, younger people, and Hispanic and American Indian patients.

“So many patients are still told to ‘stop drinking’ or ‘cut back’ but are provided no additional resources. Without offering referrals to treatment programs or pharmacologic therapies to assist in abstinence, many patients are not successful,” Dr. Jophlin said. “We hope these guidelines empower providers to consider selected [Food and Drug Administration]-approved medications, well-studied off-label therapies, and nonpharmacologic interventions to aid their patients’ journeys to abstinence and hopefully avert the progression of ALD.”

In addition, the guidelines provide recommendations for AH treatment. In patients with severe AH, the authors offered strong recommendations against the use of pentoxifylline and prophylactic antibiotics, and in support of corticosteroid therapy and intravenous N-acetyl cysteine as an adjuvant to corticosteroids.

Liver transplantation, which may be recommended for carefully selected patients, is being performed at many centers but remains relatively controversial, Dr. Jophlin said.

“Questions remain about ideal patient selection as center practices vary considerably, yet we have started to realize the impacts of relapse after transplantation,” she said. “The guidelines highlight the knowns and unknowns in this area and will hopefully serve as a catalyst for the dissemination of centers’ experiences and the development of a universal set of ethically sound, evidence-based guidelines to be used by all transplant centers.”
 

Policy Implications

Dr. Jophlin and colleagues noted the importance of policy aimed at alcohol use reduction, multidisciplinary care for AUD and ALD, and additional research around severe AH.

“As a practicing transplant hepatologist and medical director of a liver transplant program in the heart of Bourbon country, I am a part of just one healthcare team experiencing ALD, particularly AH, as a mass casualty event. Healthcare teams are fighting an unrelenting fire that the alcohol industry is pouring gasoline on,” Dr. Jophlin said. “It is imperative that healthcare providers have a voice in the policies that shape this preventable disease. We hope these guidelines inspire practitioners to explore our influence on how alcohol is regulated, marketed, and distributed.”

Additional interventions and public policy considerations could help reduce alcohol-related morbidity and mortality at a moment when the characteristics of those who present with AUD appear to be evolving.

“The typical person I’m seeing now is not someone who has been drinking heavily for decades. Rather, it’s a young person who has been drinking heavily for many months or a couple of years,” said James Burton, MD, a professor of medicine at the University of Colorado School of Medicine and medical director of liver transplantation at the University of Colorado Hospital’s Anschutz Medical Campus in Aurora.

Dr. Burton, who wasn’t involved with the guideline, noted it’s become more common for people to drink multiple alcoholic drinks per day for multiple times per week. Patients often don’t think it’s a problem, even as he discusses their liver-related issues.

“We can’t just keep living and working the way we were 10 years ago,” he said. “We’ve got to change how we approach treatment. We have to treat liver disease and AUD.”

The guideline was supported by several National Institutes of Health grants and an American College of Gastroenterology faculty development grant. The authors declared potential competing interests with various pharmaceutical companies. Dr. Burton reported no financial disclosures.

A version of this article appeared on Medscape.com.

To curb alcohol-associated liver disease (ALD), alcohol consumption should be avoided among those with underlying obesity, chronic hepatitis C infection, hepatitis B virus infection, or a history of gastric bypass, according to a new clinical guideline from the American College of Gastroenterology.

In addition, health systems need to overcome barriers to treating alcohol use disorder (AUD) and commit to creating a multidisciplinary care model with behavioral interventions and pharmacotherapy for patients.

Experts were convened to develop these guidelines because it was “imperative to provide an up-to-date, evidence-based blueprint for how to care for patients, as well as guide prevention and research efforts in the field of ALD for the coming years,” said the first author, Loretta Jophlin, MD, PhD, assistant professor of medicine in gastroenterology, hepatology, and nutrition and medical director of liver transplantation at the University of Louisville in Kentucky.

“In recent years, perhaps fueled by the COVID-19 pandemic, alcohol use has been normalized in an increasing number of situations,” she said. “Drinking was normalized as a coping mechanism to deal with many of the sorrows we experienced during the pandemic, including loss of purposeful work and social isolation, and many more people are struggling with AUD. So many aspects of our culture have been inundated by the presence of alcohol use, and we need to work hard to denormalize this, first focusing on at-risk populations.”

The guideline was published in the January issue of the American Journal of Gastroenterology.
 

Updating ALD Recommendations

With ALD as the most common cause of advanced hepatic disease and a frequent indicator of eventual liver transplantation, the rising incidence of alcohol use during the past decade has led to rapid growth in ALD-related healthcare burdens, the guideline authors wrote.

In particular, those with ALD tend to present at an advanced stage and progress faster, which can lead to progressive fibrosis, cirrhosis, and hepatocellular carcinoma. This can include alcohol-associated hepatitis (AH), which often presents with a rapid onset or worsening of jaundice and can lead to acute or chronic liver failure.

To update the guideline, Dr. Jophlin and colleagues analyzed data based on a patient-intervention-comparison-outcome format, resulting in 34 key concepts or statements and 21 recommendations.

Among them, the authors recommended screening and treating AUD with the goal of helping patients who have not yet developed significant liver injury and preventing progression to advanced stages of ALD, particularly among at-risk groups who have had an increasing prevalence of severe AUD, including women, younger people, and Hispanic and American Indian patients.

“So many patients are still told to ‘stop drinking’ or ‘cut back’ but are provided no additional resources. Without offering referrals to treatment programs or pharmacologic therapies to assist in abstinence, many patients are not successful,” Dr. Jophlin said. “We hope these guidelines empower providers to consider selected [Food and Drug Administration]-approved medications, well-studied off-label therapies, and nonpharmacologic interventions to aid their patients’ journeys to abstinence and hopefully avert the progression of ALD.”

In addition, the guidelines provide recommendations for AH treatment. In patients with severe AH, the authors offered strong recommendations against the use of pentoxifylline and prophylactic antibiotics, and in support of corticosteroid therapy and intravenous N-acetyl cysteine as an adjuvant to corticosteroids.

Liver transplantation, which may be recommended for carefully selected patients, is being performed at many centers but remains relatively controversial, Dr. Jophlin said.

“Questions remain about ideal patient selection as center practices vary considerably, yet we have started to realize the impacts of relapse after transplantation,” she said. “The guidelines highlight the knowns and unknowns in this area and will hopefully serve as a catalyst for the dissemination of centers’ experiences and the development of a universal set of ethically sound, evidence-based guidelines to be used by all transplant centers.”
 

Policy Implications

Dr. Jophlin and colleagues noted the importance of policy aimed at alcohol use reduction, multidisciplinary care for AUD and ALD, and additional research around severe AH.

“As a practicing transplant hepatologist and medical director of a liver transplant program in the heart of Bourbon country, I am a part of just one healthcare team experiencing ALD, particularly AH, as a mass casualty event. Healthcare teams are fighting an unrelenting fire that the alcohol industry is pouring gasoline on,” Dr. Jophlin said. “It is imperative that healthcare providers have a voice in the policies that shape this preventable disease. We hope these guidelines inspire practitioners to explore our influence on how alcohol is regulated, marketed, and distributed.”

Additional interventions and public policy considerations could help reduce alcohol-related morbidity and mortality at a moment when the characteristics of those who present with AUD appear to be evolving.

“The typical person I’m seeing now is not someone who has been drinking heavily for decades. Rather, it’s a young person who has been drinking heavily for many months or a couple of years,” said James Burton, MD, a professor of medicine at the University of Colorado School of Medicine and medical director of liver transplantation at the University of Colorado Hospital’s Anschutz Medical Campus in Aurora.

Dr. Burton, who wasn’t involved with the guideline, noted it’s become more common for people to drink multiple alcoholic drinks per day for multiple times per week. Patients often don’t think it’s a problem, even as he discusses their liver-related issues.

“We can’t just keep living and working the way we were 10 years ago,” he said. “We’ve got to change how we approach treatment. We have to treat liver disease and AUD.”

The guideline was supported by several National Institutes of Health grants and an American College of Gastroenterology faculty development grant. The authors declared potential competing interests with various pharmaceutical companies. Dr. Burton reported no financial disclosures.

A version of this article appeared on Medscape.com.

To curb alcohol-associated liver disease (ALD), alcohol consumption should be avoided among those with underlying obesity, chronic hepatitis C infection, hepatitis B virus infection, or a history of gastric bypass, according to a new clinical guideline from the American College of Gastroenterology.

In addition, health systems need to overcome barriers to treating alcohol use disorder (AUD) and commit to creating a multidisciplinary care model with behavioral interventions and pharmacotherapy for patients.

Experts were convened to develop these guidelines because it was “imperative to provide an up-to-date, evidence-based blueprint for how to care for patients, as well as guide prevention and research efforts in the field of ALD for the coming years,” said the first author, Loretta Jophlin, MD, PhD, assistant professor of medicine in gastroenterology, hepatology, and nutrition and medical director of liver transplantation at the University of Louisville in Kentucky.

“In recent years, perhaps fueled by the COVID-19 pandemic, alcohol use has been normalized in an increasing number of situations,” she said. “Drinking was normalized as a coping mechanism to deal with many of the sorrows we experienced during the pandemic, including loss of purposeful work and social isolation, and many more people are struggling with AUD. So many aspects of our culture have been inundated by the presence of alcohol use, and we need to work hard to denormalize this, first focusing on at-risk populations.”

The guideline was published in the January issue of the American Journal of Gastroenterology.
 

Updating ALD Recommendations

With ALD as the most common cause of advanced hepatic disease and a frequent indicator of eventual liver transplantation, the rising incidence of alcohol use during the past decade has led to rapid growth in ALD-related healthcare burdens, the guideline authors wrote.

In particular, those with ALD tend to present at an advanced stage and progress faster, which can lead to progressive fibrosis, cirrhosis, and hepatocellular carcinoma. This can include alcohol-associated hepatitis (AH), which often presents with a rapid onset or worsening of jaundice and can lead to acute or chronic liver failure.

To update the guideline, Dr. Jophlin and colleagues analyzed data based on a patient-intervention-comparison-outcome format, resulting in 34 key concepts or statements and 21 recommendations.

Among them, the authors recommended screening and treating AUD with the goal of helping patients who have not yet developed significant liver injury and preventing progression to advanced stages of ALD, particularly among at-risk groups who have had an increasing prevalence of severe AUD, including women, younger people, and Hispanic and American Indian patients.

“So many patients are still told to ‘stop drinking’ or ‘cut back’ but are provided no additional resources. Without offering referrals to treatment programs or pharmacologic therapies to assist in abstinence, many patients are not successful,” Dr. Jophlin said. “We hope these guidelines empower providers to consider selected [Food and Drug Administration]-approved medications, well-studied off-label therapies, and nonpharmacologic interventions to aid their patients’ journeys to abstinence and hopefully avert the progression of ALD.”

In addition, the guidelines provide recommendations for AH treatment. In patients with severe AH, the authors offered strong recommendations against the use of pentoxifylline and prophylactic antibiotics, and in support of corticosteroid therapy and intravenous N-acetyl cysteine as an adjuvant to corticosteroids.

Liver transplantation, which may be recommended for carefully selected patients, is being performed at many centers but remains relatively controversial, Dr. Jophlin said.

“Questions remain about ideal patient selection as center practices vary considerably, yet we have started to realize the impacts of relapse after transplantation,” she said. “The guidelines highlight the knowns and unknowns in this area and will hopefully serve as a catalyst for the dissemination of centers’ experiences and the development of a universal set of ethically sound, evidence-based guidelines to be used by all transplant centers.”
 

Policy Implications

Dr. Jophlin and colleagues noted the importance of policy aimed at alcohol use reduction, multidisciplinary care for AUD and ALD, and additional research around severe AH.

“As a practicing transplant hepatologist and medical director of a liver transplant program in the heart of Bourbon country, I am a part of just one healthcare team experiencing ALD, particularly AH, as a mass casualty event. Healthcare teams are fighting an unrelenting fire that the alcohol industry is pouring gasoline on,” Dr. Jophlin said. “It is imperative that healthcare providers have a voice in the policies that shape this preventable disease. We hope these guidelines inspire practitioners to explore our influence on how alcohol is regulated, marketed, and distributed.”

Additional interventions and public policy considerations could help reduce alcohol-related morbidity and mortality at a moment when the characteristics of those who present with AUD appear to be evolving.

“The typical person I’m seeing now is not someone who has been drinking heavily for decades. Rather, it’s a young person who has been drinking heavily for many months or a couple of years,” said James Burton, MD, a professor of medicine at the University of Colorado School of Medicine and medical director of liver transplantation at the University of Colorado Hospital’s Anschutz Medical Campus in Aurora.

Dr. Burton, who wasn’t involved with the guideline, noted it’s become more common for people to drink multiple alcoholic drinks per day for multiple times per week. Patients often don’t think it’s a problem, even as he discusses their liver-related issues.

“We can’t just keep living and working the way we were 10 years ago,” he said. “We’ve got to change how we approach treatment. We have to treat liver disease and AUD.”

The guideline was supported by several National Institutes of Health grants and an American College of Gastroenterology faculty development grant. The authors declared potential competing interests with various pharmaceutical companies. Dr. Burton reported no financial disclosures.

A version of this article appeared on Medscape.com.

TOPLINE:

Patients with heart failure (HF) and depression who receive psychotherapy have the same (almost 50% reduction) in depressive symptoms as those treated with pharmacotherapy, show more improvement in physical-related quality of life, and are less likely to visit emergency departments (EDs), a comparative trial of these interventions found.

METHODOLOGY:

• The study included 416 patients with HF and a confirmed depressive disorder from the Cedars-Sinai Health System, with a mean age of 60.71 years, including nearly 42% women and 30% Black individuals, who were randomized to receive one of two evidence-based treatments for depression in HF: Antidepressant medication management (MEDS) or behavioral activation (BA) psychotherapy. BA therapy promotes engaging in pleasurable and rewarding activities without delving into complex cognitive domains explored in cognitive behavioral therapy, another psychotherapy type.
• All patients received 12 weekly sessions delivered via video or telephone, followed by monthly sessions for 3 months, and were then contacted as needed for an additional 6 months.
• The primary outcome was depressive symptom severity at 6 months, measured by the Patient Health Questionnaire 9-Item (PHQ-9), and secondary outcomes included three measures of health-related quality of life (HRQOL) — caregiver burden, morbidity, and mortality — collected at 3, 6, and 12 months.
• Physical and mental HRQOL were measured with the 12-Item Short-Form Medical Outcomes Study (SF-12), HF-specific HRQOL with the 23-item patient-reported Kansas City Cardiomyopathy Questionnaire, caregiver burden with the 26-item Caregiver Burden Questionnaire for HF, morbidity by ED visits, hospital readmissions, and days hospitalized, and mortality data came from medical records and family or caregiver reports, with survival assessed using Kaplan-Meier plots at 3, 6, and 12 months.
• Covariates included age, sex, race, ethnicity, marital status, employment, education, insurance type, recruitment site (inpatient or outpatient), ejection fraction (preserved or reduced), New York Heart Association class, medical history, and medications.

TAKEAWAY:

• Depressive symptom severity was reduced at 6 months by nearly 50% for both BA (mean PHQ-9 score, 7.53; P vs baseline < .001) and MEDS (mean PHQ-9 score, 8.09; P vs baseline < .001) participants, with reductions persisting at 12 months and no significant difference between groups.
• Compared with MEDS recipients, those who received BA had slightly higher improvement in physical HRQOL at 6 months (multivariable mean difference without imputation, 2.13; 95% CI, 0.06-4.20; P = .04), but there were no statistically significant differences between groups in mental HRQOL, HF-specific HRQOL, or caregiver burden at 3, 6, or 12 months.
• Patients who received BA were significantly less likely than those in the MEDS group to have ED visits and spent fewer days in hospital at 3, 6, and 12 months, but there was no significant difference in number of hospital readmissions or in mortality at 3, 6, or 12 months.

IN PRACTICE:

“Our findings of comparable primary effects between BA and MEDS suggest both options are effective and that personal preferences, patient values, and availability of services could inform decisions,” the authors wrote. They noted BA has no pharmacological adverse effects but requires more engagement than drug therapy and might be less accessible.

SOURCE:

The study was conducted by Waguih William IsHak, MD, Department of Psychiatry and Behavioral Neurosciences, Cedars-Sinai Medical Center, Los Angeles, and others. It was published online on January 17, 2024, in JAMA Network Open.

LIMITATIONS:

As the study had no control group, such as a waiting list, it was impossible to draw conclusions about the natural course of depressive symptoms in HF. However, the authors noted improvements were sustained at 12 months despite substantially diminished contact with intervention teams after 6 months. Researchers were unable to collect data for ED visits, readmissions, and hospital stays outside of California and didn’t assess treatment preference at enrollment, which could have helped inform the association with outcomes and adherence.

DISCLOSURES:

The study was funded by the Patient-Centered Outcome Research Institute, paid to Cedars-Sinai Medical Center. Dr. IsHak reported receiving royalties from Springer Nature and Cambridge University Press. No other disclosures were reported.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Patients with heart failure (HF) and depression who receive psychotherapy have the same (almost 50% reduction) in depressive symptoms as those treated with pharmacotherapy, show more improvement in physical-related quality of life, and are less likely to visit emergency departments (EDs), a comparative trial of these interventions found.

METHODOLOGY:

• The study included 416 patients with HF and a confirmed depressive disorder from the Cedars-Sinai Health System, with a mean age of 60.71 years, including nearly 42% women and 30% Black individuals, who were randomized to receive one of two evidence-based treatments for depression in HF: Antidepressant medication management (MEDS) or behavioral activation (BA) psychotherapy. BA therapy promotes engaging in pleasurable and rewarding activities without delving into complex cognitive domains explored in cognitive behavioral therapy, another psychotherapy type.
• All patients received 12 weekly sessions delivered via video or telephone, followed by monthly sessions for 3 months, and were then contacted as needed for an additional 6 months.
• The primary outcome was depressive symptom severity at 6 months, measured by the Patient Health Questionnaire 9-Item (PHQ-9), and secondary outcomes included three measures of health-related quality of life (HRQOL) — caregiver burden, morbidity, and mortality — collected at 3, 6, and 12 months.
• Physical and mental HRQOL were measured with the 12-Item Short-Form Medical Outcomes Study (SF-12), HF-specific HRQOL with the 23-item patient-reported Kansas City Cardiomyopathy Questionnaire, caregiver burden with the 26-item Caregiver Burden Questionnaire for HF, morbidity by ED visits, hospital readmissions, and days hospitalized, and mortality data came from medical records and family or caregiver reports, with survival assessed using Kaplan-Meier plots at 3, 6, and 12 months.
• Covariates included age, sex, race, ethnicity, marital status, employment, education, insurance type, recruitment site (inpatient or outpatient), ejection fraction (preserved or reduced), New York Heart Association class, medical history, and medications.

TAKEAWAY:

• Depressive symptom severity was reduced at 6 months by nearly 50% for both BA (mean PHQ-9 score, 7.53; P vs baseline < .001) and MEDS (mean PHQ-9 score, 8.09; P vs baseline < .001) participants, with reductions persisting at 12 months and no significant difference between groups.
• Compared with MEDS recipients, those who received BA had slightly higher improvement in physical HRQOL at 6 months (multivariable mean difference without imputation, 2.13; 95% CI, 0.06-4.20; P = .04), but there were no statistically significant differences between groups in mental HRQOL, HF-specific HRQOL, or caregiver burden at 3, 6, or 12 months.
• Patients who received BA were significantly less likely than those in the MEDS group to have ED visits and spent fewer days in hospital at 3, 6, and 12 months, but there was no significant difference in number of hospital readmissions or in mortality at 3, 6, or 12 months.

IN PRACTICE:

“Our findings of comparable primary effects between BA and MEDS suggest both options are effective and that personal preferences, patient values, and availability of services could inform decisions,” the authors wrote. They noted BA has no pharmacological adverse effects but requires more engagement than drug therapy and might be less accessible.

SOURCE:

The study was conducted by Waguih William IsHak, MD, Department of Psychiatry and Behavioral Neurosciences, Cedars-Sinai Medical Center, Los Angeles, and others. It was published online on January 17, 2024, in JAMA Network Open.

LIMITATIONS:

As the study had no control group, such as a waiting list, it was impossible to draw conclusions about the natural course of depressive symptoms in HF. However, the authors noted improvements were sustained at 12 months despite substantially diminished contact with intervention teams after 6 months. Researchers were unable to collect data for ED visits, readmissions, and hospital stays outside of California and didn’t assess treatment preference at enrollment, which could have helped inform the association with outcomes and adherence.

DISCLOSURES:

The study was funded by the Patient-Centered Outcome Research Institute, paid to Cedars-Sinai Medical Center. Dr. IsHak reported receiving royalties from Springer Nature and Cambridge University Press. No other disclosures were reported.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Patients with heart failure (HF) and depression who receive psychotherapy have the same (almost 50% reduction) in depressive symptoms as those treated with pharmacotherapy, show more improvement in physical-related quality of life, and are less likely to visit emergency departments (EDs), a comparative trial of these interventions found.

METHODOLOGY:

• The study included 416 patients with HF and a confirmed depressive disorder from the Cedars-Sinai Health System, with a mean age of 60.71 years, including nearly 42% women and 30% Black individuals, who were randomized to receive one of two evidence-based treatments for depression in HF: Antidepressant medication management (MEDS) or behavioral activation (BA) psychotherapy. BA therapy promotes engaging in pleasurable and rewarding activities without delving into complex cognitive domains explored in cognitive behavioral therapy, another psychotherapy type.
• All patients received 12 weekly sessions delivered via video or telephone, followed by monthly sessions for 3 months, and were then contacted as needed for an additional 6 months.
• The primary outcome was depressive symptom severity at 6 months, measured by the Patient Health Questionnaire 9-Item (PHQ-9), and secondary outcomes included three measures of health-related quality of life (HRQOL) — caregiver burden, morbidity, and mortality — collected at 3, 6, and 12 months.
• Physical and mental HRQOL were measured with the 12-Item Short-Form Medical Outcomes Study (SF-12), HF-specific HRQOL with the 23-item patient-reported Kansas City Cardiomyopathy Questionnaire, caregiver burden with the 26-item Caregiver Burden Questionnaire for HF, morbidity by ED visits, hospital readmissions, and days hospitalized, and mortality data came from medical records and family or caregiver reports, with survival assessed using Kaplan-Meier plots at 3, 6, and 12 months.
• Covariates included age, sex, race, ethnicity, marital status, employment, education, insurance type, recruitment site (inpatient or outpatient), ejection fraction (preserved or reduced), New York Heart Association class, medical history, and medications.

TAKEAWAY:

• Depressive symptom severity was reduced at 6 months by nearly 50% for both BA (mean PHQ-9 score, 7.53; P vs baseline < .001) and MEDS (mean PHQ-9 score, 8.09; P vs baseline < .001) participants, with reductions persisting at 12 months and no significant difference between groups.
• Compared with MEDS recipients, those who received BA had slightly higher improvement in physical HRQOL at 6 months (multivariable mean difference without imputation, 2.13; 95% CI, 0.06-4.20; P = .04), but there were no statistically significant differences between groups in mental HRQOL, HF-specific HRQOL, or caregiver burden at 3, 6, or 12 months.
• Patients who received BA were significantly less likely than those in the MEDS group to have ED visits and spent fewer days in hospital at 3, 6, and 12 months, but there was no significant difference in number of hospital readmissions or in mortality at 3, 6, or 12 months.

IN PRACTICE:

“Our findings of comparable primary effects between BA and MEDS suggest both options are effective and that personal preferences, patient values, and availability of services could inform decisions,” the authors wrote. They noted BA has no pharmacological adverse effects but requires more engagement than drug therapy and might be less accessible.

SOURCE:

The study was conducted by Waguih William IsHak, MD, Department of Psychiatry and Behavioral Neurosciences, Cedars-Sinai Medical Center, Los Angeles, and others. It was published online on January 17, 2024, in JAMA Network Open.

LIMITATIONS:

As the study had no control group, such as a waiting list, it was impossible to draw conclusions about the natural course of depressive symptoms in HF. However, the authors noted improvements were sustained at 12 months despite substantially diminished contact with intervention teams after 6 months. Researchers were unable to collect data for ED visits, readmissions, and hospital stays outside of California and didn’t assess treatment preference at enrollment, which could have helped inform the association with outcomes and adherence.

DISCLOSURES:

The study was funded by the Patient-Centered Outcome Research Institute, paid to Cedars-Sinai Medical Center. Dr. IsHak reported receiving royalties from Springer Nature and Cambridge University Press. No other disclosures were reported.
 

A version of this article appeared on Medscape.com.

Santé Publique France (SPF), the French national public health agency, has released the findings of the PEPS’PE study, which was launched in 2021. The study aims to prioritize, following extensive consultation, the health effects to be monitored for their potential link to endocrine disruptors (EDs). Out of 59 health effects suspected to be associated with exposure to EDs, 21 have been considered a priority for surveillance. Based on these results and others, SPF will expand the scope of the Agency’s surveillance by incorporating new pathologies.

As part of its environmental health program and the National Strategy on EDs, SPF has been conducting surveillance related to EDs targeting reproductive health since 2015. To incorporate new scientific knowledge, the PEPS’PE project aims to prioritize health effects related to EDs and identify health events to integrate into the agency’s current surveillance. The 59 health effects suspected to be associated with exposure to EDs were to be evaluated based on two criteria: The weight of evidence and the epidemiological and societal impact of the health effect. A diverse panel of international experts and French stakeholders in the field of EDs classified 21 health effects as a priority for surveillance.

Among these effects, six reproductive health effects are already monitored in the surveillance program: Cryptorchidism, hypospadias, early puberty, testicular cancer, alteration of sperm quality, and endometriosis. In addition, infertility and decreased fertility (which are not currently monitored for their link to EDs) have been included.

Metabolic effects (including overweight and obesity, cardiovascular diseases, type 2 diabetes, and metabolic syndrome), child neurodevelopmental disorders (including behavioral disorders, intellectual deficits, and attention-deficit disorders), cancers (including breast cancer, prostate cancer, lymphomas, and leukemias in children), and asthma have also been highlighted.

Furthermore, 22 effects were considered low priorities or deemed nonpriorities when, for example, they presented weak or moderate evidence with varying levels of interest in implementing surveillance. Finally, 16 health effects could not be prioritized because of a lack of scientific experts on these topics and a failure to achieve consensus (eg, bone disorders, adrenal disorders, and skin and eye disorders). Consensus was sought during this consultation using a Delphi method.

“These results indicate the need to expand the scope of the Agency’s surveillance beyond reproductive health, incorporating new pathologies when surveillance data are available,” SPF declared in a press release.

“With the initial decision elements obtained through this study, Santé Publique France will analyze the feasibility of implementing surveillance for effects classified as priorities.”
 

This article was translated from the Medscape French edition. A version of this article appeared on Medscape.com.

Santé Publique France (SPF), the French national public health agency, has released the findings of the PEPS’PE study, which was launched in 2021. The study aims to prioritize, following extensive consultation, the health effects to be monitored for their potential link to endocrine disruptors (EDs). Out of 59 health effects suspected to be associated with exposure to EDs, 21 have been considered a priority for surveillance. Based on these results and others, SPF will expand the scope of the Agency’s surveillance by incorporating new pathologies.

As part of its environmental health program and the National Strategy on EDs, SPF has been conducting surveillance related to EDs targeting reproductive health since 2015. To incorporate new scientific knowledge, the PEPS’PE project aims to prioritize health effects related to EDs and identify health events to integrate into the agency’s current surveillance. The 59 health effects suspected to be associated with exposure to EDs were to be evaluated based on two criteria: The weight of evidence and the epidemiological and societal impact of the health effect. A diverse panel of international experts and French stakeholders in the field of EDs classified 21 health effects as a priority for surveillance.

Among these effects, six reproductive health effects are already monitored in the surveillance program: Cryptorchidism, hypospadias, early puberty, testicular cancer, alteration of sperm quality, and endometriosis. In addition, infertility and decreased fertility (which are not currently monitored for their link to EDs) have been included.

Metabolic effects (including overweight and obesity, cardiovascular diseases, type 2 diabetes, and metabolic syndrome), child neurodevelopmental disorders (including behavioral disorders, intellectual deficits, and attention-deficit disorders), cancers (including breast cancer, prostate cancer, lymphomas, and leukemias in children), and asthma have also been highlighted.

Furthermore, 22 effects were considered low priorities or deemed nonpriorities when, for example, they presented weak or moderate evidence with varying levels of interest in implementing surveillance. Finally, 16 health effects could not be prioritized because of a lack of scientific experts on these topics and a failure to achieve consensus (eg, bone disorders, adrenal disorders, and skin and eye disorders). Consensus was sought during this consultation using a Delphi method.

“These results indicate the need to expand the scope of the Agency’s surveillance beyond reproductive health, incorporating new pathologies when surveillance data are available,” SPF declared in a press release.

“With the initial decision elements obtained through this study, Santé Publique France will analyze the feasibility of implementing surveillance for effects classified as priorities.”
 

This article was translated from the Medscape French edition. A version of this article appeared on Medscape.com.

Santé Publique France (SPF), the French national public health agency, has released the findings of the PEPS’PE study, which was launched in 2021. The study aims to prioritize, following extensive consultation, the health effects to be monitored for their potential link to endocrine disruptors (EDs). Out of 59 health effects suspected to be associated with exposure to EDs, 21 have been considered a priority for surveillance. Based on these results and others, SPF will expand the scope of the Agency’s surveillance by incorporating new pathologies.

As part of its environmental health program and the National Strategy on EDs, SPF has been conducting surveillance related to EDs targeting reproductive health since 2015. To incorporate new scientific knowledge, the PEPS’PE project aims to prioritize health effects related to EDs and identify health events to integrate into the agency’s current surveillance. The 59 health effects suspected to be associated with exposure to EDs were to be evaluated based on two criteria: The weight of evidence and the epidemiological and societal impact of the health effect. A diverse panel of international experts and French stakeholders in the field of EDs classified 21 health effects as a priority for surveillance.

Among these effects, six reproductive health effects are already monitored in the surveillance program: Cryptorchidism, hypospadias, early puberty, testicular cancer, alteration of sperm quality, and endometriosis. In addition, infertility and decreased fertility (which are not currently monitored for their link to EDs) have been included.

Metabolic effects (including overweight and obesity, cardiovascular diseases, type 2 diabetes, and metabolic syndrome), child neurodevelopmental disorders (including behavioral disorders, intellectual deficits, and attention-deficit disorders), cancers (including breast cancer, prostate cancer, lymphomas, and leukemias in children), and asthma have also been highlighted.

Furthermore, 22 effects were considered low priorities or deemed nonpriorities when, for example, they presented weak or moderate evidence with varying levels of interest in implementing surveillance. Finally, 16 health effects could not be prioritized because of a lack of scientific experts on these topics and a failure to achieve consensus (eg, bone disorders, adrenal disorders, and skin and eye disorders). Consensus was sought during this consultation using a Delphi method.

“These results indicate the need to expand the scope of the Agency’s surveillance beyond reproductive health, incorporating new pathologies when surveillance data are available,” SPF declared in a press release.

“With the initial decision elements obtained through this study, Santé Publique France will analyze the feasibility of implementing surveillance for effects classified as priorities.”
 

This article was translated from the Medscape French edition. A version of this article appeared on Medscape.com.

It’s that time of the year, when social media is rife with many top 5 and top 10 lists. Perhaps the beginning of a new year is a good time to review how different medications can have side effects beyond the disease state they’re used to address. Among the most common complications of many medications is the potential to disrupt glycemic control. Let’s revisit some of the most commonly used medications known to increase glucose levels and look at some practical tips on overcoming these.

1. Glucocorticoids

Without a doubt, corticosteroids are at the top of the list when it comes to the potential for increasing blood glucose levels. High-dose glucocorticoid therapy is known to lead to new-onset diabetes (steroid-induced diabetes). Similarly, people with preexisting diabetes may notice significant worsening of glycemic control when they start on glucocorticoid therapy. The extent of glucose elevation depends on their glycemic status prior to initiation on steroids, the dose and duration of glucocorticoid therapy, and comorbid conditions, among other factors.

Management tip: For those with previously well-controlled diabetes or borderline diabetes, glucocorticoid-induced hyperglycemia may be managed by metformin with or without sulfonylurea therapy, especially if corticosteroid treatment is low-dose and for a shorter duration. However, for many individuals with preexisting poorly controlled diabetes or those initiated on high-dose corticosteroids, insulin therapy would perhaps be the treatment of choice. Glucocorticoid therapy generally leads to more pronounced postprandial hyperglycemia compared with fasting hyperglycemia; hence, the use of short-acting insulin therapy or perhaps NPH insulin in the morning might be a better option for many individuals. Dietary modification plays an important role in limiting the extent of postprandial hyperglycemia. Use of continuous glucose monitoring (CGM) devices may also be very helpful for understanding glycemic excursions and how to adjust insulin. In individuals for whom glucocorticoid therapy is tapered down, it is important to adjust the dose of medications with potential to cause hypoglycemia, such as insulin/sulfonylurea therapy, as the degree of hyperglycemia may decrease with decreased dose of the glucocorticoid therapy.

2. Antipsychotic Therapy

Antipsychotic medications can be obesogenic; between 15% and 72% of people who take second-generation antipsychotics experience weight gain of 7% or more. Increases in weight are not the only factor contributing to an elevated risk of developing type 2 diabetes. Antipsychotics are thought to cause downregulation of intracellular insulin signaling, leading to insulin resistance. At the same time, there seems to be a direct effect on the pancreatic beta cells. Antagonism of the dopamine D2, serotonin 5-HT2C, and muscarinic M3 receptors impairs beta-cell response to changes in blood glucose. In addition to the pharmacologic effects, cell culture experiments have shown that antipsychotics increase apoptosis of beta cells. Increased weight and concomitant development of type 2 diabetes is seen particularly in agents that exhibit high muscarinic M3 and histamine H1 receptor blockade. The effect on glucose metabolism is seen the most with agents such as clozapine, olanzapine, and haloperidol and the least with agents such as ziprasidone.

Management tip: Given the ongoing change in the understanding of increases in weight and their association with the risk of developing type 2 diabetes, a metabolically safer approach involves starting with medications that have a lower propensity for weight gain, and the partial agonists/third-generation antipsychotics as a family presently have the best overall data.

3. Thiazide Diuretics

Thiazide diuretics are commonly used for the management of hypertension and are associated with metabolic complications including hypokalemia; higher cholesterol, triglycerides, and other circulating lipids; and elevated glucose. It’s thought that the reduced potassium level occurring as a result of these medications might contribute to new-onset diabetes. The hypokalemia occurring from these medications is thought to lead to a decrease in insulin secretion and sensitivity, which is dose dependent. Studies show that the number needed to harm for chlorthalidone-induced diabetes is 29 over 1 year. There is believed to be no additional risk beyond 1 year.

Management tip: It’s important to monitor potassium levels for those initiated on thiazide diuretics. If hypokalemia occurs, it would be pertinent to correct the hypokalemia with potassium supplements to mitigate the risk for new-onset diabetes.

4. Statin Therapy

Statin therapy is thought to be associated with decreased insulin sensitivity and impairment in insulin secretion. The overall incidence of diabetes is pegged to be between 9% and 12% on statin therapy on the basis of meta-analysis studies, and higher on the basis of population-based studies. Overall, the estimated number needed to harm is: 1 out of every 255 patients on statin therapy for 4 years may develop new-onset diabetes. Compare this with the extremely strong evidence for number needed to treat being 39 for 5 years with statin therapy in patients with preexisting heart disease to prevent one occurrence of a nonfatal myocardial infarction.

Management tip: Although statins are associated with a small incident increase in the risk of developing diabetes, the potential benefits of using statin therapy for both primary and secondary prevention of cardiovascular disease significantly outweigh any of the potential risks associated with hyperglycemia. This is an important discussion to have with patients who are reluctant to use statin therapy because of the potential risk for new-onset diabetes as a side effect.

5. Beta-Blockers

Beta-blockers are another commonly used group of medications for managing hypertension, heart failure, coronary artery disease, and arrhythmia. Nonvasodilating beta-blockers such as metoprolol and atenolol are more likely to be associated with increases in A1c, mean plasma glucose, body weight, and triglycerides compared with vasodilating beta-blockers such as carvedilol, nebivolol, and labetalol (Bakris GL et al; Giugliano D et al). Similarly, studies have also shown that atenolol and metoprolol are associated with increased odds of hypoglycemia compared with carvedilol. People on beta-blockers may have masking of some of the symptoms of hypoglycemia, such as tremor, irritability, and palpitations, while other symptoms such as diaphoresis may remain unaffected on beta-blockers.

Management tip: Education on recognizing and managing hypoglycemia would be important when starting patients on beta-blockers if they are on preexisting insulin/sulfonylurea therapy. Use of CGM devices may be helpful if there is a high risk for hypoglycemia, especially as symptoms of hypoglycemia are often masked.

Honorable Mention

Several other medications — including antiretroviral therapy, tyrosine kinase inhibitors, mechanistic target of rapamycin (mTOR) inhibitors, immunosuppressants, and interferon alpha — are associated with worsening glycemic control and new-onset diabetes. Consider these agents’ effects on blood glucose, especially in people with an elevated risk of developing diabetes or those with preexisting diabetes, when prescribing.

A special mention should also be made of androgen deprivation therapy. These include treatment options like goserelin and leuprolide, which are gonadotropin-releasing hormone (GnRH) agonist therapies and are commonly used for prostate cancer management. Depending on the patient, these agents may be used for prolonged duration. Androgen deprivation therapy, by definition, decreases testosterone levels in men, thereby leading to worsening insulin resistance. Increase in fat mass and concomitant muscle wasting have been associated with the use of these medications; these, in turn, lead to peripheral insulin resistance. Nearly 1 out of every 5 men treated with long-term androgen deprivation therapy may be prone to developing worsening of A1c by 1% or more.

Management tip: Men on androgen deprivation therapy should be encouraged to participate in regular physical activity to reduce the burden of insulin resistance and to promote cardiovascular health.

Drug-induced diabetes is potentially reversible in many cases. Similarly, worsening of glycemic control due to medications in people with preexisting diabetes may also attenuate once the effect of the drug wears off. Blood glucose should be monitored on an ongoing basis so that diabetes medications can be adjusted. For some individuals, however, the worsening of glycemic status may be more chronic and may require long-term use of antihyperglycemic agents, especially if the benefits of continuation of the medication leading to hyperglycemia far exceed any potential risks.
 

Dr. Jain is Clinical Instructor, Department of Endocrinology, University of British Columbia; Endocrinologist, Fraser River Endocrinology, Vancouver, British Columbia, Canada. He disclosed ties with Abbott, Amgen, Boehringer Ingelheim, Dexcom, Eli Lilly, Janssen, Medtronic, Merck, and Novo Nordisk.

A version of this article appeared on Medscape.com.

It’s that time of the year, when social media is rife with many top 5 and top 10 lists. Perhaps the beginning of a new year is a good time to review how different medications can have side effects beyond the disease state they’re used to address. Among the most common complications of many medications is the potential to disrupt glycemic control. Let’s revisit some of the most commonly used medications known to increase glucose levels and look at some practical tips on overcoming these.

1. Glucocorticoids

Without a doubt, corticosteroids are at the top of the list when it comes to the potential for increasing blood glucose levels. High-dose glucocorticoid therapy is known to lead to new-onset diabetes (steroid-induced diabetes). Similarly, people with preexisting diabetes may notice significant worsening of glycemic control when they start on glucocorticoid therapy. The extent of glucose elevation depends on their glycemic status prior to initiation on steroids, the dose and duration of glucocorticoid therapy, and comorbid conditions, among other factors.

Management tip: For those with previously well-controlled diabetes or borderline diabetes, glucocorticoid-induced hyperglycemia may be managed by metformin with or without sulfonylurea therapy, especially if corticosteroid treatment is low-dose and for a shorter duration. However, for many individuals with preexisting poorly controlled diabetes or those initiated on high-dose corticosteroids, insulin therapy would perhaps be the treatment of choice. Glucocorticoid therapy generally leads to more pronounced postprandial hyperglycemia compared with fasting hyperglycemia; hence, the use of short-acting insulin therapy or perhaps NPH insulin in the morning might be a better option for many individuals. Dietary modification plays an important role in limiting the extent of postprandial hyperglycemia. Use of continuous glucose monitoring (CGM) devices may also be very helpful for understanding glycemic excursions and how to adjust insulin. In individuals for whom glucocorticoid therapy is tapered down, it is important to adjust the dose of medications with potential to cause hypoglycemia, such as insulin/sulfonylurea therapy, as the degree of hyperglycemia may decrease with decreased dose of the glucocorticoid therapy.

2. Antipsychotic Therapy

Antipsychotic medications can be obesogenic; between 15% and 72% of people who take second-generation antipsychotics experience weight gain of 7% or more. Increases in weight are not the only factor contributing to an elevated risk of developing type 2 diabetes. Antipsychotics are thought to cause downregulation of intracellular insulin signaling, leading to insulin resistance. At the same time, there seems to be a direct effect on the pancreatic beta cells. Antagonism of the dopamine D2, serotonin 5-HT2C, and muscarinic M3 receptors impairs beta-cell response to changes in blood glucose. In addition to the pharmacologic effects, cell culture experiments have shown that antipsychotics increase apoptosis of beta cells. Increased weight and concomitant development of type 2 diabetes is seen particularly in agents that exhibit high muscarinic M3 and histamine H1 receptor blockade. The effect on glucose metabolism is seen the most with agents such as clozapine, olanzapine, and haloperidol and the least with agents such as ziprasidone.

Management tip: Given the ongoing change in the understanding of increases in weight and their association with the risk of developing type 2 diabetes, a metabolically safer approach involves starting with medications that have a lower propensity for weight gain, and the partial agonists/third-generation antipsychotics as a family presently have the best overall data.

3. Thiazide Diuretics

Thiazide diuretics are commonly used for the management of hypertension and are associated with metabolic complications including hypokalemia; higher cholesterol, triglycerides, and other circulating lipids; and elevated glucose. It’s thought that the reduced potassium level occurring as a result of these medications might contribute to new-onset diabetes. The hypokalemia occurring from these medications is thought to lead to a decrease in insulin secretion and sensitivity, which is dose dependent. Studies show that the number needed to harm for chlorthalidone-induced diabetes is 29 over 1 year. There is believed to be no additional risk beyond 1 year.

Management tip: It’s important to monitor potassium levels for those initiated on thiazide diuretics. If hypokalemia occurs, it would be pertinent to correct the hypokalemia with potassium supplements to mitigate the risk for new-onset diabetes.

4. Statin Therapy

Statin therapy is thought to be associated with decreased insulin sensitivity and impairment in insulin secretion. The overall incidence of diabetes is pegged to be between 9% and 12% on statin therapy on the basis of meta-analysis studies, and higher on the basis of population-based studies. Overall, the estimated number needed to harm is: 1 out of every 255 patients on statin therapy for 4 years may develop new-onset diabetes. Compare this with the extremely strong evidence for number needed to treat being 39 for 5 years with statin therapy in patients with preexisting heart disease to prevent one occurrence of a nonfatal myocardial infarction.

Management tip: Although statins are associated with a small incident increase in the risk of developing diabetes, the potential benefits of using statin therapy for both primary and secondary prevention of cardiovascular disease significantly outweigh any of the potential risks associated with hyperglycemia. This is an important discussion to have with patients who are reluctant to use statin therapy because of the potential risk for new-onset diabetes as a side effect.

5. Beta-Blockers

Beta-blockers are another commonly used group of medications for managing hypertension, heart failure, coronary artery disease, and arrhythmia. Nonvasodilating beta-blockers such as metoprolol and atenolol are more likely to be associated with increases in A1c, mean plasma glucose, body weight, and triglycerides compared with vasodilating beta-blockers such as carvedilol, nebivolol, and labetalol (Bakris GL et al; Giugliano D et al). Similarly, studies have also shown that atenolol and metoprolol are associated with increased odds of hypoglycemia compared with carvedilol. People on beta-blockers may have masking of some of the symptoms of hypoglycemia, such as tremor, irritability, and palpitations, while other symptoms such as diaphoresis may remain unaffected on beta-blockers.

Management tip: Education on recognizing and managing hypoglycemia would be important when starting patients on beta-blockers if they are on preexisting insulin/sulfonylurea therapy. Use of CGM devices may be helpful if there is a high risk for hypoglycemia, especially as symptoms of hypoglycemia are often masked.

Honorable Mention

Several other medications — including antiretroviral therapy, tyrosine kinase inhibitors, mechanistic target of rapamycin (mTOR) inhibitors, immunosuppressants, and interferon alpha — are associated with worsening glycemic control and new-onset diabetes. Consider these agents’ effects on blood glucose, especially in people with an elevated risk of developing diabetes or those with preexisting diabetes, when prescribing.

A special mention should also be made of androgen deprivation therapy. These include treatment options like goserelin and leuprolide, which are gonadotropin-releasing hormone (GnRH) agonist therapies and are commonly used for prostate cancer management. Depending on the patient, these agents may be used for prolonged duration. Androgen deprivation therapy, by definition, decreases testosterone levels in men, thereby leading to worsening insulin resistance. Increase in fat mass and concomitant muscle wasting have been associated with the use of these medications; these, in turn, lead to peripheral insulin resistance. Nearly 1 out of every 5 men treated with long-term androgen deprivation therapy may be prone to developing worsening of A1c by 1% or more.

Management tip: Men on androgen deprivation therapy should be encouraged to participate in regular physical activity to reduce the burden of insulin resistance and to promote cardiovascular health.

Drug-induced diabetes is potentially reversible in many cases. Similarly, worsening of glycemic control due to medications in people with preexisting diabetes may also attenuate once the effect of the drug wears off. Blood glucose should be monitored on an ongoing basis so that diabetes medications can be adjusted. For some individuals, however, the worsening of glycemic status may be more chronic and may require long-term use of antihyperglycemic agents, especially if the benefits of continuation of the medication leading to hyperglycemia far exceed any potential risks.
 

Dr. Jain is Clinical Instructor, Department of Endocrinology, University of British Columbia; Endocrinologist, Fraser River Endocrinology, Vancouver, British Columbia, Canada. He disclosed ties with Abbott, Amgen, Boehringer Ingelheim, Dexcom, Eli Lilly, Janssen, Medtronic, Merck, and Novo Nordisk.

A version of this article appeared on Medscape.com.

It’s that time of the year, when social media is rife with many top 5 and top 10 lists. Perhaps the beginning of a new year is a good time to review how different medications can have side effects beyond the disease state they’re used to address. Among the most common complications of many medications is the potential to disrupt glycemic control. Let’s revisit some of the most commonly used medications known to increase glucose levels and look at some practical tips on overcoming these.

1. Glucocorticoids

Without a doubt, corticosteroids are at the top of the list when it comes to the potential for increasing blood glucose levels. High-dose glucocorticoid therapy is known to lead to new-onset diabetes (steroid-induced diabetes). Similarly, people with preexisting diabetes may notice significant worsening of glycemic control when they start on glucocorticoid therapy. The extent of glucose elevation depends on their glycemic status prior to initiation on steroids, the dose and duration of glucocorticoid therapy, and comorbid conditions, among other factors.

Management tip: For those with previously well-controlled diabetes or borderline diabetes, glucocorticoid-induced hyperglycemia may be managed by metformin with or without sulfonylurea therapy, especially if corticosteroid treatment is low-dose and for a shorter duration. However, for many individuals with preexisting poorly controlled diabetes or those initiated on high-dose corticosteroids, insulin therapy would perhaps be the treatment of choice. Glucocorticoid therapy generally leads to more pronounced postprandial hyperglycemia compared with fasting hyperglycemia; hence, the use of short-acting insulin therapy or perhaps NPH insulin in the morning might be a better option for many individuals. Dietary modification plays an important role in limiting the extent of postprandial hyperglycemia. Use of continuous glucose monitoring (CGM) devices may also be very helpful for understanding glycemic excursions and how to adjust insulin. In individuals for whom glucocorticoid therapy is tapered down, it is important to adjust the dose of medications with potential to cause hypoglycemia, such as insulin/sulfonylurea therapy, as the degree of hyperglycemia may decrease with decreased dose of the glucocorticoid therapy.

2. Antipsychotic Therapy

Antipsychotic medications can be obesogenic; between 15% and 72% of people who take second-generation antipsychotics experience weight gain of 7% or more. Increases in weight are not the only factor contributing to an elevated risk of developing type 2 diabetes. Antipsychotics are thought to cause downregulation of intracellular insulin signaling, leading to insulin resistance. At the same time, there seems to be a direct effect on the pancreatic beta cells. Antagonism of the dopamine D2, serotonin 5-HT2C, and muscarinic M3 receptors impairs beta-cell response to changes in blood glucose. In addition to the pharmacologic effects, cell culture experiments have shown that antipsychotics increase apoptosis of beta cells. Increased weight and concomitant development of type 2 diabetes is seen particularly in agents that exhibit high muscarinic M3 and histamine H1 receptor blockade. The effect on glucose metabolism is seen the most with agents such as clozapine, olanzapine, and haloperidol and the least with agents such as ziprasidone.

Management tip: Given the ongoing change in the understanding of increases in weight and their association with the risk of developing type 2 diabetes, a metabolically safer approach involves starting with medications that have a lower propensity for weight gain, and the partial agonists/third-generation antipsychotics as a family presently have the best overall data.

3. Thiazide Diuretics

Thiazide diuretics are commonly used for the management of hypertension and are associated with metabolic complications including hypokalemia; higher cholesterol, triglycerides, and other circulating lipids; and elevated glucose. It’s thought that the reduced potassium level occurring as a result of these medications might contribute to new-onset diabetes. The hypokalemia occurring from these medications is thought to lead to a decrease in insulin secretion and sensitivity, which is dose dependent. Studies show that the number needed to harm for chlorthalidone-induced diabetes is 29 over 1 year. There is believed to be no additional risk beyond 1 year.

Management tip: It’s important to monitor potassium levels for those initiated on thiazide diuretics. If hypokalemia occurs, it would be pertinent to correct the hypokalemia with potassium supplements to mitigate the risk for new-onset diabetes.

4. Statin Therapy

Statin therapy is thought to be associated with decreased insulin sensitivity and impairment in insulin secretion. The overall incidence of diabetes is pegged to be between 9% and 12% on statin therapy on the basis of meta-analysis studies, and higher on the basis of population-based studies. Overall, the estimated number needed to harm is: 1 out of every 255 patients on statin therapy for 4 years may develop new-onset diabetes. Compare this with the extremely strong evidence for number needed to treat being 39 for 5 years with statin therapy in patients with preexisting heart disease to prevent one occurrence of a nonfatal myocardial infarction.

Management tip: Although statins are associated with a small incident increase in the risk of developing diabetes, the potential benefits of using statin therapy for both primary and secondary prevention of cardiovascular disease significantly outweigh any of the potential risks associated with hyperglycemia. This is an important discussion to have with patients who are reluctant to use statin therapy because of the potential risk for new-onset diabetes as a side effect.

5. Beta-Blockers

Beta-blockers are another commonly used group of medications for managing hypertension, heart failure, coronary artery disease, and arrhythmia. Nonvasodilating beta-blockers such as metoprolol and atenolol are more likely to be associated with increases in A1c, mean plasma glucose, body weight, and triglycerides compared with vasodilating beta-blockers such as carvedilol, nebivolol, and labetalol (Bakris GL et al; Giugliano D et al). Similarly, studies have also shown that atenolol and metoprolol are associated with increased odds of hypoglycemia compared with carvedilol. People on beta-blockers may have masking of some of the symptoms of hypoglycemia, such as tremor, irritability, and palpitations, while other symptoms such as diaphoresis may remain unaffected on beta-blockers.

Management tip: Education on recognizing and managing hypoglycemia would be important when starting patients on beta-blockers if they are on preexisting insulin/sulfonylurea therapy. Use of CGM devices may be helpful if there is a high risk for hypoglycemia, especially as symptoms of hypoglycemia are often masked.

Honorable Mention

Several other medications — including antiretroviral therapy, tyrosine kinase inhibitors, mechanistic target of rapamycin (mTOR) inhibitors, immunosuppressants, and interferon alpha — are associated with worsening glycemic control and new-onset diabetes. Consider these agents’ effects on blood glucose, especially in people with an elevated risk of developing diabetes or those with preexisting diabetes, when prescribing.

A special mention should also be made of androgen deprivation therapy. These include treatment options like goserelin and leuprolide, which are gonadotropin-releasing hormone (GnRH) agonist therapies and are commonly used for prostate cancer management. Depending on the patient, these agents may be used for prolonged duration. Androgen deprivation therapy, by definition, decreases testosterone levels in men, thereby leading to worsening insulin resistance. Increase in fat mass and concomitant muscle wasting have been associated with the use of these medications; these, in turn, lead to peripheral insulin resistance. Nearly 1 out of every 5 men treated with long-term androgen deprivation therapy may be prone to developing worsening of A1c by 1% or more.

Management tip: Men on androgen deprivation therapy should be encouraged to participate in regular physical activity to reduce the burden of insulin resistance and to promote cardiovascular health.

Drug-induced diabetes is potentially reversible in many cases. Similarly, worsening of glycemic control due to medications in people with preexisting diabetes may also attenuate once the effect of the drug wears off. Blood glucose should be monitored on an ongoing basis so that diabetes medications can be adjusted. For some individuals, however, the worsening of glycemic status may be more chronic and may require long-term use of antihyperglycemic agents, especially if the benefits of continuation of the medication leading to hyperglycemia far exceed any potential risks.
 

Dr. Jain is Clinical Instructor, Department of Endocrinology, University of British Columbia; Endocrinologist, Fraser River Endocrinology, Vancouver, British Columbia, Canada. He disclosed ties with Abbott, Amgen, Boehringer Ingelheim, Dexcom, Eli Lilly, Janssen, Medtronic, Merck, and Novo Nordisk.

A version of this article appeared on Medscape.com.