Federal Practitioner

New results suggest that allogeneic hematopoietic cell transplantation (HCT), which is typically reserved for younger patients, may well be offered to older patients with advanced myelodysplastic syndrome (MDS).

In patients with a median age of 66 years who had received a donor transplant, the overall survival (OS) at 3 years was almost double compared with patients who did not receive a transplant – 47.9% vs. 26.6% for the “no-donor” group.  

The finding comes from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Study 1102 (NCT02016781) presented at the American Society of Hematology (ASH) 2020 virtual meeting.

“This study conclusively solidifies the role of transplantation in older individuals with MDS,” presenter Corey Cutler, MD, MPH, of the Dana-Farber Cancer Center, Boston, said in an interview.

Coauthor Ryotaro Nakamura, MD, of City of Hope, Duarte, Calif., said in an interview that this was the largest and first trial in the United States to determine in a prospective fashion that allogeneic stem cell transplantation offers a significant survival in older patients. “There was more than a 20% benefit in OS in this age group,” he said.

“This is an incredibly important study,” said Andrew Brunner, MD, medical oncologist at the Mass General Cancer Center in Boston, who was approached for comment. He explained that for years early transplant was recommended as important for patients who have higher-risk MDS. “This study validates this in a prospective, pseudo-randomized (donor/no donor) fashion,” he said in an interview.

“[This study] is really a seminal advance in the care of patients with MDS. Transplant should be integrated into the care algorithm, if not already, and we as a community need to build upon this study further,” Dr. Brunner added.

Several experts in addition to the authors hailed the study as practice changing.

Robert A. Brodsky, MD, ASH, director of the division of hematology at Johns Hopkins University, Baltimore, noted that in younger patients bone marrow transplant is the standard of care for aggressive MDS, but a lot of practices do not refer older patients or those with comorbidities for transplant and prefer to give these patients palliative care with hypomethylating agents for fear that the transplant process would be too toxic.

“There has been an institutional bias to do transplant in older patients, but until now there was no randomized clinical trial to show that this is the right choice. Now we have the data,” Dr Brodsky said, predicting that “this study will change the standard of care.”

Henry Fung, MD, chair of the department of bone marrow transplant and cellular therapies at Fox Chase Cancer Center, Philadelphia, agreed. “We should congratulate all the investigators and our patients who participated in this study. Reduced intensity allogeneic stem cell transplantation improved disease control and overall survival with similar quality of life.

“I will recommend all patients with intermediate-2 or higher-risk MDS to be evaluated by the transplant team at diagnosis and eligible patients should be considered for a transplant,” Dr. Fung said in an interview.

Immediate impact on clinical practice

Lead author Dr. Cutler suggested that the study results had an immediate impact for changing clinical practice. “Individuals between the ages of 50 and 75 years with intermediate-2 or high-risk MDS who are eligible to undergo reduced-intensity transplantation had superior outcomes if they had a suitable donor for transplantation in comparison with those who did not have a donor,” he said.

Dr. Cutler further explained that many community-based hematologists do not refer their patients for transplantation. In addition, there is a lack of a uniform payer position for transplantation for MDS, he noted. Also, there is a lack of understanding of the cost-effectiveness of transplantation in comparison to nontransplant strategies, he suggested.

“Transplant is curative for MDS,” he emphasized. Most transplant recipients will eventually become transfusion-independent within weeks to months from transplant.

“We do transplants in this age group all the time,” Dr. Cutler noted. He said that academic centers will continue to offer transplants, and suggested that community oncologists encourage referral to transplant centers early in a patient’s disease course to maximize search time and provide patients all potential options for therapy.

Dr. Brunner agreed and noted that there is a need to build capacity for higher transplant volume, and in general physicians should seek ways to expand this treatment option to more patients. “At this time, allogeneic transplant still requires close collaboration with referral centers; that said, more and more we are able to work closely with colleagues in the community to share management, including earlier after the actual transplant,” he said.

He noted that one silver lining of the pandemic in 2020 has been increased use of telemedicine to collaborate. “Ongoing advances may be able to further encourage these virtual connections to enhance the entire patient care experience,” Dr. Brunner said.
 

Reimbursement by CMS for Medicare recipients

Despite the data showing benefit, allogeneic stem cell transplantation is not offered to older individuals with high-risk MDS and is not covered by Medicare in the United States, Dr. Cutler noted in his presentation.

“This study was spurred by the CMS [Centers for Medicare & Medicaid Services] ruling for transplantation in MDS and the story has come full circle,” Aaron T. Gerds, MD, MS, noted at a preconference press briefing. Dr. Gerds is chair of the ASH Committee on Communications and assistant professor at the Cleveland Clinic Taussig Cancer Institute, Cleveland.

Dr. Nakamura explained that in 2010 a CMS decision memo noted that the evidence of a benefit for transplantation in MDS was lacking and Medicare would not cover transplant unless patients were enrolled in a clinical study. That memo outlined criteria that a clinical trial would have to address before it could consider reimbursement for Medicare beneficiaries.

“The BMT CTN Study 1102 was one of two studies that met the criteria set by CMS,” Dr. Nakamura said, noting that the data are being prepared for CMS review.

“This study will likely be the deciding factor for CMS to begin to cover payment for transplantation for MDS,” said Dr. Cutler.

The other study, published earlier this year in JAMA Oncology, showed that outcomes for patients older than ager 65 were similar to those of patients aged 55-65.
 

BMT CTN 1102 study details

Dr. Cutler noted that the study was designed to address the issue of whether transplantation was beneficial to Medicare-aged individuals with high-risk MDS, and the trial had been approved by Medicare.

The multicenter study enrolled patients who were between ages 50 and 75 years and had newly diagnosed MDS of higher risk (International Prognostic Scoring System [IPSS] intermediate-2 or higher) and were candidates for reduced intensity conditioning (RIC) allogeneic HCT.

Patients were enrolled prior to a formal donor search and were initially assigned to the “no donor” group and reassigned to the donor group when a suitable donor (matched sibling or unrelated donor) was identified. Patients underwent RIC HCT according to institution protocol.

Of 384 patients, 260 received RIC HCT and 124 received hypomethylating therapy. Median follow-up was 34.2 months for the donor group and 26.9 months for the no-donor group.

The two arms were well balanced with respect to age (median 66 years), gender, disease risk [two-thirds of the patients had an intermediate-2 and one third had a high-risk MDS], and response to hypomethylating therapy. The majority of subjects in the donor arm had unrelated donors and more than one-third had a high comorbidity score, Dr. Cutler indicated.

At 3 years, absolute improvement in OS was 21.3% in favor of donor-arm subjects. Leukemia-free survival was also higher in the donor group: 35.8% vs. 20.6% for the no-donor group.

Improvement in OS for patients receiving transplants was seen across all patient subtypes, regardless of age, response to hypomethylating therapy, and IPSS score. “Treatment effects were seen in any subgroup, but particularly in subjects above age 65,” Dr. Cutler stressed.

In an as-treated analysis that excluded subjects who died, the treatment effects were even more pronounced, with an absolute improvement in OS of 31.4% (47.4% vs. 16% for the no-donor arm) and improvement in leukemia-free survival of 28.4% (39.3% vs. 10.9% for the no-donor arm).

In 25 patients in the no-donor arm who subsequently went on to receive alternate donor transplant, the 3-year OS and leukemia-free survival was 58.5%, underscoring the potential value of alternate donor transplant, Dr. Cutler noted.

Dr. Nakamura emphasized that the gains in survival benefits were not seen at the expense of quality of life, as preliminary results showed no difference in quality-of-life measures across those who received donor transplants and those who did not.

Dr. Brunner noted that physicians often highlight the toxicities of transplant as a consideration for whether to proceed, and while there are toxicities specific to transplant that should be considered, in this study it is seen that, even early on, survival is improved in those patients who move toward early transplant. “It also underscores the limitations of current nontransplant treatments for MDS – there is much room to improve,” he said.
 

Role for alternate donors

Dr. Cutler noted that the majority of patients in the no-donor group died without transplantation. “We need to establish the role of alternative donor transplantation in this population,” he said. Dr. Nakamura indicated that mismatched donors and haploidentical donors such as family donors and umbilical cord blood may be alternate donor sources; outcomes from published studies show similar results, he said.

However, Dr. Brunner noted that the study looked only at traditional fully matched donors, leaving open some questions about alternative donor options such as haploidentical donors and umbilical cord blood donation.

“Our experience in other areas of transplant would suggest that these donor sources may be as good as traditional fully matched options, when using newer conditioning and prophylaxis regimens,” Dr. Brunner said.

Dr. Cutler added, “With the increased acceptance of alternate transplant modalities, we need to determine the outcomes associated with these in prospective trials.”

“I think a significant consideration here as well is health equity,” Dr. Brunner said. “Donor options vary according to race and ethnicity and we need to be proactive as a community to ensure that all MDS patients have access to a potentially curative option early in their diagnosis.”

Dr. Cutler reports consultancy for Mesoblast, Generon, Medsenic, Jazz, Kadmon, and Incyte. Dr. Nakamura reports relationships with Magenta Therapeutics, Kyowa-Kirin, Alexion, Merck, NapaJen Pharma, Kadmon Corporation, Celgene, and Viracor. Dr. Fung has disclosed no relevant financial relationships. Dr. Brodsky reports receiving funding from and being on the board/advisory committee for Achillion Pharmaceuticals, consults with Alexion Pharmaceuticals, and receives honoraria from UpToDate. Dr. Brunner reports relationships with Biogen, Acceleron Pharma Inc, Celgene/BMS, Forty Seven Inc, Jazz Pharma, Novartis, Takeda, Xcenda, GSK, Janssen, and AstraZeneca.

A version of this article originally appeared on Medscape.com.

New results suggest that allogeneic hematopoietic cell transplantation (HCT), which is typically reserved for younger patients, may well be offered to older patients with advanced myelodysplastic syndrome (MDS).

In patients with a median age of 66 years who had received a donor transplant, the overall survival (OS) at 3 years was almost double compared with patients who did not receive a transplant – 47.9% vs. 26.6% for the “no-donor” group.  

The finding comes from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Study 1102 (NCT02016781) presented at the American Society of Hematology (ASH) 2020 virtual meeting.

“This study conclusively solidifies the role of transplantation in older individuals with MDS,” presenter Corey Cutler, MD, MPH, of the Dana-Farber Cancer Center, Boston, said in an interview.

Coauthor Ryotaro Nakamura, MD, of City of Hope, Duarte, Calif., said in an interview that this was the largest and first trial in the United States to determine in a prospective fashion that allogeneic stem cell transplantation offers a significant survival in older patients. “There was more than a 20% benefit in OS in this age group,” he said.

“This is an incredibly important study,” said Andrew Brunner, MD, medical oncologist at the Mass General Cancer Center in Boston, who was approached for comment. He explained that for years early transplant was recommended as important for patients who have higher-risk MDS. “This study validates this in a prospective, pseudo-randomized (donor/no donor) fashion,” he said in an interview.

“[This study] is really a seminal advance in the care of patients with MDS. Transplant should be integrated into the care algorithm, if not already, and we as a community need to build upon this study further,” Dr. Brunner added.

Several experts in addition to the authors hailed the study as practice changing.

Robert A. Brodsky, MD, ASH, director of the division of hematology at Johns Hopkins University, Baltimore, noted that in younger patients bone marrow transplant is the standard of care for aggressive MDS, but a lot of practices do not refer older patients or those with comorbidities for transplant and prefer to give these patients palliative care with hypomethylating agents for fear that the transplant process would be too toxic.

“There has been an institutional bias to do transplant in older patients, but until now there was no randomized clinical trial to show that this is the right choice. Now we have the data,” Dr Brodsky said, predicting that “this study will change the standard of care.”

Henry Fung, MD, chair of the department of bone marrow transplant and cellular therapies at Fox Chase Cancer Center, Philadelphia, agreed. “We should congratulate all the investigators and our patients who participated in this study. Reduced intensity allogeneic stem cell transplantation improved disease control and overall survival with similar quality of life.

“I will recommend all patients with intermediate-2 or higher-risk MDS to be evaluated by the transplant team at diagnosis and eligible patients should be considered for a transplant,” Dr. Fung said in an interview.

Immediate impact on clinical practice

Lead author Dr. Cutler suggested that the study results had an immediate impact for changing clinical practice. “Individuals between the ages of 50 and 75 years with intermediate-2 or high-risk MDS who are eligible to undergo reduced-intensity transplantation had superior outcomes if they had a suitable donor for transplantation in comparison with those who did not have a donor,” he said.

Dr. Cutler further explained that many community-based hematologists do not refer their patients for transplantation. In addition, there is a lack of a uniform payer position for transplantation for MDS, he noted. Also, there is a lack of understanding of the cost-effectiveness of transplantation in comparison to nontransplant strategies, he suggested.

“Transplant is curative for MDS,” he emphasized. Most transplant recipients will eventually become transfusion-independent within weeks to months from transplant.

“We do transplants in this age group all the time,” Dr. Cutler noted. He said that academic centers will continue to offer transplants, and suggested that community oncologists encourage referral to transplant centers early in a patient’s disease course to maximize search time and provide patients all potential options for therapy.

Dr. Brunner agreed and noted that there is a need to build capacity for higher transplant volume, and in general physicians should seek ways to expand this treatment option to more patients. “At this time, allogeneic transplant still requires close collaboration with referral centers; that said, more and more we are able to work closely with colleagues in the community to share management, including earlier after the actual transplant,” he said.

He noted that one silver lining of the pandemic in 2020 has been increased use of telemedicine to collaborate. “Ongoing advances may be able to further encourage these virtual connections to enhance the entire patient care experience,” Dr. Brunner said.
 

Reimbursement by CMS for Medicare recipients

Despite the data showing benefit, allogeneic stem cell transplantation is not offered to older individuals with high-risk MDS and is not covered by Medicare in the United States, Dr. Cutler noted in his presentation.

“This study was spurred by the CMS [Centers for Medicare & Medicaid Services] ruling for transplantation in MDS and the story has come full circle,” Aaron T. Gerds, MD, MS, noted at a preconference press briefing. Dr. Gerds is chair of the ASH Committee on Communications and assistant professor at the Cleveland Clinic Taussig Cancer Institute, Cleveland.

Dr. Nakamura explained that in 2010 a CMS decision memo noted that the evidence of a benefit for transplantation in MDS was lacking and Medicare would not cover transplant unless patients were enrolled in a clinical study. That memo outlined criteria that a clinical trial would have to address before it could consider reimbursement for Medicare beneficiaries.

“The BMT CTN Study 1102 was one of two studies that met the criteria set by CMS,” Dr. Nakamura said, noting that the data are being prepared for CMS review.

“This study will likely be the deciding factor for CMS to begin to cover payment for transplantation for MDS,” said Dr. Cutler.

The other study, published earlier this year in JAMA Oncology, showed that outcomes for patients older than ager 65 were similar to those of patients aged 55-65.
 

BMT CTN 1102 study details

Dr. Cutler noted that the study was designed to address the issue of whether transplantation was beneficial to Medicare-aged individuals with high-risk MDS, and the trial had been approved by Medicare.

The multicenter study enrolled patients who were between ages 50 and 75 years and had newly diagnosed MDS of higher risk (International Prognostic Scoring System [IPSS] intermediate-2 or higher) and were candidates for reduced intensity conditioning (RIC) allogeneic HCT.

Patients were enrolled prior to a formal donor search and were initially assigned to the “no donor” group and reassigned to the donor group when a suitable donor (matched sibling or unrelated donor) was identified. Patients underwent RIC HCT according to institution protocol.

Of 384 patients, 260 received RIC HCT and 124 received hypomethylating therapy. Median follow-up was 34.2 months for the donor group and 26.9 months for the no-donor group.

The two arms were well balanced with respect to age (median 66 years), gender, disease risk [two-thirds of the patients had an intermediate-2 and one third had a high-risk MDS], and response to hypomethylating therapy. The majority of subjects in the donor arm had unrelated donors and more than one-third had a high comorbidity score, Dr. Cutler indicated.

At 3 years, absolute improvement in OS was 21.3% in favor of donor-arm subjects. Leukemia-free survival was also higher in the donor group: 35.8% vs. 20.6% for the no-donor group.

Improvement in OS for patients receiving transplants was seen across all patient subtypes, regardless of age, response to hypomethylating therapy, and IPSS score. “Treatment effects were seen in any subgroup, but particularly in subjects above age 65,” Dr. Cutler stressed.

In an as-treated analysis that excluded subjects who died, the treatment effects were even more pronounced, with an absolute improvement in OS of 31.4% (47.4% vs. 16% for the no-donor arm) and improvement in leukemia-free survival of 28.4% (39.3% vs. 10.9% for the no-donor arm).

In 25 patients in the no-donor arm who subsequently went on to receive alternate donor transplant, the 3-year OS and leukemia-free survival was 58.5%, underscoring the potential value of alternate donor transplant, Dr. Cutler noted.

Dr. Nakamura emphasized that the gains in survival benefits were not seen at the expense of quality of life, as preliminary results showed no difference in quality-of-life measures across those who received donor transplants and those who did not.

Dr. Brunner noted that physicians often highlight the toxicities of transplant as a consideration for whether to proceed, and while there are toxicities specific to transplant that should be considered, in this study it is seen that, even early on, survival is improved in those patients who move toward early transplant. “It also underscores the limitations of current nontransplant treatments for MDS – there is much room to improve,” he said.
 

Role for alternate donors

Dr. Cutler noted that the majority of patients in the no-donor group died without transplantation. “We need to establish the role of alternative donor transplantation in this population,” he said. Dr. Nakamura indicated that mismatched donors and haploidentical donors such as family donors and umbilical cord blood may be alternate donor sources; outcomes from published studies show similar results, he said.

However, Dr. Brunner noted that the study looked only at traditional fully matched donors, leaving open some questions about alternative donor options such as haploidentical donors and umbilical cord blood donation.

“Our experience in other areas of transplant would suggest that these donor sources may be as good as traditional fully matched options, when using newer conditioning and prophylaxis regimens,” Dr. Brunner said.

Dr. Cutler added, “With the increased acceptance of alternate transplant modalities, we need to determine the outcomes associated with these in prospective trials.”

“I think a significant consideration here as well is health equity,” Dr. Brunner said. “Donor options vary according to race and ethnicity and we need to be proactive as a community to ensure that all MDS patients have access to a potentially curative option early in their diagnosis.”

Dr. Cutler reports consultancy for Mesoblast, Generon, Medsenic, Jazz, Kadmon, and Incyte. Dr. Nakamura reports relationships with Magenta Therapeutics, Kyowa-Kirin, Alexion, Merck, NapaJen Pharma, Kadmon Corporation, Celgene, and Viracor. Dr. Fung has disclosed no relevant financial relationships. Dr. Brodsky reports receiving funding from and being on the board/advisory committee for Achillion Pharmaceuticals, consults with Alexion Pharmaceuticals, and receives honoraria from UpToDate. Dr. Brunner reports relationships with Biogen, Acceleron Pharma Inc, Celgene/BMS, Forty Seven Inc, Jazz Pharma, Novartis, Takeda, Xcenda, GSK, Janssen, and AstraZeneca.

A version of this article originally appeared on Medscape.com.

New results suggest that allogeneic hematopoietic cell transplantation (HCT), which is typically reserved for younger patients, may well be offered to older patients with advanced myelodysplastic syndrome (MDS).

In patients with a median age of 66 years who had received a donor transplant, the overall survival (OS) at 3 years was almost double compared with patients who did not receive a transplant – 47.9% vs. 26.6% for the “no-donor” group.  

The finding comes from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Study 1102 (NCT02016781) presented at the American Society of Hematology (ASH) 2020 virtual meeting.

“This study conclusively solidifies the role of transplantation in older individuals with MDS,” presenter Corey Cutler, MD, MPH, of the Dana-Farber Cancer Center, Boston, said in an interview.

Coauthor Ryotaro Nakamura, MD, of City of Hope, Duarte, Calif., said in an interview that this was the largest and first trial in the United States to determine in a prospective fashion that allogeneic stem cell transplantation offers a significant survival in older patients. “There was more than a 20% benefit in OS in this age group,” he said.

“This is an incredibly important study,” said Andrew Brunner, MD, medical oncologist at the Mass General Cancer Center in Boston, who was approached for comment. He explained that for years early transplant was recommended as important for patients who have higher-risk MDS. “This study validates this in a prospective, pseudo-randomized (donor/no donor) fashion,” he said in an interview.

“[This study] is really a seminal advance in the care of patients with MDS. Transplant should be integrated into the care algorithm, if not already, and we as a community need to build upon this study further,” Dr. Brunner added.

Several experts in addition to the authors hailed the study as practice changing.

Robert A. Brodsky, MD, ASH, director of the division of hematology at Johns Hopkins University, Baltimore, noted that in younger patients bone marrow transplant is the standard of care for aggressive MDS, but a lot of practices do not refer older patients or those with comorbidities for transplant and prefer to give these patients palliative care with hypomethylating agents for fear that the transplant process would be too toxic.

“There has been an institutional bias to do transplant in older patients, but until now there was no randomized clinical trial to show that this is the right choice. Now we have the data,” Dr Brodsky said, predicting that “this study will change the standard of care.”

Henry Fung, MD, chair of the department of bone marrow transplant and cellular therapies at Fox Chase Cancer Center, Philadelphia, agreed. “We should congratulate all the investigators and our patients who participated in this study. Reduced intensity allogeneic stem cell transplantation improved disease control and overall survival with similar quality of life.

“I will recommend all patients with intermediate-2 or higher-risk MDS to be evaluated by the transplant team at diagnosis and eligible patients should be considered for a transplant,” Dr. Fung said in an interview.

Immediate impact on clinical practice

Lead author Dr. Cutler suggested that the study results had an immediate impact for changing clinical practice. “Individuals between the ages of 50 and 75 years with intermediate-2 or high-risk MDS who are eligible to undergo reduced-intensity transplantation had superior outcomes if they had a suitable donor for transplantation in comparison with those who did not have a donor,” he said.

Dr. Cutler further explained that many community-based hematologists do not refer their patients for transplantation. In addition, there is a lack of a uniform payer position for transplantation for MDS, he noted. Also, there is a lack of understanding of the cost-effectiveness of transplantation in comparison to nontransplant strategies, he suggested.

“Transplant is curative for MDS,” he emphasized. Most transplant recipients will eventually become transfusion-independent within weeks to months from transplant.

“We do transplants in this age group all the time,” Dr. Cutler noted. He said that academic centers will continue to offer transplants, and suggested that community oncologists encourage referral to transplant centers early in a patient’s disease course to maximize search time and provide patients all potential options for therapy.

Dr. Brunner agreed and noted that there is a need to build capacity for higher transplant volume, and in general physicians should seek ways to expand this treatment option to more patients. “At this time, allogeneic transplant still requires close collaboration with referral centers; that said, more and more we are able to work closely with colleagues in the community to share management, including earlier after the actual transplant,” he said.

He noted that one silver lining of the pandemic in 2020 has been increased use of telemedicine to collaborate. “Ongoing advances may be able to further encourage these virtual connections to enhance the entire patient care experience,” Dr. Brunner said.
 

Reimbursement by CMS for Medicare recipients

Despite the data showing benefit, allogeneic stem cell transplantation is not offered to older individuals with high-risk MDS and is not covered by Medicare in the United States, Dr. Cutler noted in his presentation.

“This study was spurred by the CMS [Centers for Medicare & Medicaid Services] ruling for transplantation in MDS and the story has come full circle,” Aaron T. Gerds, MD, MS, noted at a preconference press briefing. Dr. Gerds is chair of the ASH Committee on Communications and assistant professor at the Cleveland Clinic Taussig Cancer Institute, Cleveland.

Dr. Nakamura explained that in 2010 a CMS decision memo noted that the evidence of a benefit for transplantation in MDS was lacking and Medicare would not cover transplant unless patients were enrolled in a clinical study. That memo outlined criteria that a clinical trial would have to address before it could consider reimbursement for Medicare beneficiaries.

“The BMT CTN Study 1102 was one of two studies that met the criteria set by CMS,” Dr. Nakamura said, noting that the data are being prepared for CMS review.

“This study will likely be the deciding factor for CMS to begin to cover payment for transplantation for MDS,” said Dr. Cutler.

The other study, published earlier this year in JAMA Oncology, showed that outcomes for patients older than ager 65 were similar to those of patients aged 55-65.
 

BMT CTN 1102 study details

Dr. Cutler noted that the study was designed to address the issue of whether transplantation was beneficial to Medicare-aged individuals with high-risk MDS, and the trial had been approved by Medicare.

The multicenter study enrolled patients who were between ages 50 and 75 years and had newly diagnosed MDS of higher risk (International Prognostic Scoring System [IPSS] intermediate-2 or higher) and were candidates for reduced intensity conditioning (RIC) allogeneic HCT.

Patients were enrolled prior to a formal donor search and were initially assigned to the “no donor” group and reassigned to the donor group when a suitable donor (matched sibling or unrelated donor) was identified. Patients underwent RIC HCT according to institution protocol.

Of 384 patients, 260 received RIC HCT and 124 received hypomethylating therapy. Median follow-up was 34.2 months for the donor group and 26.9 months for the no-donor group.

The two arms were well balanced with respect to age (median 66 years), gender, disease risk [two-thirds of the patients had an intermediate-2 and one third had a high-risk MDS], and response to hypomethylating therapy. The majority of subjects in the donor arm had unrelated donors and more than one-third had a high comorbidity score, Dr. Cutler indicated.

At 3 years, absolute improvement in OS was 21.3% in favor of donor-arm subjects. Leukemia-free survival was also higher in the donor group: 35.8% vs. 20.6% for the no-donor group.

Improvement in OS for patients receiving transplants was seen across all patient subtypes, regardless of age, response to hypomethylating therapy, and IPSS score. “Treatment effects were seen in any subgroup, but particularly in subjects above age 65,” Dr. Cutler stressed.

In an as-treated analysis that excluded subjects who died, the treatment effects were even more pronounced, with an absolute improvement in OS of 31.4% (47.4% vs. 16% for the no-donor arm) and improvement in leukemia-free survival of 28.4% (39.3% vs. 10.9% for the no-donor arm).

In 25 patients in the no-donor arm who subsequently went on to receive alternate donor transplant, the 3-year OS and leukemia-free survival was 58.5%, underscoring the potential value of alternate donor transplant, Dr. Cutler noted.

Dr. Nakamura emphasized that the gains in survival benefits were not seen at the expense of quality of life, as preliminary results showed no difference in quality-of-life measures across those who received donor transplants and those who did not.

Dr. Brunner noted that physicians often highlight the toxicities of transplant as a consideration for whether to proceed, and while there are toxicities specific to transplant that should be considered, in this study it is seen that, even early on, survival is improved in those patients who move toward early transplant. “It also underscores the limitations of current nontransplant treatments for MDS – there is much room to improve,” he said.
 

Role for alternate donors

Dr. Cutler noted that the majority of patients in the no-donor group died without transplantation. “We need to establish the role of alternative donor transplantation in this population,” he said. Dr. Nakamura indicated that mismatched donors and haploidentical donors such as family donors and umbilical cord blood may be alternate donor sources; outcomes from published studies show similar results, he said.

However, Dr. Brunner noted that the study looked only at traditional fully matched donors, leaving open some questions about alternative donor options such as haploidentical donors and umbilical cord blood donation.

“Our experience in other areas of transplant would suggest that these donor sources may be as good as traditional fully matched options, when using newer conditioning and prophylaxis regimens,” Dr. Brunner said.

Dr. Cutler added, “With the increased acceptance of alternate transplant modalities, we need to determine the outcomes associated with these in prospective trials.”

“I think a significant consideration here as well is health equity,” Dr. Brunner said. “Donor options vary according to race and ethnicity and we need to be proactive as a community to ensure that all MDS patients have access to a potentially curative option early in their diagnosis.”

Dr. Cutler reports consultancy for Mesoblast, Generon, Medsenic, Jazz, Kadmon, and Incyte. Dr. Nakamura reports relationships with Magenta Therapeutics, Kyowa-Kirin, Alexion, Merck, NapaJen Pharma, Kadmon Corporation, Celgene, and Viracor. Dr. Fung has disclosed no relevant financial relationships. Dr. Brodsky reports receiving funding from and being on the board/advisory committee for Achillion Pharmaceuticals, consults with Alexion Pharmaceuticals, and receives honoraria from UpToDate. Dr. Brunner reports relationships with Biogen, Acceleron Pharma Inc, Celgene/BMS, Forty Seven Inc, Jazz Pharma, Novartis, Takeda, Xcenda, GSK, Janssen, and AstraZeneca.

A version of this article originally appeared on Medscape.com.

While cardiovascular mortality rates have declined, heart disease continues to be the leading cause of death in the US, and the number of people with cardiovascular disease (CVD) is rising.¹ CVD is more prevalent among military veterans than it is among nonveterans aged ≥ 25 years, and veteran status is associated with higher risk of incident heart disease after controlling for socioeconomic status, other medical diseases, depression, and lifestyle.^2-4 Combat exposure, posttraumatic stress disorder (PTSD), and Purple Heart commendation are associated with higher rates of CVD, including adverse cardiovascular events.^5-7 Many patients seeking care in the Veterans Health Administration (VHA), including those who undergo cardiac catheterization, meet the criteria for multimorbidity (defined as having ≥ 2 chronic diseases⁸), which is common among veterans.^9,10 Multimorbidity presents a challenge for lifestyle intervention, as different diets may be prescribed to treat different conditions, such as Dietary Approaches to Stop Hypertension, and low-glycemic diet for diabetes mellitus (DM). Veterans with CVD are often clinically complex and may require more multifaceted secondary prevention programs.

During the coronavirus 2019 (COVID-19) pandemic, effective secondary prevention intervention is needed more than ever. Older age, CVD, and common comorbidities, including hypertension, DM, and obesity, place patients at the highest risk for severe COVID-19 infection.¹¹ COVID-19 social distancing encourages vulnerable populations to stay home, which can make engaging in any levels of physical activity more challenging. The International Food Council found that 85% of adults have made a change to their food consumption pattern, including eating more, during the COVID-19 pandemic.¹² Thus, secondary CVD prevention programs for veterans need to provide treatment that addresses these specific challenges and can be delivered via telehealth for continuity of care after disruption of traditional services.

Nutrition may be the most powerful Ornish ICR component. The initial RCT conducted by Ornish and colleagues included only stress management training and a whole-food, plant-based (WFPB) diet, including grains, legumes, vegetables, fruits, nuts, and seeds. The trial found 91% of participants experienced reduced angina after only 24 days.¹⁵ The only single-component intervention study resulting in partial reversal of atherosclerosis was a WFPB diet-only study, which documented regression of atherosclerotic plaques after 5 years, using coronary angiography in 73% of participants, with arrested progression in the other 27%.²² Participants reported no cardiovascular AEs after 12 years.²³ Furthermore, a number of other recent studies have demonstrated the benefits of WFPB diet-only interventions for type 2 DM (T2DM), hypertension, and obesity.^24-27 The Heart Disease Reversal Program (HDRP) was developed to create an interdisciplinary lifestyle intervention that emphasized nutrition for a broad population of veterans with atherosclerotic CVD, of varying levels of functional ability, to promote comprehensive CVD risk reduction and bring heart disease reversal intervention into routine clinical practice.

Program Description 

The Mental Health, Cardiology, and Nutrition and Food services all approved the launch of HDRP. We contacted veterans by mail, and 11% expressed interest (Figure). Among patients who received the initial mailed letter (prior to our accepting staff referrals), only 5% of patients who enrolled in HDRP reported previously being told about or prescribed a WFPB diet by any health care provider (HCP). Currently, patients are primarily referred to HDRP by Cardiology, Primary Care, and Mental Health services.

Design

HDRP is an adaptation of interdisciplinary lifestyle interventions that have resulted in regression of atherosclerotic blockages confirmed with invasive coronary angiography.^15-17,22,28 HDRP currently is offered in a Behavioral Medicine Clinic at the Sacramento US Department of Veterans Affairs (VA) Medical Center (VAMC) in California. Program staff include a clinical health psychologist who organizes, coordinates, and act as the lead facilitator of the program; registered dietitians; clinical pharmacists; and a consulting physician. Patients engage in the 4-month core HDRP program in small cohorts (ie, 6-10 patients), and spouses/partners are highly encouraged to attend all sessions.

Components

Telephone screening. Patients are screened for the inclusion and exclusion criteria (Table 1). Patients engaging in a traditional CR program are included in the screening. Patients are informed that the program consists of lifestyle intervention, including emphasis on following a WFPB diet.

A psychologist delivers the physical activity component. Patients are encouraged to meet the American Heart Association/American College of Cardiology recommendations for aerobic exercise (at least 150 minutes of moderate intensity physical activity per week) through a walking program.³⁵ Patients with medical contraindications (eg, severe pain, mobility restrictions) are encouraged to follow the exercise/activity recommendations they had been given by their primary care provider (PCP), physical therapist, or other HCP.

A psychologist provides evidence-based cognitive behavioral stress management (CBSM) training, adapted from models developed for patients with stable ischemic heart disease, HIV/AIDS, and cancer.^36-38 CBSM is a psychotherapy grounded in stress/coping theory and cognitive behavioral theory of psychopathology that integrates cognitive restructuring, coping skills training, communication/assertiveness training, anger management, and mindfulness/acceptance-based approaches. Additional emphasis is placed on assisting patients’ adjustment to the lifestyle challenges for following a plant-based diet, dealing with food cravings and emotional eating, and connecting lifestyle change to patients’ deepest values and goals.

A clinical pharmacist conducts a medication reconciliation for each patient at baseline. The pharmacist consults with each patient’s PCP, cardiologist, and HDRP consulting physician, as needed, to ensure safe adjustments to medications. Pharmacists also provide education on medications at group sessions.

After completion of the 12-week core program, graduates are encouraged to attend the monthly graduates’ group indefinitely, and as often as they desire to promote maintenance of the disease reversal lifestyle. Patients are encouraged to complete our recommended fasting laboratory work every 3 to 6 months to facilitate maintenance of treatment gains.

Program Evaluation

Patients frequently reported that the group format was vital to their success. Patients requested a cooking class, yet we lacked a full teaching kitchen. Integrating plant-based meal samples at every session and cooking videos helped. Patients reported that 100% adherence to the WFPB diet led to significant changes in their food preferences, including a loss of interest in meat.³⁹ Patients encouraged us to keep the “disease reversal” language and focus. One veteran stated: “Disease reversal, that is the reason I called you when I got your letter.” Showing before and after images of coronary angiograms and cardiac positron emission tomography scans depicting regression of atherosclerotic plaque and restored myocardial perfusion were described as highly motivating and generated willingness to commit to a more aggressive lifestyle change.³¹

Patients routinely stated that they lacked understanding of their laboratory test results, which HDRP remedied. Some patients reported their adult children followed a plant-based diet, and our program resulted in a new commonality and source of bonding that was highly valued. Some patients reported that HDRP was helpful for controlling their COVID-19 anxiety and feeling in control of their health. Satisfaction surveys were completed by participants at the end of the core program, which demonstrated very high satisfaction with and acceptability of HDRP (Table 3).

COVID-19 Response

Face-to-face group appointments were converted to videoconferencing as a result of the COVID-19 pandemic. While HDRP always promoted the use of technology and mHealth tools, the pandemic led us to develop novel technology-based interventions.⁴⁰ One cohort transitioned from in-person to videoconferencing sessions, and 2 cohorts recently started this format and are ongoing. We have successfully used videoconferencing with Cisco Webex, the VA-approved backup platform, as we encountered technical barriers when using VA Video Connect. Program materials were shared electronically, and participants sent blood pressure/sugar logs by secure messaging. Guidance for online grocery shopping with home delivery was provided, and research on the benefits of the HDRP lifestyle on immune function was incorporated.

The stress management component incorporated coping with COVID-19, including normalizing common emotional difficulties with sheltering-in-place and quarantine, acknowledging and processing fear and anxiety related to being at very high risk for severe COVID-19. We presented heart disease reversal as an urgent and feasible goal during the pandemic both reducing risk of premature death and major adverse cardiovascular events in the long-term and also reducing personal risk of severe COVID complications. The new VA COVID Coach app was also presented as a resource. Reputable sources of COVID-19 and public health information were shared. Walking continued to be the primary recommended form of exercise, while indoor home exercise options were promoted during the periods of very poor air quality due to the widespread California fires and smoke.

Considering the research suggesting benefits of our intervention for treating T2DM,promoting sustained weight loss, and promoting comprehensive cardiometabolic risk reduction, we have begun accepting referrals for patients with any type of atherosclerotic CVD (eg, peripheral artery disease, carotid artery disease), patients with T2DM (without CVD), and patients with only a history of ischemic stroke or transient ischemic attack.^24-27 Vascular surgery has become a new referral source, primarily for patients with peripheral and carotid artery diseases. Finally, we are leveraging videoconferencing and accepting referrals across the VA Northern California Health Care System (VANCHCS)catchment (from the California-Oregon state border to the San Francisco Bay Area). This also helps address a long-standing problem with reaching the many rural veterans who live far from a VA clinic. We successfully implemented a consult/referral process within the EHR that is available to providers across VANCHCS.

Discussion

The efficacy and effectiveness of reversal programs are well established in intensive programs (eg, ICR), yet such programs have yet to be streamlined and disseminated broadly into routine clinical care. HDRP has endeavored to address this by emphasizing nutrition relative to other program components. We have learned that the words “disease reversal” are very often the reason patients initially reach out or accept referral to our program.

Consistent with past research on plant-based nutrition interventions, the group format was indispensable.⁴¹ Individual sessions with a clinical health psychologist enabled tailored feedback and education on how behavior changes could impact laboratory results and how certain psychosocial factors could support success. Participants reported that seeing significantly favorable laboratory results was highly motivating and confirmed the power of their lifestyle changes. Furthermore, a psychosocial health assessment with individual sessions promoted a tailored treatment plan with targeted clinical interventions, such as behavioral health education, motivational interviewing, and advanced methods, including cognitive behavioral therapy and techniques drawn from dialectical behavior therapy and acceptance and commitment therapy.

Veterans with multimorbidity face the difficult task of learning and maintaining a complex disease self-management program and implementing a lifestyle approach that is feasible, effective, promotes weight loss, and treats multiple conditions. HDRP is a model approach for this population, as demonstrated by a recent case report of a 65-year-old male veteran with atherosclerotic CVD, T2DM, hypertension, and myasthenia gravis who had 2 heart attacks within 2 months.⁴² His neurologic disease precluded significant physical activity. Although he achieved some initial weight loss through lifestyle changes, he continued to have daily angina despite optimal and aggressive cardiology management. After enrolling in HDRP and adopting the WFPB diet, the patient reported almost complete resolution of angina within 1 month, similar to that found in other studies.¹⁵

The literature suggests that concern over the acceptability of plant-based diets and patients’ ability to adhere to them long-term may be misplaced. A review paper on dietary interventions lasting > 1 year found that 51 to 61% of vegetarian and vegan study participants had maintained dietary adherence, while 20 to 55% of omnivorous diet intervention participants adhered to their study diets.⁴³ Remarkably, there were no statistically significant differences in the acceptability of the vegan, vegetarian, or omnivorous diets in the studies reviewed.⁴³ Recent dietary research also suggests that providing patients with higher goals (eg, adopting a vegan diet instead of only moderate dietary changes) results in greater weight loss and maintenance.²⁶ HDRP provides training on consumption of whole plant foods, which may offer patients a unique advantage for maximizing results and higher adherence over time.

Limitations

Hands-on cooking instruction was not provided at our VAMC. The total time of the intervention was significantly less in HDRP (25 hours) than it was for the Ornish ICR program (72 hours), which may hinder long-term adherence. Without an exercise facility, we were not able to provide more detailed exercise instruction and supervised exercise.

Program Improvements Planned

There are a number of improvements that are planned for HDRP. First, the program anticipates requesting medical clearance at the telephone screening stage for self-referred patients. Second, HDRP will provide regular presentations on the program to VAMC clinics and community-based outpatient clinics, including reminders about inclusion/exclusion criteria and the referral process, and to solicit feedback on processes. Third, we hope to routinely provide education and address common questions and concerns of HCPs, including expected results. Fourth, we would like to lengthen the patient commitment to HDRP (eg, 1- to 2-year commitment to the graduate group), consistent with other HDRPs.²⁸ Fifth, we hope to further integrate technology-based components to promote behavior change/maintenance, such as automated text messaging.

Conclusions

Although our patient population was self-selected for participation, early program evaluation demonstrates high acceptability. Very few patients had ever been told about a heart disease reversing lifestyle, and we found direct-to-patient clinical outreach an effective method for launching a disease reversal program (optimally timed with HCP presentations). Furthermore, the program is adaptable to current restrictions on in-person appointments due to the COVID-19 pandemic, and much more convenient for rural veterans who live far from any VA clinic. Being able to offer sustainable health care for individuals during unexpected public health crises is critically important. Additionally, treating veterans who are most vulnerable to pandemic illness due to existing medical conditions, such as CVD, should be a high priority. Last, HDRP also may represent a novel integrated treatment for COVID-19 anxiety and secondary CVD prevention, as lifestyle habits are optimized to improve chronic diseases that elevate risk for severe COVID-19 infection and mortality, as well as including coping strategies consistent with evidence-based psychotherapies for anxiety disorders.⁴⁴

We believe that beyond the clinical benefits to patients, there is significant value and benefit added to the health care system by offering an intervention within the “disease reversal” paradigm. Efforts of the health care team to reverse a disease can be considered the highest aim of medicine and health care.⁴⁵

Acknowledgments

This work was supported by the US Department of Veterans Affairs. We give special thanks to David M. Gellerman, MD, PhD, and David W. Schafer, PsyD, for providing Mental Health Service support for initiating the Heart Disease Reversal Program, and to Joseph Giorgio, PsyD (Program Manager, Integrated Care Program) for sustaining it. We thank Amogh Bhat, MD, Chief of Cardiology, for his continued support and partnership with the Cardiology Department. We express thanks to Stephanie Mohney, RDN (Chief, Nutrition and Food Service), Amy Klotz, RDN (Supervisory Dietician), Sian M. Carr-Lopez, PharmD (Associate Chief of Pharmacy, Primary Care), and Michelle Rand, PharmD, CACP (Anticoagulation Clinical Pharmacist-Supervisor) for their staff support of this interdisciplinary program. We thank the patients and their families for their participation in the program and commitment to the lifestyle changes. We also thank the following individuals for their contributions to this program: Lisa Wagaman, RDN, Karen Soong, PharmD, Sara S. Ali, PharmD, Suzan Hua, PharmD, and Stephen Cooperman.

While cardiovascular mortality rates have declined, heart disease continues to be the leading cause of death in the US, and the number of people with cardiovascular disease (CVD) is rising.¹ CVD is more prevalent among military veterans than it is among nonveterans aged ≥ 25 years, and veteran status is associated with higher risk of incident heart disease after controlling for socioeconomic status, other medical diseases, depression, and lifestyle.^2-4 Combat exposure, posttraumatic stress disorder (PTSD), and Purple Heart commendation are associated with higher rates of CVD, including adverse cardiovascular events.^5-7 Many patients seeking care in the Veterans Health Administration (VHA), including those who undergo cardiac catheterization, meet the criteria for multimorbidity (defined as having ≥ 2 chronic diseases⁸), which is common among veterans.^9,10 Multimorbidity presents a challenge for lifestyle intervention, as different diets may be prescribed to treat different conditions, such as Dietary Approaches to Stop Hypertension, and low-glycemic diet for diabetes mellitus (DM). Veterans with CVD are often clinically complex and may require more multifaceted secondary prevention programs.

During the coronavirus 2019 (COVID-19) pandemic, effective secondary prevention intervention is needed more than ever. Older age, CVD, and common comorbidities, including hypertension, DM, and obesity, place patients at the highest risk for severe COVID-19 infection.¹¹ COVID-19 social distancing encourages vulnerable populations to stay home, which can make engaging in any levels of physical activity more challenging. The International Food Council found that 85% of adults have made a change to their food consumption pattern, including eating more, during the COVID-19 pandemic.¹² Thus, secondary CVD prevention programs for veterans need to provide treatment that addresses these specific challenges and can be delivered via telehealth for continuity of care after disruption of traditional services.

Nutrition may be the most powerful Ornish ICR component. The initial RCT conducted by Ornish and colleagues included only stress management training and a whole-food, plant-based (WFPB) diet, including grains, legumes, vegetables, fruits, nuts, and seeds. The trial found 91% of participants experienced reduced angina after only 24 days.¹⁵ The only single-component intervention study resulting in partial reversal of atherosclerosis was a WFPB diet-only study, which documented regression of atherosclerotic plaques after 5 years, using coronary angiography in 73% of participants, with arrested progression in the other 27%.²² Participants reported no cardiovascular AEs after 12 years.²³ Furthermore, a number of other recent studies have demonstrated the benefits of WFPB diet-only interventions for type 2 DM (T2DM), hypertension, and obesity.^24-27 The Heart Disease Reversal Program (HDRP) was developed to create an interdisciplinary lifestyle intervention that emphasized nutrition for a broad population of veterans with atherosclerotic CVD, of varying levels of functional ability, to promote comprehensive CVD risk reduction and bring heart disease reversal intervention into routine clinical practice.

Program Description 

The Mental Health, Cardiology, and Nutrition and Food services all approved the launch of HDRP. We contacted veterans by mail, and 11% expressed interest (Figure). Among patients who received the initial mailed letter (prior to our accepting staff referrals), only 5% of patients who enrolled in HDRP reported previously being told about or prescribed a WFPB diet by any health care provider (HCP). Currently, patients are primarily referred to HDRP by Cardiology, Primary Care, and Mental Health services.

Design

HDRP is an adaptation of interdisciplinary lifestyle interventions that have resulted in regression of atherosclerotic blockages confirmed with invasive coronary angiography.^15-17,22,28 HDRP currently is offered in a Behavioral Medicine Clinic at the Sacramento US Department of Veterans Affairs (VA) Medical Center (VAMC) in California. Program staff include a clinical health psychologist who organizes, coordinates, and act as the lead facilitator of the program; registered dietitians; clinical pharmacists; and a consulting physician. Patients engage in the 4-month core HDRP program in small cohorts (ie, 6-10 patients), and spouses/partners are highly encouraged to attend all sessions.

Components

Telephone screening. Patients are screened for the inclusion and exclusion criteria (Table 1). Patients engaging in a traditional CR program are included in the screening. Patients are informed that the program consists of lifestyle intervention, including emphasis on following a WFPB diet.

A psychologist delivers the physical activity component. Patients are encouraged to meet the American Heart Association/American College of Cardiology recommendations for aerobic exercise (at least 150 minutes of moderate intensity physical activity per week) through a walking program.³⁵ Patients with medical contraindications (eg, severe pain, mobility restrictions) are encouraged to follow the exercise/activity recommendations they had been given by their primary care provider (PCP), physical therapist, or other HCP.

A psychologist provides evidence-based cognitive behavioral stress management (CBSM) training, adapted from models developed for patients with stable ischemic heart disease, HIV/AIDS, and cancer.^36-38 CBSM is a psychotherapy grounded in stress/coping theory and cognitive behavioral theory of psychopathology that integrates cognitive restructuring, coping skills training, communication/assertiveness training, anger management, and mindfulness/acceptance-based approaches. Additional emphasis is placed on assisting patients’ adjustment to the lifestyle challenges for following a plant-based diet, dealing with food cravings and emotional eating, and connecting lifestyle change to patients’ deepest values and goals.

A clinical pharmacist conducts a medication reconciliation for each patient at baseline. The pharmacist consults with each patient’s PCP, cardiologist, and HDRP consulting physician, as needed, to ensure safe adjustments to medications. Pharmacists also provide education on medications at group sessions.

After completion of the 12-week core program, graduates are encouraged to attend the monthly graduates’ group indefinitely, and as often as they desire to promote maintenance of the disease reversal lifestyle. Patients are encouraged to complete our recommended fasting laboratory work every 3 to 6 months to facilitate maintenance of treatment gains.

Program Evaluation

Patients frequently reported that the group format was vital to their success. Patients requested a cooking class, yet we lacked a full teaching kitchen. Integrating plant-based meal samples at every session and cooking videos helped. Patients reported that 100% adherence to the WFPB diet led to significant changes in their food preferences, including a loss of interest in meat.³⁹ Patients encouraged us to keep the “disease reversal” language and focus. One veteran stated: “Disease reversal, that is the reason I called you when I got your letter.” Showing before and after images of coronary angiograms and cardiac positron emission tomography scans depicting regression of atherosclerotic plaque and restored myocardial perfusion were described as highly motivating and generated willingness to commit to a more aggressive lifestyle change.³¹

Patients routinely stated that they lacked understanding of their laboratory test results, which HDRP remedied. Some patients reported their adult children followed a plant-based diet, and our program resulted in a new commonality and source of bonding that was highly valued. Some patients reported that HDRP was helpful for controlling their COVID-19 anxiety and feeling in control of their health. Satisfaction surveys were completed by participants at the end of the core program, which demonstrated very high satisfaction with and acceptability of HDRP (Table 3).

COVID-19 Response

Face-to-face group appointments were converted to videoconferencing as a result of the COVID-19 pandemic. While HDRP always promoted the use of technology and mHealth tools, the pandemic led us to develop novel technology-based interventions.⁴⁰ One cohort transitioned from in-person to videoconferencing sessions, and 2 cohorts recently started this format and are ongoing. We have successfully used videoconferencing with Cisco Webex, the VA-approved backup platform, as we encountered technical barriers when using VA Video Connect. Program materials were shared electronically, and participants sent blood pressure/sugar logs by secure messaging. Guidance for online grocery shopping with home delivery was provided, and research on the benefits of the HDRP lifestyle on immune function was incorporated.

The stress management component incorporated coping with COVID-19, including normalizing common emotional difficulties with sheltering-in-place and quarantine, acknowledging and processing fear and anxiety related to being at very high risk for severe COVID-19. We presented heart disease reversal as an urgent and feasible goal during the pandemic both reducing risk of premature death and major adverse cardiovascular events in the long-term and also reducing personal risk of severe COVID complications. The new VA COVID Coach app was also presented as a resource. Reputable sources of COVID-19 and public health information were shared. Walking continued to be the primary recommended form of exercise, while indoor home exercise options were promoted during the periods of very poor air quality due to the widespread California fires and smoke.

Considering the research suggesting benefits of our intervention for treating T2DM,promoting sustained weight loss, and promoting comprehensive cardiometabolic risk reduction, we have begun accepting referrals for patients with any type of atherosclerotic CVD (eg, peripheral artery disease, carotid artery disease), patients with T2DM (without CVD), and patients with only a history of ischemic stroke or transient ischemic attack.^24-27 Vascular surgery has become a new referral source, primarily for patients with peripheral and carotid artery diseases. Finally, we are leveraging videoconferencing and accepting referrals across the VA Northern California Health Care System (VANCHCS)catchment (from the California-Oregon state border to the San Francisco Bay Area). This also helps address a long-standing problem with reaching the many rural veterans who live far from a VA clinic. We successfully implemented a consult/referral process within the EHR that is available to providers across VANCHCS.

Discussion

The efficacy and effectiveness of reversal programs are well established in intensive programs (eg, ICR), yet such programs have yet to be streamlined and disseminated broadly into routine clinical care. HDRP has endeavored to address this by emphasizing nutrition relative to other program components. We have learned that the words “disease reversal” are very often the reason patients initially reach out or accept referral to our program.

Consistent with past research on plant-based nutrition interventions, the group format was indispensable.⁴¹ Individual sessions with a clinical health psychologist enabled tailored feedback and education on how behavior changes could impact laboratory results and how certain psychosocial factors could support success. Participants reported that seeing significantly favorable laboratory results was highly motivating and confirmed the power of their lifestyle changes. Furthermore, a psychosocial health assessment with individual sessions promoted a tailored treatment plan with targeted clinical interventions, such as behavioral health education, motivational interviewing, and advanced methods, including cognitive behavioral therapy and techniques drawn from dialectical behavior therapy and acceptance and commitment therapy.

Veterans with multimorbidity face the difficult task of learning and maintaining a complex disease self-management program and implementing a lifestyle approach that is feasible, effective, promotes weight loss, and treats multiple conditions. HDRP is a model approach for this population, as demonstrated by a recent case report of a 65-year-old male veteran with atherosclerotic CVD, T2DM, hypertension, and myasthenia gravis who had 2 heart attacks within 2 months.⁴² His neurologic disease precluded significant physical activity. Although he achieved some initial weight loss through lifestyle changes, he continued to have daily angina despite optimal and aggressive cardiology management. After enrolling in HDRP and adopting the WFPB diet, the patient reported almost complete resolution of angina within 1 month, similar to that found in other studies.¹⁵

The literature suggests that concern over the acceptability of plant-based diets and patients’ ability to adhere to them long-term may be misplaced. A review paper on dietary interventions lasting > 1 year found that 51 to 61% of vegetarian and vegan study participants had maintained dietary adherence, while 20 to 55% of omnivorous diet intervention participants adhered to their study diets.⁴³ Remarkably, there were no statistically significant differences in the acceptability of the vegan, vegetarian, or omnivorous diets in the studies reviewed.⁴³ Recent dietary research also suggests that providing patients with higher goals (eg, adopting a vegan diet instead of only moderate dietary changes) results in greater weight loss and maintenance.²⁶ HDRP provides training on consumption of whole plant foods, which may offer patients a unique advantage for maximizing results and higher adherence over time.

Limitations

Hands-on cooking instruction was not provided at our VAMC. The total time of the intervention was significantly less in HDRP (25 hours) than it was for the Ornish ICR program (72 hours), which may hinder long-term adherence. Without an exercise facility, we were not able to provide more detailed exercise instruction and supervised exercise.

Program Improvements Planned

There are a number of improvements that are planned for HDRP. First, the program anticipates requesting medical clearance at the telephone screening stage for self-referred patients. Second, HDRP will provide regular presentations on the program to VAMC clinics and community-based outpatient clinics, including reminders about inclusion/exclusion criteria and the referral process, and to solicit feedback on processes. Third, we hope to routinely provide education and address common questions and concerns of HCPs, including expected results. Fourth, we would like to lengthen the patient commitment to HDRP (eg, 1- to 2-year commitment to the graduate group), consistent with other HDRPs.²⁸ Fifth, we hope to further integrate technology-based components to promote behavior change/maintenance, such as automated text messaging.

Conclusions

Although our patient population was self-selected for participation, early program evaluation demonstrates high acceptability. Very few patients had ever been told about a heart disease reversing lifestyle, and we found direct-to-patient clinical outreach an effective method for launching a disease reversal program (optimally timed with HCP presentations). Furthermore, the program is adaptable to current restrictions on in-person appointments due to the COVID-19 pandemic, and much more convenient for rural veterans who live far from any VA clinic. Being able to offer sustainable health care for individuals during unexpected public health crises is critically important. Additionally, treating veterans who are most vulnerable to pandemic illness due to existing medical conditions, such as CVD, should be a high priority. Last, HDRP also may represent a novel integrated treatment for COVID-19 anxiety and secondary CVD prevention, as lifestyle habits are optimized to improve chronic diseases that elevate risk for severe COVID-19 infection and mortality, as well as including coping strategies consistent with evidence-based psychotherapies for anxiety disorders.⁴⁴

We believe that beyond the clinical benefits to patients, there is significant value and benefit added to the health care system by offering an intervention within the “disease reversal” paradigm. Efforts of the health care team to reverse a disease can be considered the highest aim of medicine and health care.⁴⁵

Acknowledgments

This work was supported by the US Department of Veterans Affairs. We give special thanks to David M. Gellerman, MD, PhD, and David W. Schafer, PsyD, for providing Mental Health Service support for initiating the Heart Disease Reversal Program, and to Joseph Giorgio, PsyD (Program Manager, Integrated Care Program) for sustaining it. We thank Amogh Bhat, MD, Chief of Cardiology, for his continued support and partnership with the Cardiology Department. We express thanks to Stephanie Mohney, RDN (Chief, Nutrition and Food Service), Amy Klotz, RDN (Supervisory Dietician), Sian M. Carr-Lopez, PharmD (Associate Chief of Pharmacy, Primary Care), and Michelle Rand, PharmD, CACP (Anticoagulation Clinical Pharmacist-Supervisor) for their staff support of this interdisciplinary program. We thank the patients and their families for their participation in the program and commitment to the lifestyle changes. We also thank the following individuals for their contributions to this program: Lisa Wagaman, RDN, Karen Soong, PharmD, Sara S. Ali, PharmD, Suzan Hua, PharmD, and Stephen Cooperman.

While cardiovascular mortality rates have declined, heart disease continues to be the leading cause of death in the US, and the number of people with cardiovascular disease (CVD) is rising.¹ CVD is more prevalent among military veterans than it is among nonveterans aged ≥ 25 years, and veteran status is associated with higher risk of incident heart disease after controlling for socioeconomic status, other medical diseases, depression, and lifestyle.^2-4 Combat exposure, posttraumatic stress disorder (PTSD), and Purple Heart commendation are associated with higher rates of CVD, including adverse cardiovascular events.^5-7 Many patients seeking care in the Veterans Health Administration (VHA), including those who undergo cardiac catheterization, meet the criteria for multimorbidity (defined as having ≥ 2 chronic diseases⁸), which is common among veterans.^9,10 Multimorbidity presents a challenge for lifestyle intervention, as different diets may be prescribed to treat different conditions, such as Dietary Approaches to Stop Hypertension, and low-glycemic diet for diabetes mellitus (DM). Veterans with CVD are often clinically complex and may require more multifaceted secondary prevention programs.

During the coronavirus 2019 (COVID-19) pandemic, effective secondary prevention intervention is needed more than ever. Older age, CVD, and common comorbidities, including hypertension, DM, and obesity, place patients at the highest risk for severe COVID-19 infection.¹¹ COVID-19 social distancing encourages vulnerable populations to stay home, which can make engaging in any levels of physical activity more challenging. The International Food Council found that 85% of adults have made a change to their food consumption pattern, including eating more, during the COVID-19 pandemic.¹² Thus, secondary CVD prevention programs for veterans need to provide treatment that addresses these specific challenges and can be delivered via telehealth for continuity of care after disruption of traditional services.

Nutrition may be the most powerful Ornish ICR component. The initial RCT conducted by Ornish and colleagues included only stress management training and a whole-food, plant-based (WFPB) diet, including grains, legumes, vegetables, fruits, nuts, and seeds. The trial found 91% of participants experienced reduced angina after only 24 days.¹⁵ The only single-component intervention study resulting in partial reversal of atherosclerosis was a WFPB diet-only study, which documented regression of atherosclerotic plaques after 5 years, using coronary angiography in 73% of participants, with arrested progression in the other 27%.²² Participants reported no cardiovascular AEs after 12 years.²³ Furthermore, a number of other recent studies have demonstrated the benefits of WFPB diet-only interventions for type 2 DM (T2DM), hypertension, and obesity.^24-27 The Heart Disease Reversal Program (HDRP) was developed to create an interdisciplinary lifestyle intervention that emphasized nutrition for a broad population of veterans with atherosclerotic CVD, of varying levels of functional ability, to promote comprehensive CVD risk reduction and bring heart disease reversal intervention into routine clinical practice.

Program Description 

The Mental Health, Cardiology, and Nutrition and Food services all approved the launch of HDRP. We contacted veterans by mail, and 11% expressed interest (Figure). Among patients who received the initial mailed letter (prior to our accepting staff referrals), only 5% of patients who enrolled in HDRP reported previously being told about or prescribed a WFPB diet by any health care provider (HCP). Currently, patients are primarily referred to HDRP by Cardiology, Primary Care, and Mental Health services.

Design

HDRP is an adaptation of interdisciplinary lifestyle interventions that have resulted in regression of atherosclerotic blockages confirmed with invasive coronary angiography.^15-17,22,28 HDRP currently is offered in a Behavioral Medicine Clinic at the Sacramento US Department of Veterans Affairs (VA) Medical Center (VAMC) in California. Program staff include a clinical health psychologist who organizes, coordinates, and act as the lead facilitator of the program; registered dietitians; clinical pharmacists; and a consulting physician. Patients engage in the 4-month core HDRP program in small cohorts (ie, 6-10 patients), and spouses/partners are highly encouraged to attend all sessions.

Components

Telephone screening. Patients are screened for the inclusion and exclusion criteria (Table 1). Patients engaging in a traditional CR program are included in the screening. Patients are informed that the program consists of lifestyle intervention, including emphasis on following a WFPB diet.

A psychologist delivers the physical activity component. Patients are encouraged to meet the American Heart Association/American College of Cardiology recommendations for aerobic exercise (at least 150 minutes of moderate intensity physical activity per week) through a walking program.³⁵ Patients with medical contraindications (eg, severe pain, mobility restrictions) are encouraged to follow the exercise/activity recommendations they had been given by their primary care provider (PCP), physical therapist, or other HCP.

A psychologist provides evidence-based cognitive behavioral stress management (CBSM) training, adapted from models developed for patients with stable ischemic heart disease, HIV/AIDS, and cancer.^36-38 CBSM is a psychotherapy grounded in stress/coping theory and cognitive behavioral theory of psychopathology that integrates cognitive restructuring, coping skills training, communication/assertiveness training, anger management, and mindfulness/acceptance-based approaches. Additional emphasis is placed on assisting patients’ adjustment to the lifestyle challenges for following a plant-based diet, dealing with food cravings and emotional eating, and connecting lifestyle change to patients’ deepest values and goals.

A clinical pharmacist conducts a medication reconciliation for each patient at baseline. The pharmacist consults with each patient’s PCP, cardiologist, and HDRP consulting physician, as needed, to ensure safe adjustments to medications. Pharmacists also provide education on medications at group sessions.

After completion of the 12-week core program, graduates are encouraged to attend the monthly graduates’ group indefinitely, and as often as they desire to promote maintenance of the disease reversal lifestyle. Patients are encouraged to complete our recommended fasting laboratory work every 3 to 6 months to facilitate maintenance of treatment gains.

Program Evaluation

Patients frequently reported that the group format was vital to their success. Patients requested a cooking class, yet we lacked a full teaching kitchen. Integrating plant-based meal samples at every session and cooking videos helped. Patients reported that 100% adherence to the WFPB diet led to significant changes in their food preferences, including a loss of interest in meat.³⁹ Patients encouraged us to keep the “disease reversal” language and focus. One veteran stated: “Disease reversal, that is the reason I called you when I got your letter.” Showing before and after images of coronary angiograms and cardiac positron emission tomography scans depicting regression of atherosclerotic plaque and restored myocardial perfusion were described as highly motivating and generated willingness to commit to a more aggressive lifestyle change.³¹

Patients routinely stated that they lacked understanding of their laboratory test results, which HDRP remedied. Some patients reported their adult children followed a plant-based diet, and our program resulted in a new commonality and source of bonding that was highly valued. Some patients reported that HDRP was helpful for controlling their COVID-19 anxiety and feeling in control of their health. Satisfaction surveys were completed by participants at the end of the core program, which demonstrated very high satisfaction with and acceptability of HDRP (Table 3).

COVID-19 Response

Face-to-face group appointments were converted to videoconferencing as a result of the COVID-19 pandemic. While HDRP always promoted the use of technology and mHealth tools, the pandemic led us to develop novel technology-based interventions.⁴⁰ One cohort transitioned from in-person to videoconferencing sessions, and 2 cohorts recently started this format and are ongoing. We have successfully used videoconferencing with Cisco Webex, the VA-approved backup platform, as we encountered technical barriers when using VA Video Connect. Program materials were shared electronically, and participants sent blood pressure/sugar logs by secure messaging. Guidance for online grocery shopping with home delivery was provided, and research on the benefits of the HDRP lifestyle on immune function was incorporated.

The stress management component incorporated coping with COVID-19, including normalizing common emotional difficulties with sheltering-in-place and quarantine, acknowledging and processing fear and anxiety related to being at very high risk for severe COVID-19. We presented heart disease reversal as an urgent and feasible goal during the pandemic both reducing risk of premature death and major adverse cardiovascular events in the long-term and also reducing personal risk of severe COVID complications. The new VA COVID Coach app was also presented as a resource. Reputable sources of COVID-19 and public health information were shared. Walking continued to be the primary recommended form of exercise, while indoor home exercise options were promoted during the periods of very poor air quality due to the widespread California fires and smoke.

Considering the research suggesting benefits of our intervention for treating T2DM,promoting sustained weight loss, and promoting comprehensive cardiometabolic risk reduction, we have begun accepting referrals for patients with any type of atherosclerotic CVD (eg, peripheral artery disease, carotid artery disease), patients with T2DM (without CVD), and patients with only a history of ischemic stroke or transient ischemic attack.^24-27 Vascular surgery has become a new referral source, primarily for patients with peripheral and carotid artery diseases. Finally, we are leveraging videoconferencing and accepting referrals across the VA Northern California Health Care System (VANCHCS)catchment (from the California-Oregon state border to the San Francisco Bay Area). This also helps address a long-standing problem with reaching the many rural veterans who live far from a VA clinic. We successfully implemented a consult/referral process within the EHR that is available to providers across VANCHCS.

Discussion

The efficacy and effectiveness of reversal programs are well established in intensive programs (eg, ICR), yet such programs have yet to be streamlined and disseminated broadly into routine clinical care. HDRP has endeavored to address this by emphasizing nutrition relative to other program components. We have learned that the words “disease reversal” are very often the reason patients initially reach out or accept referral to our program.

Consistent with past research on plant-based nutrition interventions, the group format was indispensable.⁴¹ Individual sessions with a clinical health psychologist enabled tailored feedback and education on how behavior changes could impact laboratory results and how certain psychosocial factors could support success. Participants reported that seeing significantly favorable laboratory results was highly motivating and confirmed the power of their lifestyle changes. Furthermore, a psychosocial health assessment with individual sessions promoted a tailored treatment plan with targeted clinical interventions, such as behavioral health education, motivational interviewing, and advanced methods, including cognitive behavioral therapy and techniques drawn from dialectical behavior therapy and acceptance and commitment therapy.

Veterans with multimorbidity face the difficult task of learning and maintaining a complex disease self-management program and implementing a lifestyle approach that is feasible, effective, promotes weight loss, and treats multiple conditions. HDRP is a model approach for this population, as demonstrated by a recent case report of a 65-year-old male veteran with atherosclerotic CVD, T2DM, hypertension, and myasthenia gravis who had 2 heart attacks within 2 months.⁴² His neurologic disease precluded significant physical activity. Although he achieved some initial weight loss through lifestyle changes, he continued to have daily angina despite optimal and aggressive cardiology management. After enrolling in HDRP and adopting the WFPB diet, the patient reported almost complete resolution of angina within 1 month, similar to that found in other studies.¹⁵

The literature suggests that concern over the acceptability of plant-based diets and patients’ ability to adhere to them long-term may be misplaced. A review paper on dietary interventions lasting > 1 year found that 51 to 61% of vegetarian and vegan study participants had maintained dietary adherence, while 20 to 55% of omnivorous diet intervention participants adhered to their study diets.⁴³ Remarkably, there were no statistically significant differences in the acceptability of the vegan, vegetarian, or omnivorous diets in the studies reviewed.⁴³ Recent dietary research also suggests that providing patients with higher goals (eg, adopting a vegan diet instead of only moderate dietary changes) results in greater weight loss and maintenance.²⁶ HDRP provides training on consumption of whole plant foods, which may offer patients a unique advantage for maximizing results and higher adherence over time.

Limitations

Hands-on cooking instruction was not provided at our VAMC. The total time of the intervention was significantly less in HDRP (25 hours) than it was for the Ornish ICR program (72 hours), which may hinder long-term adherence. Without an exercise facility, we were not able to provide more detailed exercise instruction and supervised exercise.

Program Improvements Planned

There are a number of improvements that are planned for HDRP. First, the program anticipates requesting medical clearance at the telephone screening stage for self-referred patients. Second, HDRP will provide regular presentations on the program to VAMC clinics and community-based outpatient clinics, including reminders about inclusion/exclusion criteria and the referral process, and to solicit feedback on processes. Third, we hope to routinely provide education and address common questions and concerns of HCPs, including expected results. Fourth, we would like to lengthen the patient commitment to HDRP (eg, 1- to 2-year commitment to the graduate group), consistent with other HDRPs.²⁸ Fifth, we hope to further integrate technology-based components to promote behavior change/maintenance, such as automated text messaging.

Conclusions

Although our patient population was self-selected for participation, early program evaluation demonstrates high acceptability. Very few patients had ever been told about a heart disease reversing lifestyle, and we found direct-to-patient clinical outreach an effective method for launching a disease reversal program (optimally timed with HCP presentations). Furthermore, the program is adaptable to current restrictions on in-person appointments due to the COVID-19 pandemic, and much more convenient for rural veterans who live far from any VA clinic. Being able to offer sustainable health care for individuals during unexpected public health crises is critically important. Additionally, treating veterans who are most vulnerable to pandemic illness due to existing medical conditions, such as CVD, should be a high priority. Last, HDRP also may represent a novel integrated treatment for COVID-19 anxiety and secondary CVD prevention, as lifestyle habits are optimized to improve chronic diseases that elevate risk for severe COVID-19 infection and mortality, as well as including coping strategies consistent with evidence-based psychotherapies for anxiety disorders.⁴⁴

We believe that beyond the clinical benefits to patients, there is significant value and benefit added to the health care system by offering an intervention within the “disease reversal” paradigm. Efforts of the health care team to reverse a disease can be considered the highest aim of medicine and health care.⁴⁵

Acknowledgments

This work was supported by the US Department of Veterans Affairs. We give special thanks to David M. Gellerman, MD, PhD, and David W. Schafer, PsyD, for providing Mental Health Service support for initiating the Heart Disease Reversal Program, and to Joseph Giorgio, PsyD (Program Manager, Integrated Care Program) for sustaining it. We thank Amogh Bhat, MD, Chief of Cardiology, for his continued support and partnership with the Cardiology Department. We express thanks to Stephanie Mohney, RDN (Chief, Nutrition and Food Service), Amy Klotz, RDN (Supervisory Dietician), Sian M. Carr-Lopez, PharmD (Associate Chief of Pharmacy, Primary Care), and Michelle Rand, PharmD, CACP (Anticoagulation Clinical Pharmacist-Supervisor) for their staff support of this interdisciplinary program. We thank the patients and their families for their participation in the program and commitment to the lifestyle changes. We also thank the following individuals for their contributions to this program: Lisa Wagaman, RDN, Karen Soong, PharmD, Sara S. Ali, PharmD, Suzan Hua, PharmD, and Stephen Cooperman.

A cute colonic pseudo-obstruction, or Ogilvie syndrome, is dilatation of the colon without mechanical obstruction. It is often seen postoperatively after cesarean section , pelvic , spinal, or other orthopedic surgery, such as knee arthroplasty. ¹ One study demonstrated an incidence of acute colonic pseudo-obstruction of 1.3% following hip replacement surgery. ²

The most common symptoms are abdominal distension, pain, nausea, vomiting, constipation, or diarrhea. Bowel sounds are present in the majority of cases.³ It is important to recognize the varied presentations of ileus in the postoperative setting. The most serious complications of acute colonic pseudo-obstruction are colonic ischemia and bowel perforation.

Case Presentation

An 84-year-old man underwent a total left hip arthroplasty revision. The evening after his surgery, his blood pressure (BP) decreased from 93/54 to 71/47 mm Hg, and his heart rate was 73 beats per minute. He was awake, in no acute distress, but reported loose stools. Results of cardiac and pulmonary examinations were normal, showing a regular rate and rhythm with no murmurs and clear lungs. There was normal jugular venous pressure and chronic pitting edema of the lower extremities bilaterally.

An abdominal examination revealed positive bowel sounds, a large ventral hernia, which was easily reducible, and a distended abdomen. His BP remained unchanged after IV normal saline 4 L, and urine output was 200 cc over 4 hours, which the care team determined represented adequate resuscitation. An infection workup, including chest X-ray, urinalysis, and blood and urine cultures, was unrevealing. Hemoglobin was stable at 8.5 g/dL (normal range 14-18), and creatinine level 0.66 mg/dL (normal range 0.7-1.2) at baseline. A transthoracic echocardiogram showed impaired diastolic filling suggestive of extrinsic compression of the left ventricle by mediastinal contents (Figure 1). An abdominal X-ray revealed diffuse dilatation of large bowel loops up to 10 cm, causing elevation and rightward shift of the heart (Figure 2A). A computed tomography scan of the abdomen showed total colonic dilatation without obstruction (Figure 2B).

Discussion

We present an unusual case of left ventricular compression leading to hypotension due to acute colonic pseudo-obstruction. Our patient presented with the rare complication of hypotension due to cardiac compression, which we have not previously seen reported in the literature. Analogous instance of cardiac compression may arise from hiatal hernias and diaphragmatic paralysis. ^4-6

Management of acute colonic pseudo-obstruction is through nothing by mouth status and abdominal decompression. For more severe cases, neostigmine, colonoscopic decompression, and surgery can be considered.

This surgical complication was diagnosed by internal medicine hospitalist consultants on a surgical comanagement service. In the comanagement model, the surgical specialties of orthopedic surgery, neurosurgery, and podiatry at San Francisco Veterans Affairs Medical Center in California have hospitalists who work with the team as active consultants for the medical care of the patients. Hospitalists develop a unique skill set in which they can anticipate new diagnoses, prevent or identify early complications, and individualize a patient’s postoperative care.⁷ One study found that a surgical comanagement service was associated with a decrease in the number of patients with at least 1 surgical complication, decrease in length of stay and 30-day readmissions for a medical cause, decreased consultant use, and an average cost savings per patient of about $2,600 to $4,300.⁸

Conclusions

With the increasing prevalence of hospitalist comanagement services, it is important for surgeons and nonsurgeons alike to recognize acute colonic pseudo-obstruction as a possible surgical complication.

A cute colonic pseudo-obstruction, or Ogilvie syndrome, is dilatation of the colon without mechanical obstruction. It is often seen postoperatively after cesarean section , pelvic , spinal, or other orthopedic surgery, such as knee arthroplasty. ¹ One study demonstrated an incidence of acute colonic pseudo-obstruction of 1.3% following hip replacement surgery. ²

The most common symptoms are abdominal distension, pain, nausea, vomiting, constipation, or diarrhea. Bowel sounds are present in the majority of cases.³ It is important to recognize the varied presentations of ileus in the postoperative setting. The most serious complications of acute colonic pseudo-obstruction are colonic ischemia and bowel perforation.

Case Presentation

An 84-year-old man underwent a total left hip arthroplasty revision. The evening after his surgery, his blood pressure (BP) decreased from 93/54 to 71/47 mm Hg, and his heart rate was 73 beats per minute. He was awake, in no acute distress, but reported loose stools. Results of cardiac and pulmonary examinations were normal, showing a regular rate and rhythm with no murmurs and clear lungs. There was normal jugular venous pressure and chronic pitting edema of the lower extremities bilaterally.

An abdominal examination revealed positive bowel sounds, a large ventral hernia, which was easily reducible, and a distended abdomen. His BP remained unchanged after IV normal saline 4 L, and urine output was 200 cc over 4 hours, which the care team determined represented adequate resuscitation. An infection workup, including chest X-ray, urinalysis, and blood and urine cultures, was unrevealing. Hemoglobin was stable at 8.5 g/dL (normal range 14-18), and creatinine level 0.66 mg/dL (normal range 0.7-1.2) at baseline. A transthoracic echocardiogram showed impaired diastolic filling suggestive of extrinsic compression of the left ventricle by mediastinal contents (Figure 1). An abdominal X-ray revealed diffuse dilatation of large bowel loops up to 10 cm, causing elevation and rightward shift of the heart (Figure 2A). A computed tomography scan of the abdomen showed total colonic dilatation without obstruction (Figure 2B).

Discussion

We present an unusual case of left ventricular compression leading to hypotension due to acute colonic pseudo-obstruction. Our patient presented with the rare complication of hypotension due to cardiac compression, which we have not previously seen reported in the literature. Analogous instance of cardiac compression may arise from hiatal hernias and diaphragmatic paralysis. ^4-6

Management of acute colonic pseudo-obstruction is through nothing by mouth status and abdominal decompression. For more severe cases, neostigmine, colonoscopic decompression, and surgery can be considered.

This surgical complication was diagnosed by internal medicine hospitalist consultants on a surgical comanagement service. In the comanagement model, the surgical specialties of orthopedic surgery, neurosurgery, and podiatry at San Francisco Veterans Affairs Medical Center in California have hospitalists who work with the team as active consultants for the medical care of the patients. Hospitalists develop a unique skill set in which they can anticipate new diagnoses, prevent or identify early complications, and individualize a patient’s postoperative care.⁷ One study found that a surgical comanagement service was associated with a decrease in the number of patients with at least 1 surgical complication, decrease in length of stay and 30-day readmissions for a medical cause, decreased consultant use, and an average cost savings per patient of about $2,600 to $4,300.⁸

Conclusions

With the increasing prevalence of hospitalist comanagement services, it is important for surgeons and nonsurgeons alike to recognize acute colonic pseudo-obstruction as a possible surgical complication.

A cute colonic pseudo-obstruction, or Ogilvie syndrome, is dilatation of the colon without mechanical obstruction. It is often seen postoperatively after cesarean section , pelvic , spinal, or other orthopedic surgery, such as knee arthroplasty. ¹ One study demonstrated an incidence of acute colonic pseudo-obstruction of 1.3% following hip replacement surgery. ²

The most common symptoms are abdominal distension, pain, nausea, vomiting, constipation, or diarrhea. Bowel sounds are present in the majority of cases.³ It is important to recognize the varied presentations of ileus in the postoperative setting. The most serious complications of acute colonic pseudo-obstruction are colonic ischemia and bowel perforation.

Case Presentation

An 84-year-old man underwent a total left hip arthroplasty revision. The evening after his surgery, his blood pressure (BP) decreased from 93/54 to 71/47 mm Hg, and his heart rate was 73 beats per minute. He was awake, in no acute distress, but reported loose stools. Results of cardiac and pulmonary examinations were normal, showing a regular rate and rhythm with no murmurs and clear lungs. There was normal jugular venous pressure and chronic pitting edema of the lower extremities bilaterally.

An abdominal examination revealed positive bowel sounds, a large ventral hernia, which was easily reducible, and a distended abdomen. His BP remained unchanged after IV normal saline 4 L, and urine output was 200 cc over 4 hours, which the care team determined represented adequate resuscitation. An infection workup, including chest X-ray, urinalysis, and blood and urine cultures, was unrevealing. Hemoglobin was stable at 8.5 g/dL (normal range 14-18), and creatinine level 0.66 mg/dL (normal range 0.7-1.2) at baseline. A transthoracic echocardiogram showed impaired diastolic filling suggestive of extrinsic compression of the left ventricle by mediastinal contents (Figure 1). An abdominal X-ray revealed diffuse dilatation of large bowel loops up to 10 cm, causing elevation and rightward shift of the heart (Figure 2A). A computed tomography scan of the abdomen showed total colonic dilatation without obstruction (Figure 2B).

Discussion

We present an unusual case of left ventricular compression leading to hypotension due to acute colonic pseudo-obstruction. Our patient presented with the rare complication of hypotension due to cardiac compression, which we have not previously seen reported in the literature. Analogous instance of cardiac compression may arise from hiatal hernias and diaphragmatic paralysis. ^4-6

Management of acute colonic pseudo-obstruction is through nothing by mouth status and abdominal decompression. For more severe cases, neostigmine, colonoscopic decompression, and surgery can be considered.

This surgical complication was diagnosed by internal medicine hospitalist consultants on a surgical comanagement service. In the comanagement model, the surgical specialties of orthopedic surgery, neurosurgery, and podiatry at San Francisco Veterans Affairs Medical Center in California have hospitalists who work with the team as active consultants for the medical care of the patients. Hospitalists develop a unique skill set in which they can anticipate new diagnoses, prevent or identify early complications, and individualize a patient’s postoperative care.⁷ One study found that a surgical comanagement service was associated with a decrease in the number of patients with at least 1 surgical complication, decrease in length of stay and 30-day readmissions for a medical cause, decreased consultant use, and an average cost savings per patient of about $2,600 to $4,300.⁸

Conclusions

With the increasing prevalence of hospitalist comanagement services, it is important for surgeons and nonsurgeons alike to recognize acute colonic pseudo-obstruction as a possible surgical complication.

Leptospirosis (LS) is considered the most common and widespread zoonotic disease in the world. Numerous outbreaks have occurred in the past 10 years. Due to its technically difficult diagnosis, LS is severely underrecognized, underdiagnosed, and therefore, underreported.^1,2 The Centers for Disease Control and Prevention (CDC) estimate 100 to 150 cases of LS are identified annually in the US, with about 50% of those cases occurring in Puerto Rico (PR).³ Specifically in PR, about 15 to 100 cases of suspected LS were reported annually between 2000 and 2009, with 59 cases and 1 death reported in 2010. The data are thought to be severely underreported due to a lack of widespread diagnostic testing availability in PR and no formal veterinary and environmental surveillance programs to monitor the incidence of animal cases and actual circulating serovars.⁴

A recent systematic review of 80 studies from 34 countries on morbidity and mortality of LS revealed that the global incidence and mortality is about 1.03 million cases and 58,900 deaths every year. Almost half of the reported deaths were adult males aged 20 to 49 years.⁵ Although mild cases of LS are not associated with an elevated mortality, icteric LS with renal failure (Weil disease) carries a mortality rate of 10%.⁶ In patients who develop hemorrhagic pneumonitis, mortality may be as high as 50 to 70%.⁷ Therefore, it is pivotal that clinicians recognize the disease early, that novel modalities of treatment continue to be developed, and that their impact on patient morbidity and mortality are studied and documented.

Case Presentation

A 43-year-old man with a medical history of schizophrenia presented to the emergency department at the US Department of Veterans Affairs (VA) Caribbean Healthcare System in San Juan, PR, after experiencing 1 week of intermittent fever, myalgia, and general weakness. Emergency medical services had found him disheveled and in a rodent-infested swamp area several days before admission. Initial vital signs were within normal limits.

On physical examination, the patient was afebrile, without acute distress, but he had diffuse jaundice and mild epigastric tenderness without evidence of peritoneal irritation. His complete blood count was remarkable for leukocytosis with left shifting, adequate hemoglobin levels but with 9 × 10³ U/L platelets. The complete metabolic panel demonstrated an aspartate aminotransferase level of 564 U/L, alanine transaminase level of 462 U/L, total bilirubin of 12 mg/dL, which 10.2 mg/dL were direct bilirubin, and an alkaline phosphate of 345 U/L. Lipase levels were measured at 626 U/L. Marked coagulopathy also was present. The toxicology panel, including acetaminophen and salicylate acid levels, did not reveal the presence of any of the tested substances, and chest imaging did not demonstrate any infiltrates.

An abdominal ultrasound was negative for acute cholestatic pathologies, such as cholelithiasis, cholecystitis, or choledocholithiasis. Nonetheless, a noncontrast abdominopelvic computed tomography was remarkable for peripancreatic fat stranding, which raised suspicion for a diagnosis of pancreatitis.

Once the patient was transferred to the intensive care unit, he developed several episodes of hematemesis, leading to hemodynamical instability and severe respiratory distress. Due to anticipated respiratory failure and need for airway securement, endotracheal intubation was performed. Multiple packed red blood cells were transfused, and the patient was started in vasopressor support.

Diagnosis

A presumptive diagnosis of LS was made due to a considerable history of rodent exposure. The patient was started on broad-spectrum parenteral antibiotics, vancomycin 750 mg every 24 hours, metronidazole 500 mg every 8 hours, and ceftriaxone 2 g IV daily for adequate coverage against Leptospira spp. Despite 72 hours of antibiotic treatment, the patient’s clinical state deteriorated. He required high dosages of norepinephrine (1.5 mcg/kg/min) and vasopressin (0.03 U/min) to maintain adequate organ perfusion. Despite lung protective settings with low tidal volume and a high positive end-expiratory pressure, there was difficulty maintaining adequate oxygenation. Chest imaging was remarkable for bilateral infiltrates concerning for acute respiratory distress syndrome (ARDS).

The coagulopathy and cholestasis continued to worsen, and the renal failure progressed from nonoliguric to anuric. Because of this progression, the patient was started on continuous renal replacement therapy (CRRT) by hemodialysis. Within 24 hours of initiating CRRT, the patient’s clinical status improved dramatically. Vasopressor support was weaned, the coagulopathy resolved, and the cholestasis was improving. The patient’s respiratory status improved in such a manner that he was extubated by the seventh day after being placed on mechanical ventilation. The urine and blood samples sent for identification of Leptospira spp. through polymerase chain reaction (PCR) returned positive by the ninth day of admission. While on CRRT, the patient’s renal function eventually returned to baseline, and he was discharged 12 days after admission.

Discussion

The spirochetes of the genus Leptospira include both saprophytic and pathogenic species. These pathogenic Leptospira spp. have adapted to a grand variety of zoonotic hosts, the most important being rodents. They serve as vectors for the contraction of the disease by humans. Initial infection in rodents by Leptospira spp. causes a systemic illness followed by a persistent colonization of renal tubules from which they are excreted in the urine and into the environment. Humans, in turn, are an incidental host unable to induce a carrier state for the transmission of the pathogenic organism.¹ The time from exposure to onset of symptoms, or incubation phase, averages 7 to 12 days but may range from 3 to 30 days.⁸

LS has been described as having 2 discernable but often coexisting phases. The first, an acute febrile bacteremic phase, has been noted to last about 9 days in about 85% of patients, although a minority have persistent fever from 2 weeks to > 30 days. A second phase, the immune or inflammatory phase, is characterized by a second fever spike preceded by 1 to 5 afebrile days in which there is presence of IgM antibodies and resolution of leptospiremia but positive urine cultures.⁹ Weil disease may present as the second phase of the disease or as a single, progressive illness from its first manifestation. It is characterized by a triad of jaundice, renal failure, and hemorrhage or coagulopathy.¹⁰ Weil disease is of great concern and importance due to its associated higher mortality than that found with the mildest form of the disease.

There are studies that advocate for RRT as an intricate part of the treatment regimen in LS to remove the inflammatory cytokines produced as a reaction to the spirochete.¹¹ In tropical countries with a higher incidence of the disease, leptospirosis is an important cause of acute kidney injury (AKI), depending on multiple factors, including the AKI definition that is used.¹² Renal invasion by Leptospira spp. produces acute tubular necrosis (ATN) and cell edema during the first week and then could progress to acute interstitial nephritis (AIN) in 2 to 3 weeks. It is believed that the mechanism for the Leptospira spp. invasion of the tubules that results in damage is associated with the antigenic components in its outer membrane; the most important outer membrane protein expressed during infection is LipL32. This protein increases the production of proinflammatory proteins, such as inducible nitric oxide synthase, monocyte chemotactic protein-1 (CCL2/MCP-1), T cells, and tumor necrosis factor.¹³

Although doxycycline has been recommended for the prophylaxis and treatment of mild LS, the preferred agent and the conferred benefits of antibiotic treatment overall for the severe form of the disease has been controversial. Traditionally, penicillin G sodium has been recommended as the first-line antibiotic treatment for moderate-to-severe LS.¹⁴ Nonetheless, there has been an increasing pattern of penicillin resistance among Leptospira spp. that has prompted the study and use of alternative agents.

An open-label, randomized comparison of parenteral cefotaxime, penicillin G sodium, and doxycycline for the treatment of suspected severe leptospirosis conducted by Suputtamongkol and colleagues showed no difference in mortality, defervescence, or time to resolution of abnormal laboratory findings.¹⁵ Current CDC recommendations include the use of parenteral penicillin 1.5 MU every 6 hours as the drug of choice, with ceftriaxone 1 g administered IV every 24 hours equally as effective.³

In addition to antimicrobial therapy, supportive care has shifted to include hemodialysis in those patients who develop AKI as part of the disease. Andrade and colleagues conducted a study of 33 patients with LS in Brazil that was set to compare the impact of door-to-dialysis time and dosage of hemodialysis on mortality. In patients with a quicker door-to-dialysis time and daily hemodialysis sessions, there was a 50% (16.7% vs 66.7%) absolute mortality reduction when compared with those with delayed initiation and alternate-day hemodialysis sessions.¹¹ A follow-up prospective study compared the use of traditional sustained low-efficiency dialysis (SLED) with the use of extended SLED via hemodiafiltration in patients with LS presenting with ARDS and AKI. Although hemodiafiltration resulted in a relative decrease in serum levels of interleukin (IL)-17, IL-7, and CCL2/MCP-1, there was no significant difference in mortality.¹⁶ The most important prognostic factor in severe LS presenting with AKI and relating to RRT is a shorter door-to-dialysis time and increased dose, not the mode of dialysis clearance. Nonetheless, both RRT methods resulted in a progressive decrease in inflammatory mediators that have been associated with ATN and AIN in the context of LS.¹⁶ The authors argue that using CRRT instead of SLED via hemodiafiltration could have accentuated the effects of the reduction that inflammatory mediators may have on mortality in patients with severe LS.

Conclusions

LS continues to be of interest due to its current status as the most common zoonotic disease and its widespread prevalence throughout the globe. Novel treatment modalities for LS, specifically for Weil disease, continue to be developed with the goal of reducing the current mortality rate associated with the disease.

In endemic areas, prompt recognition is essential to initiate the recommended therapy. Parenteral antibiotics, such as penicillin G sodium and ceftriaxone, continue to be the mainstay of treatment and constitute the current CDC recommendations. Nonetheless, early initiation of CRRT has been shown to greatly reduce the mortality associated with Weil disease and, when available, should be considered in these patients.

Our patient failed to improve while receiving parenteral antibiotics alone but showed marked improvement after being placed on CRRT. Furthermore, initiation of CRRT resulted in near-complete resolution of his organ dysfunction and eventual discharge from the hospital. This case serves to further support the use of early CRRT as part of the standard of care in severe LS.

Leptospirosis (LS) is considered the most common and widespread zoonotic disease in the world. Numerous outbreaks have occurred in the past 10 years. Due to its technically difficult diagnosis, LS is severely underrecognized, underdiagnosed, and therefore, underreported.^1,2 The Centers for Disease Control and Prevention (CDC) estimate 100 to 150 cases of LS are identified annually in the US, with about 50% of those cases occurring in Puerto Rico (PR).³ Specifically in PR, about 15 to 100 cases of suspected LS were reported annually between 2000 and 2009, with 59 cases and 1 death reported in 2010. The data are thought to be severely underreported due to a lack of widespread diagnostic testing availability in PR and no formal veterinary and environmental surveillance programs to monitor the incidence of animal cases and actual circulating serovars.⁴

A recent systematic review of 80 studies from 34 countries on morbidity and mortality of LS revealed that the global incidence and mortality is about 1.03 million cases and 58,900 deaths every year. Almost half of the reported deaths were adult males aged 20 to 49 years.⁵ Although mild cases of LS are not associated with an elevated mortality, icteric LS with renal failure (Weil disease) carries a mortality rate of 10%.⁶ In patients who develop hemorrhagic pneumonitis, mortality may be as high as 50 to 70%.⁷ Therefore, it is pivotal that clinicians recognize the disease early, that novel modalities of treatment continue to be developed, and that their impact on patient morbidity and mortality are studied and documented.

Case Presentation

A 43-year-old man with a medical history of schizophrenia presented to the emergency department at the US Department of Veterans Affairs (VA) Caribbean Healthcare System in San Juan, PR, after experiencing 1 week of intermittent fever, myalgia, and general weakness. Emergency medical services had found him disheveled and in a rodent-infested swamp area several days before admission. Initial vital signs were within normal limits.

On physical examination, the patient was afebrile, without acute distress, but he had diffuse jaundice and mild epigastric tenderness without evidence of peritoneal irritation. His complete blood count was remarkable for leukocytosis with left shifting, adequate hemoglobin levels but with 9 × 10³ U/L platelets. The complete metabolic panel demonstrated an aspartate aminotransferase level of 564 U/L, alanine transaminase level of 462 U/L, total bilirubin of 12 mg/dL, which 10.2 mg/dL were direct bilirubin, and an alkaline phosphate of 345 U/L. Lipase levels were measured at 626 U/L. Marked coagulopathy also was present. The toxicology panel, including acetaminophen and salicylate acid levels, did not reveal the presence of any of the tested substances, and chest imaging did not demonstrate any infiltrates.

An abdominal ultrasound was negative for acute cholestatic pathologies, such as cholelithiasis, cholecystitis, or choledocholithiasis. Nonetheless, a noncontrast abdominopelvic computed tomography was remarkable for peripancreatic fat stranding, which raised suspicion for a diagnosis of pancreatitis.

Once the patient was transferred to the intensive care unit, he developed several episodes of hematemesis, leading to hemodynamical instability and severe respiratory distress. Due to anticipated respiratory failure and need for airway securement, endotracheal intubation was performed. Multiple packed red blood cells were transfused, and the patient was started in vasopressor support.

Diagnosis

A presumptive diagnosis of LS was made due to a considerable history of rodent exposure. The patient was started on broad-spectrum parenteral antibiotics, vancomycin 750 mg every 24 hours, metronidazole 500 mg every 8 hours, and ceftriaxone 2 g IV daily for adequate coverage against Leptospira spp. Despite 72 hours of antibiotic treatment, the patient’s clinical state deteriorated. He required high dosages of norepinephrine (1.5 mcg/kg/min) and vasopressin (0.03 U/min) to maintain adequate organ perfusion. Despite lung protective settings with low tidal volume and a high positive end-expiratory pressure, there was difficulty maintaining adequate oxygenation. Chest imaging was remarkable for bilateral infiltrates concerning for acute respiratory distress syndrome (ARDS).

The coagulopathy and cholestasis continued to worsen, and the renal failure progressed from nonoliguric to anuric. Because of this progression, the patient was started on continuous renal replacement therapy (CRRT) by hemodialysis. Within 24 hours of initiating CRRT, the patient’s clinical status improved dramatically. Vasopressor support was weaned, the coagulopathy resolved, and the cholestasis was improving. The patient’s respiratory status improved in such a manner that he was extubated by the seventh day after being placed on mechanical ventilation. The urine and blood samples sent for identification of Leptospira spp. through polymerase chain reaction (PCR) returned positive by the ninth day of admission. While on CRRT, the patient’s renal function eventually returned to baseline, and he was discharged 12 days after admission.

Discussion

The spirochetes of the genus Leptospira include both saprophytic and pathogenic species. These pathogenic Leptospira spp. have adapted to a grand variety of zoonotic hosts, the most important being rodents. They serve as vectors for the contraction of the disease by humans. Initial infection in rodents by Leptospira spp. causes a systemic illness followed by a persistent colonization of renal tubules from which they are excreted in the urine and into the environment. Humans, in turn, are an incidental host unable to induce a carrier state for the transmission of the pathogenic organism.¹ The time from exposure to onset of symptoms, or incubation phase, averages 7 to 12 days but may range from 3 to 30 days.⁸

LS has been described as having 2 discernable but often coexisting phases. The first, an acute febrile bacteremic phase, has been noted to last about 9 days in about 85% of patients, although a minority have persistent fever from 2 weeks to > 30 days. A second phase, the immune or inflammatory phase, is characterized by a second fever spike preceded by 1 to 5 afebrile days in which there is presence of IgM antibodies and resolution of leptospiremia but positive urine cultures.⁹ Weil disease may present as the second phase of the disease or as a single, progressive illness from its first manifestation. It is characterized by a triad of jaundice, renal failure, and hemorrhage or coagulopathy.¹⁰ Weil disease is of great concern and importance due to its associated higher mortality than that found with the mildest form of the disease.

There are studies that advocate for RRT as an intricate part of the treatment regimen in LS to remove the inflammatory cytokines produced as a reaction to the spirochete.¹¹ In tropical countries with a higher incidence of the disease, leptospirosis is an important cause of acute kidney injury (AKI), depending on multiple factors, including the AKI definition that is used.¹² Renal invasion by Leptospira spp. produces acute tubular necrosis (ATN) and cell edema during the first week and then could progress to acute interstitial nephritis (AIN) in 2 to 3 weeks. It is believed that the mechanism for the Leptospira spp. invasion of the tubules that results in damage is associated with the antigenic components in its outer membrane; the most important outer membrane protein expressed during infection is LipL32. This protein increases the production of proinflammatory proteins, such as inducible nitric oxide synthase, monocyte chemotactic protein-1 (CCL2/MCP-1), T cells, and tumor necrosis factor.¹³

Although doxycycline has been recommended for the prophylaxis and treatment of mild LS, the preferred agent and the conferred benefits of antibiotic treatment overall for the severe form of the disease has been controversial. Traditionally, penicillin G sodium has been recommended as the first-line antibiotic treatment for moderate-to-severe LS.¹⁴ Nonetheless, there has been an increasing pattern of penicillin resistance among Leptospira spp. that has prompted the study and use of alternative agents.

An open-label, randomized comparison of parenteral cefotaxime, penicillin G sodium, and doxycycline for the treatment of suspected severe leptospirosis conducted by Suputtamongkol and colleagues showed no difference in mortality, defervescence, or time to resolution of abnormal laboratory findings.¹⁵ Current CDC recommendations include the use of parenteral penicillin 1.5 MU every 6 hours as the drug of choice, with ceftriaxone 1 g administered IV every 24 hours equally as effective.³

In addition to antimicrobial therapy, supportive care has shifted to include hemodialysis in those patients who develop AKI as part of the disease. Andrade and colleagues conducted a study of 33 patients with LS in Brazil that was set to compare the impact of door-to-dialysis time and dosage of hemodialysis on mortality. In patients with a quicker door-to-dialysis time and daily hemodialysis sessions, there was a 50% (16.7% vs 66.7%) absolute mortality reduction when compared with those with delayed initiation and alternate-day hemodialysis sessions.¹¹ A follow-up prospective study compared the use of traditional sustained low-efficiency dialysis (SLED) with the use of extended SLED via hemodiafiltration in patients with LS presenting with ARDS and AKI. Although hemodiafiltration resulted in a relative decrease in serum levels of interleukin (IL)-17, IL-7, and CCL2/MCP-1, there was no significant difference in mortality.¹⁶ The most important prognostic factor in severe LS presenting with AKI and relating to RRT is a shorter door-to-dialysis time and increased dose, not the mode of dialysis clearance. Nonetheless, both RRT methods resulted in a progressive decrease in inflammatory mediators that have been associated with ATN and AIN in the context of LS.¹⁶ The authors argue that using CRRT instead of SLED via hemodiafiltration could have accentuated the effects of the reduction that inflammatory mediators may have on mortality in patients with severe LS.

Conclusions

LS continues to be of interest due to its current status as the most common zoonotic disease and its widespread prevalence throughout the globe. Novel treatment modalities for LS, specifically for Weil disease, continue to be developed with the goal of reducing the current mortality rate associated with the disease.

In endemic areas, prompt recognition is essential to initiate the recommended therapy. Parenteral antibiotics, such as penicillin G sodium and ceftriaxone, continue to be the mainstay of treatment and constitute the current CDC recommendations. Nonetheless, early initiation of CRRT has been shown to greatly reduce the mortality associated with Weil disease and, when available, should be considered in these patients.

Our patient failed to improve while receiving parenteral antibiotics alone but showed marked improvement after being placed on CRRT. Furthermore, initiation of CRRT resulted in near-complete resolution of his organ dysfunction and eventual discharge from the hospital. This case serves to further support the use of early CRRT as part of the standard of care in severe LS.

Leptospirosis (LS) is considered the most common and widespread zoonotic disease in the world. Numerous outbreaks have occurred in the past 10 years. Due to its technically difficult diagnosis, LS is severely underrecognized, underdiagnosed, and therefore, underreported.^1,2 The Centers for Disease Control and Prevention (CDC) estimate 100 to 150 cases of LS are identified annually in the US, with about 50% of those cases occurring in Puerto Rico (PR).³ Specifically in PR, about 15 to 100 cases of suspected LS were reported annually between 2000 and 2009, with 59 cases and 1 death reported in 2010. The data are thought to be severely underreported due to a lack of widespread diagnostic testing availability in PR and no formal veterinary and environmental surveillance programs to monitor the incidence of animal cases and actual circulating serovars.⁴

A recent systematic review of 80 studies from 34 countries on morbidity and mortality of LS revealed that the global incidence and mortality is about 1.03 million cases and 58,900 deaths every year. Almost half of the reported deaths were adult males aged 20 to 49 years.⁵ Although mild cases of LS are not associated with an elevated mortality, icteric LS with renal failure (Weil disease) carries a mortality rate of 10%.⁶ In patients who develop hemorrhagic pneumonitis, mortality may be as high as 50 to 70%.⁷ Therefore, it is pivotal that clinicians recognize the disease early, that novel modalities of treatment continue to be developed, and that their impact on patient morbidity and mortality are studied and documented.

Case Presentation

A 43-year-old man with a medical history of schizophrenia presented to the emergency department at the US Department of Veterans Affairs (VA) Caribbean Healthcare System in San Juan, PR, after experiencing 1 week of intermittent fever, myalgia, and general weakness. Emergency medical services had found him disheveled and in a rodent-infested swamp area several days before admission. Initial vital signs were within normal limits.

On physical examination, the patient was afebrile, without acute distress, but he had diffuse jaundice and mild epigastric tenderness without evidence of peritoneal irritation. His complete blood count was remarkable for leukocytosis with left shifting, adequate hemoglobin levels but with 9 × 10³ U/L platelets. The complete metabolic panel demonstrated an aspartate aminotransferase level of 564 U/L, alanine transaminase level of 462 U/L, total bilirubin of 12 mg/dL, which 10.2 mg/dL were direct bilirubin, and an alkaline phosphate of 345 U/L. Lipase levels were measured at 626 U/L. Marked coagulopathy also was present. The toxicology panel, including acetaminophen and salicylate acid levels, did not reveal the presence of any of the tested substances, and chest imaging did not demonstrate any infiltrates.

An abdominal ultrasound was negative for acute cholestatic pathologies, such as cholelithiasis, cholecystitis, or choledocholithiasis. Nonetheless, a noncontrast abdominopelvic computed tomography was remarkable for peripancreatic fat stranding, which raised suspicion for a diagnosis of pancreatitis.

Once the patient was transferred to the intensive care unit, he developed several episodes of hematemesis, leading to hemodynamical instability and severe respiratory distress. Due to anticipated respiratory failure and need for airway securement, endotracheal intubation was performed. Multiple packed red blood cells were transfused, and the patient was started in vasopressor support.

Diagnosis

A presumptive diagnosis of LS was made due to a considerable history of rodent exposure. The patient was started on broad-spectrum parenteral antibiotics, vancomycin 750 mg every 24 hours, metronidazole 500 mg every 8 hours, and ceftriaxone 2 g IV daily for adequate coverage against Leptospira spp. Despite 72 hours of antibiotic treatment, the patient’s clinical state deteriorated. He required high dosages of norepinephrine (1.5 mcg/kg/min) and vasopressin (0.03 U/min) to maintain adequate organ perfusion. Despite lung protective settings with low tidal volume and a high positive end-expiratory pressure, there was difficulty maintaining adequate oxygenation. Chest imaging was remarkable for bilateral infiltrates concerning for acute respiratory distress syndrome (ARDS).

The coagulopathy and cholestasis continued to worsen, and the renal failure progressed from nonoliguric to anuric. Because of this progression, the patient was started on continuous renal replacement therapy (CRRT) by hemodialysis. Within 24 hours of initiating CRRT, the patient’s clinical status improved dramatically. Vasopressor support was weaned, the coagulopathy resolved, and the cholestasis was improving. The patient’s respiratory status improved in such a manner that he was extubated by the seventh day after being placed on mechanical ventilation. The urine and blood samples sent for identification of Leptospira spp. through polymerase chain reaction (PCR) returned positive by the ninth day of admission. While on CRRT, the patient’s renal function eventually returned to baseline, and he was discharged 12 days after admission.

Discussion

The spirochetes of the genus Leptospira include both saprophytic and pathogenic species. These pathogenic Leptospira spp. have adapted to a grand variety of zoonotic hosts, the most important being rodents. They serve as vectors for the contraction of the disease by humans. Initial infection in rodents by Leptospira spp. causes a systemic illness followed by a persistent colonization of renal tubules from which they are excreted in the urine and into the environment. Humans, in turn, are an incidental host unable to induce a carrier state for the transmission of the pathogenic organism.¹ The time from exposure to onset of symptoms, or incubation phase, averages 7 to 12 days but may range from 3 to 30 days.⁸

LS has been described as having 2 discernable but often coexisting phases. The first, an acute febrile bacteremic phase, has been noted to last about 9 days in about 85% of patients, although a minority have persistent fever from 2 weeks to > 30 days. A second phase, the immune or inflammatory phase, is characterized by a second fever spike preceded by 1 to 5 afebrile days in which there is presence of IgM antibodies and resolution of leptospiremia but positive urine cultures.⁹ Weil disease may present as the second phase of the disease or as a single, progressive illness from its first manifestation. It is characterized by a triad of jaundice, renal failure, and hemorrhage or coagulopathy.¹⁰ Weil disease is of great concern and importance due to its associated higher mortality than that found with the mildest form of the disease.

There are studies that advocate for RRT as an intricate part of the treatment regimen in LS to remove the inflammatory cytokines produced as a reaction to the spirochete.¹¹ In tropical countries with a higher incidence of the disease, leptospirosis is an important cause of acute kidney injury (AKI), depending on multiple factors, including the AKI definition that is used.¹² Renal invasion by Leptospira spp. produces acute tubular necrosis (ATN) and cell edema during the first week and then could progress to acute interstitial nephritis (AIN) in 2 to 3 weeks. It is believed that the mechanism for the Leptospira spp. invasion of the tubules that results in damage is associated with the antigenic components in its outer membrane; the most important outer membrane protein expressed during infection is LipL32. This protein increases the production of proinflammatory proteins, such as inducible nitric oxide synthase, monocyte chemotactic protein-1 (CCL2/MCP-1), T cells, and tumor necrosis factor.¹³

Although doxycycline has been recommended for the prophylaxis and treatment of mild LS, the preferred agent and the conferred benefits of antibiotic treatment overall for the severe form of the disease has been controversial. Traditionally, penicillin G sodium has been recommended as the first-line antibiotic treatment for moderate-to-severe LS.¹⁴ Nonetheless, there has been an increasing pattern of penicillin resistance among Leptospira spp. that has prompted the study and use of alternative agents.

An open-label, randomized comparison of parenteral cefotaxime, penicillin G sodium, and doxycycline for the treatment of suspected severe leptospirosis conducted by Suputtamongkol and colleagues showed no difference in mortality, defervescence, or time to resolution of abnormal laboratory findings.¹⁵ Current CDC recommendations include the use of parenteral penicillin 1.5 MU every 6 hours as the drug of choice, with ceftriaxone 1 g administered IV every 24 hours equally as effective.³

In addition to antimicrobial therapy, supportive care has shifted to include hemodialysis in those patients who develop AKI as part of the disease. Andrade and colleagues conducted a study of 33 patients with LS in Brazil that was set to compare the impact of door-to-dialysis time and dosage of hemodialysis on mortality. In patients with a quicker door-to-dialysis time and daily hemodialysis sessions, there was a 50% (16.7% vs 66.7%) absolute mortality reduction when compared with those with delayed initiation and alternate-day hemodialysis sessions.¹¹ A follow-up prospective study compared the use of traditional sustained low-efficiency dialysis (SLED) with the use of extended SLED via hemodiafiltration in patients with LS presenting with ARDS and AKI. Although hemodiafiltration resulted in a relative decrease in serum levels of interleukin (IL)-17, IL-7, and CCL2/MCP-1, there was no significant difference in mortality.¹⁶ The most important prognostic factor in severe LS presenting with AKI and relating to RRT is a shorter door-to-dialysis time and increased dose, not the mode of dialysis clearance. Nonetheless, both RRT methods resulted in a progressive decrease in inflammatory mediators that have been associated with ATN and AIN in the context of LS.¹⁶ The authors argue that using CRRT instead of SLED via hemodiafiltration could have accentuated the effects of the reduction that inflammatory mediators may have on mortality in patients with severe LS.

Conclusions

LS continues to be of interest due to its current status as the most common zoonotic disease and its widespread prevalence throughout the globe. Novel treatment modalities for LS, specifically for Weil disease, continue to be developed with the goal of reducing the current mortality rate associated with the disease.

In endemic areas, prompt recognition is essential to initiate the recommended therapy. Parenteral antibiotics, such as penicillin G sodium and ceftriaxone, continue to be the mainstay of treatment and constitute the current CDC recommendations. Nonetheless, early initiation of CRRT has been shown to greatly reduce the mortality associated with Weil disease and, when available, should be considered in these patients.

Our patient failed to improve while receiving parenteral antibiotics alone but showed marked improvement after being placed on CRRT. Furthermore, initiation of CRRT resulted in near-complete resolution of his organ dysfunction and eventual discharge from the hospital. This case serves to further support the use of early CRRT as part of the standard of care in severe LS.

More than 34 million adults in the US have type 2 diabetes mellitus (T2DM), a chronic progressive disease identified by worsening hyperglycemia and micro- and macrovascular complications.¹ Consequently, 12.2% of the US adult population is currently at risk for macrovascular diseases, such as stroke and coronary artery disease (CAD) and microvascular diseases, such as neuropathy and diabetic nephropathy.¹

T2DM is the most common comorbid risk factor for chronic kidney disease (CKD) and the leading cause of end-stage renal disease (ESRD). As of 2017, about 750,000 Americans have CKD stage 5 requiring dialysis, and 50% of these patients have preexisting diabetic nephropathy.² Rates of mortality and morbidity are observed to be higher in patients with both CKD and T2DM compared with patients with CKD without T2DM.² Previous clinical trials, including the United Kingdom Prospective Diabetes Study of 1998, have proven that optimal glycemic control decreases the risk of complications of T2DM (ie, nephropathy) in the general population.³ Conversely, tight glycemic control that targets hemoglobin A_1c (HbA_1c) < 7%, in patients with T2DM with ESRD has not shown the same benefits and may lead to worse outcomes. It is postulated that this may be due to the increased incidence of hypoglycemia in this patient population.⁴

Dialysis has varying effects on patients both with and without T2DM. While patients with ESRD without T2DM have the potential to develop impaired glucose tolerance and T2DM, about 33% of patients with T2DM on dialysis actually have HbA_1c < 6%.⁵ In these patients, glycemic control improves spontaneously as their disease progresses, leading to a decrease or cessation of insulin or other antidiabetic medications. This phenomenon, known as burnt-out diabetes, is characterized by (1) alterations in glucose homeostasis and normoglycemia without antidiabetic treatment; (2) HbA_1c levels < 6% despite having established T2DM; (3) decline in insulin requirements or cessation of insulin altogether; and (4) spontaneous hypoglycemia.

There is a misconception that burnt-out diabetes is a favorable condition due to the alteration of the natural course of T2DM. Although this may be true, patients with this condition are prone to develop hypoglycemic episodes and may be linked to poor survival outcomes due to low HbA_1c.^6,7

Since Kalantar-Zadeh and colleagues presented a 2009 case study, there has been a lack of research regarding this unique condition.⁸ The purpose of this case study is to shed further light on burnt-out diabetes and present a patient case pertaining to the challenges of glycemic control in ESRD.

Case Presentation

Mr. A is a 49-year-old Hispanic male veteran with a history of ESRD on hemodialysis (HD) for 6 years, anemia of CKD, and T2DM for 22 years. The patient also has an extensive cardiovascular disease history, including hypertension, hyperlipidemia, and CAD status post-4-vessel coronary artery bypass graft in December 2014. The patient receives in-home HD Monday, Wednesday, and Friday and is on the wait list for kidney transplantation. The patient’s T2DM is managed by a primary care clinical pharmacy specialist (CPS) at the Michael E. DeBakey Veteran Affairs Medical Center (MEDVAMC) in Houston, Texas.

Mr. A’s antidiabetic regimen is 45 units of subcutaneous insulin glargine every morning; insulin aspart sliding scale (about 15-27 units) subcutaneous 3 times daily with meals; and saxagliptin 2.5 mg by mouth once daily.

At a follow-up visit with the CPS, Mr. A stated, “I feel fine except for the occasional low blood sugar episode.” The patient’s most recent HbA_1c was 6.1%, and he reported medication adherence and no signs or symptoms of hyperglycemia (ie, polydipsia, polyphagia, nocturia, visual disturbances). Mr. A reported no use of alcohol, tobacco, or illicit drugs. He walks 1 mile every other day and participates in self-monitoring blood glucose (SMBG) about 2 to 3 times daily (Table 1).

Analysis

Few articles on potential contributors to burnt-out diabetes have been published.^6,7 These articles discuss decreased renal and hepatic clearance of insulin (which increases its half-life) hypoglycemia during HD, and low HbA_1c due to preexisting anemia. Inappropriately low HbA_1c levels may be secondary to, but not limited to, hemolysis, recent blood transfusion, acute blood loss, and medications, such as erythropoietin-stimulating agents (ESAs).⁹ The conditions that affect red blood cell turnover are common in patients with advanced CKD and may result in discrepancies in HbA_1c levels.

Glycated hemoglobin is a series of minor hemoglobin components formed by the adduction of various carbohydrate molecules to hemoglobin. HbA_1c is the largest fraction formed and the most consistent index of the concentration of glucose in the blood.¹⁰ Hence, HbA_1c is the traditional indicator of overall glycemic control. The current HbA_1c goals recommended by the American Diabetes Association are derived from landmark trials conducted with patients in the general adult diabetic non-CKD population. However, hemoglobin measurements can be confounded by conditions present in ESRD and tend to underestimate glucose measurements in patients with T2DM on HD. Despite this, HbA_1c is still regarded as a reasonable measure of glycemic control even in patients with ESRD; however, alternative markers of glycemia may be preferable.¹¹

Although HbA_1c is the gold standard, there are other laboratory measures of average glycemic control available. Fructosamine is a ketoamine formed when glucose binds to serum proteins. When these proteins are exposed to high concentrations of glucose, they experience increased glycation. Fructosamine assays measure the total glycated serum proteins, of which albumin accounts for about 90%.¹¹ Because the half-life of serum proteins is about 20 days, fructosamine levels can reflect glycemic control over a 2- to 3-week period. This is advantageous in conditions that affect the average age of red blood cells, in pregnancy where frequent monitoring and measures of short-term glucose control are especially important, and in the evaluation of a medication adjustment in the management of T2DM. However, this test is not without its limitations. It is less reliable in settings of decreased protein levels (eg, liver disease), there is a lack of availability in routine practice, and reference levels have not been established.¹¹

Hypoglycemic Episodes

At the 2-month follow-up visit with the CPS, Mr. A reported having 5 hypoglycemic episodes in the past 30 days. He also stated he would forget to take his insulin aspart dose before dinner about 3 to 4 times a week but would take it 30 to 60 minutes after the meal. Mr. A did not bring his glucometer or SMBG readings to the visit, but he indicated that his blood glucose levels continued to fluctuate and were elevated when consuming carbohydrates.

Laboratory tests 1 month prior to the 2-month follow-up visit showed HbA_1c of 7.3%, which had increased from his previous level of 6.1%. He was counseled on the proper administration of insulin aspart and lifestyle modifications. A fructosamine level was ordered at this visit to further assess his glycemic control. A follow-up appointment and laboratory workup (fructosamine and HbA_1c) were scheduled for 2 months from the visit (Table 3).

Mr. A was educated on the unreliability of his HbA_1c levels secondary to his condition of ESRD on HD. He was counseled on the purpose of fructosamine and how it may be a better predictor of his glycemic control and morbidity. Mr. A continued to be followed closely by the primary care CPS for T2DM management.

Discussion

Management of T2DM in patients with ESRD presents challenges for clinicians in determining HbA_1c goals and selecting appropriate medication options. The 2012 Kidney Disease Outcomes Quality Initiative (KDOQI) diabetes guideline does not recommend treatment for patients with substantially reduced kidney function to a target HbA_1c < 7% due to risk of hypoglycemia.¹³ Although a target HbA_1c > 7% is suggested for these patients, little is known about appropriate glycemic control in these patients as there is a paucity of prospective, randomized clinical trials that include patients with advanced CKD.¹³

Moreover, many oral antidiabetic medications and their metabolites are cleared by the kidneys and, therefore, pose with potential harm for patients with CKD. Because of this, insulin is the medication of choice for patients with ESRD.⁷ Although insulin requirements may diminish with worsening kidney function, insulin provides the safest method of glycemic control. Insulin dosing can be individualized according to a patient’s renal status as there is no uniformity in renal dose adjustments. There are some noninsulin antidiabetic agents that can be used in ESRD, but use of these agents requires close monitoring and evaluation of the medication’s pharmacokinetics (Table 4). Overall, medication management can be a difficult task for patients with T2DM and ESRD, but antidiabetic regimens may be reduced or discontinued altogether in burnt-out diabetes.

Conclusions

Patients with T2DM and ESRD on dialysis may have higher morbidity and mortality rates than the rates of those without T2DM. It has been shown in various studies that very low HbA_1c (< 5%) and high HbA_1c (> 8%) are associated with poor survival. Some patients with T2DM on dialysis may experience burnt-out diabetes in which they may have normoglycemia and a HbA_1c below goal; despite these facts, this condition is not positive and can be linked to bad outcomes. In patients with T2DM and ESRD, insulin is the antidiabetic medication of choice, and we recommend a HbA_1c target of 6 to 8%. In this patient population, consider using fructosamine levels or other measures of glycemic control to supplement HbA_1c and glucose values to provide a better assessment of glycemic control, morbidity, and mortality. Larger clinical trials are needed to assist in answering questions regarding mortality and optimal HbA_1c targets in burnt-out diabetes.

More than 34 million adults in the US have type 2 diabetes mellitus (T2DM), a chronic progressive disease identified by worsening hyperglycemia and micro- and macrovascular complications.¹ Consequently, 12.2% of the US adult population is currently at risk for macrovascular diseases, such as stroke and coronary artery disease (CAD) and microvascular diseases, such as neuropathy and diabetic nephropathy.¹

T2DM is the most common comorbid risk factor for chronic kidney disease (CKD) and the leading cause of end-stage renal disease (ESRD). As of 2017, about 750,000 Americans have CKD stage 5 requiring dialysis, and 50% of these patients have preexisting diabetic nephropathy.² Rates of mortality and morbidity are observed to be higher in patients with both CKD and T2DM compared with patients with CKD without T2DM.² Previous clinical trials, including the United Kingdom Prospective Diabetes Study of 1998, have proven that optimal glycemic control decreases the risk of complications of T2DM (ie, nephropathy) in the general population.³ Conversely, tight glycemic control that targets hemoglobin A_1c (HbA_1c) < 7%, in patients with T2DM with ESRD has not shown the same benefits and may lead to worse outcomes. It is postulated that this may be due to the increased incidence of hypoglycemia in this patient population.⁴

Dialysis has varying effects on patients both with and without T2DM. While patients with ESRD without T2DM have the potential to develop impaired glucose tolerance and T2DM, about 33% of patients with T2DM on dialysis actually have HbA_1c < 6%.⁵ In these patients, glycemic control improves spontaneously as their disease progresses, leading to a decrease or cessation of insulin or other antidiabetic medications. This phenomenon, known as burnt-out diabetes, is characterized by (1) alterations in glucose homeostasis and normoglycemia without antidiabetic treatment; (2) HbA_1c levels < 6% despite having established T2DM; (3) decline in insulin requirements or cessation of insulin altogether; and (4) spontaneous hypoglycemia.

There is a misconception that burnt-out diabetes is a favorable condition due to the alteration of the natural course of T2DM. Although this may be true, patients with this condition are prone to develop hypoglycemic episodes and may be linked to poor survival outcomes due to low HbA_1c.^6,7

Since Kalantar-Zadeh and colleagues presented a 2009 case study, there has been a lack of research regarding this unique condition.⁸ The purpose of this case study is to shed further light on burnt-out diabetes and present a patient case pertaining to the challenges of glycemic control in ESRD.

Case Presentation

Mr. A is a 49-year-old Hispanic male veteran with a history of ESRD on hemodialysis (HD) for 6 years, anemia of CKD, and T2DM for 22 years. The patient also has an extensive cardiovascular disease history, including hypertension, hyperlipidemia, and CAD status post-4-vessel coronary artery bypass graft in December 2014. The patient receives in-home HD Monday, Wednesday, and Friday and is on the wait list for kidney transplantation. The patient’s T2DM is managed by a primary care clinical pharmacy specialist (CPS) at the Michael E. DeBakey Veteran Affairs Medical Center (MEDVAMC) in Houston, Texas.

Mr. A’s antidiabetic regimen is 45 units of subcutaneous insulin glargine every morning; insulin aspart sliding scale (about 15-27 units) subcutaneous 3 times daily with meals; and saxagliptin 2.5 mg by mouth once daily.

At a follow-up visit with the CPS, Mr. A stated, “I feel fine except for the occasional low blood sugar episode.” The patient’s most recent HbA_1c was 6.1%, and he reported medication adherence and no signs or symptoms of hyperglycemia (ie, polydipsia, polyphagia, nocturia, visual disturbances). Mr. A reported no use of alcohol, tobacco, or illicit drugs. He walks 1 mile every other day and participates in self-monitoring blood glucose (SMBG) about 2 to 3 times daily (Table 1).

Analysis

Few articles on potential contributors to burnt-out diabetes have been published.^6,7 These articles discuss decreased renal and hepatic clearance of insulin (which increases its half-life) hypoglycemia during HD, and low HbA_1c due to preexisting anemia. Inappropriately low HbA_1c levels may be secondary to, but not limited to, hemolysis, recent blood transfusion, acute blood loss, and medications, such as erythropoietin-stimulating agents (ESAs).⁹ The conditions that affect red blood cell turnover are common in patients with advanced CKD and may result in discrepancies in HbA_1c levels.

Glycated hemoglobin is a series of minor hemoglobin components formed by the adduction of various carbohydrate molecules to hemoglobin. HbA_1c is the largest fraction formed and the most consistent index of the concentration of glucose in the blood.¹⁰ Hence, HbA_1c is the traditional indicator of overall glycemic control. The current HbA_1c goals recommended by the American Diabetes Association are derived from landmark trials conducted with patients in the general adult diabetic non-CKD population. However, hemoglobin measurements can be confounded by conditions present in ESRD and tend to underestimate glucose measurements in patients with T2DM on HD. Despite this, HbA_1c is still regarded as a reasonable measure of glycemic control even in patients with ESRD; however, alternative markers of glycemia may be preferable.¹¹

Although HbA_1c is the gold standard, there are other laboratory measures of average glycemic control available. Fructosamine is a ketoamine formed when glucose binds to serum proteins. When these proteins are exposed to high concentrations of glucose, they experience increased glycation. Fructosamine assays measure the total glycated serum proteins, of which albumin accounts for about 90%.¹¹ Because the half-life of serum proteins is about 20 days, fructosamine levels can reflect glycemic control over a 2- to 3-week period. This is advantageous in conditions that affect the average age of red blood cells, in pregnancy where frequent monitoring and measures of short-term glucose control are especially important, and in the evaluation of a medication adjustment in the management of T2DM. However, this test is not without its limitations. It is less reliable in settings of decreased protein levels (eg, liver disease), there is a lack of availability in routine practice, and reference levels have not been established.¹¹

Hypoglycemic Episodes

At the 2-month follow-up visit with the CPS, Mr. A reported having 5 hypoglycemic episodes in the past 30 days. He also stated he would forget to take his insulin aspart dose before dinner about 3 to 4 times a week but would take it 30 to 60 minutes after the meal. Mr. A did not bring his glucometer or SMBG readings to the visit, but he indicated that his blood glucose levels continued to fluctuate and were elevated when consuming carbohydrates.

Laboratory tests 1 month prior to the 2-month follow-up visit showed HbA_1c of 7.3%, which had increased from his previous level of 6.1%. He was counseled on the proper administration of insulin aspart and lifestyle modifications. A fructosamine level was ordered at this visit to further assess his glycemic control. A follow-up appointment and laboratory workup (fructosamine and HbA_1c) were scheduled for 2 months from the visit (Table 3).

Mr. A was educated on the unreliability of his HbA_1c levels secondary to his condition of ESRD on HD. He was counseled on the purpose of fructosamine and how it may be a better predictor of his glycemic control and morbidity. Mr. A continued to be followed closely by the primary care CPS for T2DM management.

Discussion

Management of T2DM in patients with ESRD presents challenges for clinicians in determining HbA_1c goals and selecting appropriate medication options. The 2012 Kidney Disease Outcomes Quality Initiative (KDOQI) diabetes guideline does not recommend treatment for patients with substantially reduced kidney function to a target HbA_1c < 7% due to risk of hypoglycemia.¹³ Although a target HbA_1c > 7% is suggested for these patients, little is known about appropriate glycemic control in these patients as there is a paucity of prospective, randomized clinical trials that include patients with advanced CKD.¹³

Moreover, many oral antidiabetic medications and their metabolites are cleared by the kidneys and, therefore, pose with potential harm for patients with CKD. Because of this, insulin is the medication of choice for patients with ESRD.⁷ Although insulin requirements may diminish with worsening kidney function, insulin provides the safest method of glycemic control. Insulin dosing can be individualized according to a patient’s renal status as there is no uniformity in renal dose adjustments. There are some noninsulin antidiabetic agents that can be used in ESRD, but use of these agents requires close monitoring and evaluation of the medication’s pharmacokinetics (Table 4). Overall, medication management can be a difficult task for patients with T2DM and ESRD, but antidiabetic regimens may be reduced or discontinued altogether in burnt-out diabetes.

Conclusions

Patients with T2DM and ESRD on dialysis may have higher morbidity and mortality rates than the rates of those without T2DM. It has been shown in various studies that very low HbA_1c (< 5%) and high HbA_1c (> 8%) are associated with poor survival. Some patients with T2DM on dialysis may experience burnt-out diabetes in which they may have normoglycemia and a HbA_1c below goal; despite these facts, this condition is not positive and can be linked to bad outcomes. In patients with T2DM and ESRD, insulin is the antidiabetic medication of choice, and we recommend a HbA_1c target of 6 to 8%. In this patient population, consider using fructosamine levels or other measures of glycemic control to supplement HbA_1c and glucose values to provide a better assessment of glycemic control, morbidity, and mortality. Larger clinical trials are needed to assist in answering questions regarding mortality and optimal HbA_1c targets in burnt-out diabetes.

More than 34 million adults in the US have type 2 diabetes mellitus (T2DM), a chronic progressive disease identified by worsening hyperglycemia and micro- and macrovascular complications.¹ Consequently, 12.2% of the US adult population is currently at risk for macrovascular diseases, such as stroke and coronary artery disease (CAD) and microvascular diseases, such as neuropathy and diabetic nephropathy.¹

T2DM is the most common comorbid risk factor for chronic kidney disease (CKD) and the leading cause of end-stage renal disease (ESRD). As of 2017, about 750,000 Americans have CKD stage 5 requiring dialysis, and 50% of these patients have preexisting diabetic nephropathy.² Rates of mortality and morbidity are observed to be higher in patients with both CKD and T2DM compared with patients with CKD without T2DM.² Previous clinical trials, including the United Kingdom Prospective Diabetes Study of 1998, have proven that optimal glycemic control decreases the risk of complications of T2DM (ie, nephropathy) in the general population.³ Conversely, tight glycemic control that targets hemoglobin A_1c (HbA_1c) < 7%, in patients with T2DM with ESRD has not shown the same benefits and may lead to worse outcomes. It is postulated that this may be due to the increased incidence of hypoglycemia in this patient population.⁴

Dialysis has varying effects on patients both with and without T2DM. While patients with ESRD without T2DM have the potential to develop impaired glucose tolerance and T2DM, about 33% of patients with T2DM on dialysis actually have HbA_1c < 6%.⁵ In these patients, glycemic control improves spontaneously as their disease progresses, leading to a decrease or cessation of insulin or other antidiabetic medications. This phenomenon, known as burnt-out diabetes, is characterized by (1) alterations in glucose homeostasis and normoglycemia without antidiabetic treatment; (2) HbA_1c levels < 6% despite having established T2DM; (3) decline in insulin requirements or cessation of insulin altogether; and (4) spontaneous hypoglycemia.

There is a misconception that burnt-out diabetes is a favorable condition due to the alteration of the natural course of T2DM. Although this may be true, patients with this condition are prone to develop hypoglycemic episodes and may be linked to poor survival outcomes due to low HbA_1c.^6,7

Since Kalantar-Zadeh and colleagues presented a 2009 case study, there has been a lack of research regarding this unique condition.⁸ The purpose of this case study is to shed further light on burnt-out diabetes and present a patient case pertaining to the challenges of glycemic control in ESRD.

Case Presentation

Mr. A is a 49-year-old Hispanic male veteran with a history of ESRD on hemodialysis (HD) for 6 years, anemia of CKD, and T2DM for 22 years. The patient also has an extensive cardiovascular disease history, including hypertension, hyperlipidemia, and CAD status post-4-vessel coronary artery bypass graft in December 2014. The patient receives in-home HD Monday, Wednesday, and Friday and is on the wait list for kidney transplantation. The patient’s T2DM is managed by a primary care clinical pharmacy specialist (CPS) at the Michael E. DeBakey Veteran Affairs Medical Center (MEDVAMC) in Houston, Texas.

Mr. A’s antidiabetic regimen is 45 units of subcutaneous insulin glargine every morning; insulin aspart sliding scale (about 15-27 units) subcutaneous 3 times daily with meals; and saxagliptin 2.5 mg by mouth once daily.

At a follow-up visit with the CPS, Mr. A stated, “I feel fine except for the occasional low blood sugar episode.” The patient’s most recent HbA_1c was 6.1%, and he reported medication adherence and no signs or symptoms of hyperglycemia (ie, polydipsia, polyphagia, nocturia, visual disturbances). Mr. A reported no use of alcohol, tobacco, or illicit drugs. He walks 1 mile every other day and participates in self-monitoring blood glucose (SMBG) about 2 to 3 times daily (Table 1).

Analysis

Few articles on potential contributors to burnt-out diabetes have been published.^6,7 These articles discuss decreased renal and hepatic clearance of insulin (which increases its half-life) hypoglycemia during HD, and low HbA_1c due to preexisting anemia. Inappropriately low HbA_1c levels may be secondary to, but not limited to, hemolysis, recent blood transfusion, acute blood loss, and medications, such as erythropoietin-stimulating agents (ESAs).⁹ The conditions that affect red blood cell turnover are common in patients with advanced CKD and may result in discrepancies in HbA_1c levels.

Glycated hemoglobin is a series of minor hemoglobin components formed by the adduction of various carbohydrate molecules to hemoglobin. HbA_1c is the largest fraction formed and the most consistent index of the concentration of glucose in the blood.¹⁰ Hence, HbA_1c is the traditional indicator of overall glycemic control. The current HbA_1c goals recommended by the American Diabetes Association are derived from landmark trials conducted with patients in the general adult diabetic non-CKD population. However, hemoglobin measurements can be confounded by conditions present in ESRD and tend to underestimate glucose measurements in patients with T2DM on HD. Despite this, HbA_1c is still regarded as a reasonable measure of glycemic control even in patients with ESRD; however, alternative markers of glycemia may be preferable.¹¹

Although HbA_1c is the gold standard, there are other laboratory measures of average glycemic control available. Fructosamine is a ketoamine formed when glucose binds to serum proteins. When these proteins are exposed to high concentrations of glucose, they experience increased glycation. Fructosamine assays measure the total glycated serum proteins, of which albumin accounts for about 90%.¹¹ Because the half-life of serum proteins is about 20 days, fructosamine levels can reflect glycemic control over a 2- to 3-week period. This is advantageous in conditions that affect the average age of red blood cells, in pregnancy where frequent monitoring and measures of short-term glucose control are especially important, and in the evaluation of a medication adjustment in the management of T2DM. However, this test is not without its limitations. It is less reliable in settings of decreased protein levels (eg, liver disease), there is a lack of availability in routine practice, and reference levels have not been established.¹¹