Factor VIII replacement therapies and gene therapy may soon reduce the need for factor VIII concentrate in hemophilia A, but concentrate, a staple of therapy for hemophilia A since the 1950s, will still likely have a role in certain circumstances, a hematology expert said.

“Factor VIII concentrate therapy should still be available for hemophilia A therapy in the future, for the treatment of breakthrough bleeds in non–factor substitution therapy cases, to obtain retain reliable levels of laboratory-measurable hemostatic activity, for enhanced global access to hemophilia A therapy, and finally – and somewhat speculatively – to treat nonhemostatic functions if these are better defined in future preclinical investigations,” said David Lillicrap, MD, from Queen’s University in Kingston, Ont.

He discussed factor VIII biology and the pros and cons of alternatives to factor VIII concentrate at the annual congress of the European Association for Haemophilia and Allied Disorders.
 

One factor, multiple sources

It has been known since at least the late 1960s and early ‘70s that the liver is a significant source of factor VIII, primarily through liver sinusoidal endothelial cells (LSECs), but more recent studies have revealed other, nonhepatic sites of factor VIII expression, including the kidneys, lungs, spleen, lymph nodes, heat, intestines, skin an pulmonary artery, he said.

Endothelial cells proven to express factor VIII included LSECs, lymphatic endothelium, glomerular endothelium, and high endothelial venules.

“This information suggests that maybe a site of factor VIII synthesis could be important for a function that we do not yet appreciate. This is speculation, of course, but this is an unusual and enigmatic group of cells, and perhaps we’re missing something here that’s biologically important,” he said.

In addition to hemophilia, factor VIII deficiency may contribute to nonhemostatic pathologies, such as osteopenia/osteoporosis and hypertension, the latter possibly related to multiple renal bleeds or endothelial cell vasomotor dysfunction, he noted.

Despite decades-long experience with factor VIII concentrates, there are still uncertainties regarding optimal effective dosing, and about the mechanisms and management of factor VIII immunogenicity, both primary inhibitor development and immune tolerance induction, Dr. Lillicrap said.
 

Alternative therapies

Both factor VIII mimetics such as emicizumab (Hemlibra) and hemostasis rebalancing agents such as fitusiran, anti–tissue factor pathway inhibitor (TFPI) antibody and activated protein C serine protease inhibitor (APC serpin) require only infrequent subcutaneous administration, are efficacious in patients with factor VIII inhibitors, and are supported by either robust phase 3 data (in the case of mimetics) or evidence from late-phase clinical trials (in the case of the rebalancing agents).

However, “for the factor VIII mimetics we know that only partial factor VIII mimetic function, somewhere in the region of 10%-15% is obtained, and because of this, breakthrough bleeds do occur in these patients,” he said.

Additionally, the mimetics have been associated with rare, sometimes poorly explained thromboembolic complications, especially when they are given concurrently with activated prothrombin complex concentrate. Mimetic are also associated with infrequent development of antidrug antibodies, and “the fact that the factor VIII mimetic function is always ‘on’ is potentially a problem.”

For the rebalancing hemostasis agents, there are concerns about the ability to respond to dynamic challenges to the hemostatic system, such as sepsis or following trauma. These agents are also associated, albeit infrequently, with thromboembolic events, and they are somewhat difficult to monitor, he said.
 

Gene therapy

Gene therapy for hemophilia has the advantages of a single administration for a long-term effect, avoiding the peaks and troughs associated with substitution therapy, and the potential for being less immunogenic than factor VIII protein replacement.

The downside of gene therapy is that some patients may be ineligible for it because of preexisting immunity in about 50% of the population to the adeno-associated virus vectors used to carry the corrective gene.

Additional limitations are the occurrence in about 60% of patients of early although usually transient hepatotoxicity, significant variability in the factor levels ultimately attained, uncertainties about the durability of response, and the potential for long-term genotoxicity, Dr. Lillicrap said.
 

Tolerance for factor VIII

In the question and answer session following the presentation, session moderator Hervé Chambost, MD, from University Hospital La Timone and Aix-Marseille University, both in Marseille, France, asked whether there was a role for factor VIII and immune tolerance therapy (ITI) among patients who have been treated with non–factor replacement therapy.

“Is it important to have an antigenic pressure to maintain factor VIII or not for these patients?” he asked.

“I think this is a critical issue, and it’s an issue that we don’t yet have objective evidence for,” Dr. Lillicrap replied. “But the idea that we need to introduce some antigenic exposure to factor VIII in these individuals is a reasonable one, whether that be with intermittent exposure to factor VIII – weekly, monthly – we simply have no idea, but I think factor VIII will still be required in these patients because of breakthrough bleeds in patients who have been treated with non–factor replacement. So maintaining tolerance is a critical issue, and we need to develop maybe prospective trials to look at what those protocols are going to be to maintain tolerance in these patients.”

“As important, if not more so, is whether children should be tolerized at all,” commented Dan Hart, PhD, from Barts and the London School of Medicine and Dentistry, who also presented data during the session.

“The U.K. currently takes the view that, in children, new inhibitors arising may be delayed into the latter part of the first decade of their life if they have not had factors as their first choice but have had [replacement] on demand. I think we are heading into challenging times of understanding how to deliver ITI to larger children, how acceptable that is, and how we do it, but enabling [factor] VIII to be used long term rather than tolerating a chronic inhibitor I think is a really important issue where we need to head toward some consensus,” he said.

No funding source was reported. Dr. Lillicrap disclosed research funding from and advisory roles for several pharmaceutical companies. Dr. Hart disclosed grant/research support and speakers bureau activity for various companies. Dr. Chambost has previously reported no disclosures relevant to the topic at hand.

Factor VIII replacement therapies and gene therapy may soon reduce the need for factor VIII concentrate in hemophilia A, but concentrate, a staple of therapy for hemophilia A since the 1950s, will still likely have a role in certain circumstances, a hematology expert said.

“Factor VIII concentrate therapy should still be available for hemophilia A therapy in the future, for the treatment of breakthrough bleeds in non–factor substitution therapy cases, to obtain retain reliable levels of laboratory-measurable hemostatic activity, for enhanced global access to hemophilia A therapy, and finally – and somewhat speculatively – to treat nonhemostatic functions if these are better defined in future preclinical investigations,” said David Lillicrap, MD, from Queen’s University in Kingston, Ont.

He discussed factor VIII biology and the pros and cons of alternatives to factor VIII concentrate at the annual congress of the European Association for Haemophilia and Allied Disorders.
 

One factor, multiple sources

It has been known since at least the late 1960s and early ‘70s that the liver is a significant source of factor VIII, primarily through liver sinusoidal endothelial cells (LSECs), but more recent studies have revealed other, nonhepatic sites of factor VIII expression, including the kidneys, lungs, spleen, lymph nodes, heat, intestines, skin an pulmonary artery, he said.

Endothelial cells proven to express factor VIII included LSECs, lymphatic endothelium, glomerular endothelium, and high endothelial venules.

“This information suggests that maybe a site of factor VIII synthesis could be important for a function that we do not yet appreciate. This is speculation, of course, but this is an unusual and enigmatic group of cells, and perhaps we’re missing something here that’s biologically important,” he said.

In addition to hemophilia, factor VIII deficiency may contribute to nonhemostatic pathologies, such as osteopenia/osteoporosis and hypertension, the latter possibly related to multiple renal bleeds or endothelial cell vasomotor dysfunction, he noted.

Despite decades-long experience with factor VIII concentrates, there are still uncertainties regarding optimal effective dosing, and about the mechanisms and management of factor VIII immunogenicity, both primary inhibitor development and immune tolerance induction, Dr. Lillicrap said.
 

Alternative therapies

Both factor VIII mimetics such as emicizumab (Hemlibra) and hemostasis rebalancing agents such as fitusiran, anti–tissue factor pathway inhibitor (TFPI) antibody and activated protein C serine protease inhibitor (APC serpin) require only infrequent subcutaneous administration, are efficacious in patients with factor VIII inhibitors, and are supported by either robust phase 3 data (in the case of mimetics) or evidence from late-phase clinical trials (in the case of the rebalancing agents).

However, “for the factor VIII mimetics we know that only partial factor VIII mimetic function, somewhere in the region of 10%-15% is obtained, and because of this, breakthrough bleeds do occur in these patients,” he said.

Additionally, the mimetics have been associated with rare, sometimes poorly explained thromboembolic complications, especially when they are given concurrently with activated prothrombin complex concentrate. Mimetic are also associated with infrequent development of antidrug antibodies, and “the fact that the factor VIII mimetic function is always ‘on’ is potentially a problem.”

For the rebalancing hemostasis agents, there are concerns about the ability to respond to dynamic challenges to the hemostatic system, such as sepsis or following trauma. These agents are also associated, albeit infrequently, with thromboembolic events, and they are somewhat difficult to monitor, he said.
 

Gene therapy

Gene therapy for hemophilia has the advantages of a single administration for a long-term effect, avoiding the peaks and troughs associated with substitution therapy, and the potential for being less immunogenic than factor VIII protein replacement.

The downside of gene therapy is that some patients may be ineligible for it because of preexisting immunity in about 50% of the population to the adeno-associated virus vectors used to carry the corrective gene.

Additional limitations are the occurrence in about 60% of patients of early although usually transient hepatotoxicity, significant variability in the factor levels ultimately attained, uncertainties about the durability of response, and the potential for long-term genotoxicity, Dr. Lillicrap said.
 

Tolerance for factor VIII

In the question and answer session following the presentation, session moderator Hervé Chambost, MD, from University Hospital La Timone and Aix-Marseille University, both in Marseille, France, asked whether there was a role for factor VIII and immune tolerance therapy (ITI) among patients who have been treated with non–factor replacement therapy.

“Is it important to have an antigenic pressure to maintain factor VIII or not for these patients?” he asked.

“I think this is a critical issue, and it’s an issue that we don’t yet have objective evidence for,” Dr. Lillicrap replied. “But the idea that we need to introduce some antigenic exposure to factor VIII in these individuals is a reasonable one, whether that be with intermittent exposure to factor VIII – weekly, monthly – we simply have no idea, but I think factor VIII will still be required in these patients because of breakthrough bleeds in patients who have been treated with non–factor replacement. So maintaining tolerance is a critical issue, and we need to develop maybe prospective trials to look at what those protocols are going to be to maintain tolerance in these patients.”

“As important, if not more so, is whether children should be tolerized at all,” commented Dan Hart, PhD, from Barts and the London School of Medicine and Dentistry, who also presented data during the session.

“The U.K. currently takes the view that, in children, new inhibitors arising may be delayed into the latter part of the first decade of their life if they have not had factors as their first choice but have had [replacement] on demand. I think we are heading into challenging times of understanding how to deliver ITI to larger children, how acceptable that is, and how we do it, but enabling [factor] VIII to be used long term rather than tolerating a chronic inhibitor I think is a really important issue where we need to head toward some consensus,” he said.

No funding source was reported. Dr. Lillicrap disclosed research funding from and advisory roles for several pharmaceutical companies. Dr. Hart disclosed grant/research support and speakers bureau activity for various companies. Dr. Chambost has previously reported no disclosures relevant to the topic at hand.

Factor VIII replacement therapies and gene therapy may soon reduce the need for factor VIII concentrate in hemophilia A, but concentrate, a staple of therapy for hemophilia A since the 1950s, will still likely have a role in certain circumstances, a hematology expert said.

“Factor VIII concentrate therapy should still be available for hemophilia A therapy in the future, for the treatment of breakthrough bleeds in non–factor substitution therapy cases, to obtain retain reliable levels of laboratory-measurable hemostatic activity, for enhanced global access to hemophilia A therapy, and finally – and somewhat speculatively – to treat nonhemostatic functions if these are better defined in future preclinical investigations,” said David Lillicrap, MD, from Queen’s University in Kingston, Ont.

He discussed factor VIII biology and the pros and cons of alternatives to factor VIII concentrate at the annual congress of the European Association for Haemophilia and Allied Disorders.
 

One factor, multiple sources

It has been known since at least the late 1960s and early ‘70s that the liver is a significant source of factor VIII, primarily through liver sinusoidal endothelial cells (LSECs), but more recent studies have revealed other, nonhepatic sites of factor VIII expression, including the kidneys, lungs, spleen, lymph nodes, heat, intestines, skin an pulmonary artery, he said.

Endothelial cells proven to express factor VIII included LSECs, lymphatic endothelium, glomerular endothelium, and high endothelial venules.

“This information suggests that maybe a site of factor VIII synthesis could be important for a function that we do not yet appreciate. This is speculation, of course, but this is an unusual and enigmatic group of cells, and perhaps we’re missing something here that’s biologically important,” he said.

In addition to hemophilia, factor VIII deficiency may contribute to nonhemostatic pathologies, such as osteopenia/osteoporosis and hypertension, the latter possibly related to multiple renal bleeds or endothelial cell vasomotor dysfunction, he noted.

Despite decades-long experience with factor VIII concentrates, there are still uncertainties regarding optimal effective dosing, and about the mechanisms and management of factor VIII immunogenicity, both primary inhibitor development and immune tolerance induction, Dr. Lillicrap said.
 

Alternative therapies

Both factor VIII mimetics such as emicizumab (Hemlibra) and hemostasis rebalancing agents such as fitusiran, anti–tissue factor pathway inhibitor (TFPI) antibody and activated protein C serine protease inhibitor (APC serpin) require only infrequent subcutaneous administration, are efficacious in patients with factor VIII inhibitors, and are supported by either robust phase 3 data (in the case of mimetics) or evidence from late-phase clinical trials (in the case of the rebalancing agents).

However, “for the factor VIII mimetics we know that only partial factor VIII mimetic function, somewhere in the region of 10%-15% is obtained, and because of this, breakthrough bleeds do occur in these patients,” he said.

Additionally, the mimetics have been associated with rare, sometimes poorly explained thromboembolic complications, especially when they are given concurrently with activated prothrombin complex concentrate. Mimetic are also associated with infrequent development of antidrug antibodies, and “the fact that the factor VIII mimetic function is always ‘on’ is potentially a problem.”

For the rebalancing hemostasis agents, there are concerns about the ability to respond to dynamic challenges to the hemostatic system, such as sepsis or following trauma. These agents are also associated, albeit infrequently, with thromboembolic events, and they are somewhat difficult to monitor, he said.
 

Gene therapy

Gene therapy for hemophilia has the advantages of a single administration for a long-term effect, avoiding the peaks and troughs associated with substitution therapy, and the potential for being less immunogenic than factor VIII protein replacement.

The downside of gene therapy is that some patients may be ineligible for it because of preexisting immunity in about 50% of the population to the adeno-associated virus vectors used to carry the corrective gene.

Additional limitations are the occurrence in about 60% of patients of early although usually transient hepatotoxicity, significant variability in the factor levels ultimately attained, uncertainties about the durability of response, and the potential for long-term genotoxicity, Dr. Lillicrap said.
 

Tolerance for factor VIII

In the question and answer session following the presentation, session moderator Hervé Chambost, MD, from University Hospital La Timone and Aix-Marseille University, both in Marseille, France, asked whether there was a role for factor VIII and immune tolerance therapy (ITI) among patients who have been treated with non–factor replacement therapy.

“Is it important to have an antigenic pressure to maintain factor VIII or not for these patients?” he asked.

“I think this is a critical issue, and it’s an issue that we don’t yet have objective evidence for,” Dr. Lillicrap replied. “But the idea that we need to introduce some antigenic exposure to factor VIII in these individuals is a reasonable one, whether that be with intermittent exposure to factor VIII – weekly, monthly – we simply have no idea, but I think factor VIII will still be required in these patients because of breakthrough bleeds in patients who have been treated with non–factor replacement. So maintaining tolerance is a critical issue, and we need to develop maybe prospective trials to look at what those protocols are going to be to maintain tolerance in these patients.”

“As important, if not more so, is whether children should be tolerized at all,” commented Dan Hart, PhD, from Barts and the London School of Medicine and Dentistry, who also presented data during the session.

“The U.K. currently takes the view that, in children, new inhibitors arising may be delayed into the latter part of the first decade of their life if they have not had factors as their first choice but have had [replacement] on demand. I think we are heading into challenging times of understanding how to deliver ITI to larger children, how acceptable that is, and how we do it, but enabling [factor] VIII to be used long term rather than tolerating a chronic inhibitor I think is a really important issue where we need to head toward some consensus,” he said.

No funding source was reported. Dr. Lillicrap disclosed research funding from and advisory roles for several pharmaceutical companies. Dr. Hart disclosed grant/research support and speakers bureau activity for various companies. Dr. Chambost has previously reported no disclosures relevant to the topic at hand.

Immunogenicity of the high-dose influenza vaccine (HD IIV3) in patients with chronic lymphocytic leukemia (CLL) and monoclonal B-cell lymphocytosis (MBL, the precursor state to CLL) was found lower than reported in healthy adults according to a report in Vaccine.

In addition, immunogenicity to influenza B was found to be greater in those patients with MBL, compared with those with CLL.

“Acute and chronic leukemia patients hospitalized with influenza infection document a case fatality rate of 25%-37%,” according to Jennifer A. Whitaker, MD, of the Mayo Clinic, Rochester, Minn., and colleagues in pointing out the importance of their study.

The prospective pilot study assessed the humoral immune responses of patients to the 2013-2014 and 2014-2015 HD IIV3 (Fluzone High-Dose; Sanofi Pasteur), which was administered as part of routine clinical care in 30 patients (17 with previously untreated CLL and 13 with MBL). The median patient age was 69.5 years.

The primary outcomes were seroconversion and seroprotection, as measured by hemagglutination inhibition assay (HAI).
 

Lower response rate

At day 28 post vaccination, the seroprotection rates for the overall cohort were 19/30 (63.3%) for A/H1N1, 21/23 (91.3%) for A/H3N2, and 13/30 (43.3%) for influenza B. Patients with MBL achieved significantly higher day 28 HAI geometric mean titers (GMT), compared with CLL patients (54.1 vs. 12.1]; P = .01), In addition, MBL patients achieved higher day 28 seroprotection rates against the influenza B vaccine strain virus than did those with CLL (76.9% vs. 17.6%; P = .002). Seroconversion rates for the overall cohort were 3/30 (10%) for A/H1N1; 5/23 (21.7%) for A/H3N2; and 3/30 (10%) for influenza B. No individual with CLL demonstrated seroconversion for influenza B, according to the researchers.

“Our studies reinforce rigorous adherence to vaccination strategies in patients with hematologic malignancy, including those with CLL, given the increased risk of serious complications among those experiencing influenza infection,” the authors stated.

“Even suboptimal responses to influenza vaccination can provide partial protection, reduce hospitalization rates, and/or prevent serious disease complications. Given the recent major issue with novel and aggressive viruses such COVID-19, we absolutely must continue with larger prospective studies to confirm these findings and evaluate vaccine effectiveness in preventing influenza or other novel viruses in these populations,” the researchers concluded.

This study was funded by the National Institutes of Health. Dr. Whitaker reported having no disclosures. Several of the coauthors reported financial relationships with a variety of pharmaceutical and biotechnology companies.

[email protected]

Immunogenicity of the high-dose influenza vaccine (HD IIV3) in patients with chronic lymphocytic leukemia (CLL) and monoclonal B-cell lymphocytosis (MBL, the precursor state to CLL) was found lower than reported in healthy adults according to a report in Vaccine.

In addition, immunogenicity to influenza B was found to be greater in those patients with MBL, compared with those with CLL.

“Acute and chronic leukemia patients hospitalized with influenza infection document a case fatality rate of 25%-37%,” according to Jennifer A. Whitaker, MD, of the Mayo Clinic, Rochester, Minn., and colleagues in pointing out the importance of their study.

The prospective pilot study assessed the humoral immune responses of patients to the 2013-2014 and 2014-2015 HD IIV3 (Fluzone High-Dose; Sanofi Pasteur), which was administered as part of routine clinical care in 30 patients (17 with previously untreated CLL and 13 with MBL). The median patient age was 69.5 years.

The primary outcomes were seroconversion and seroprotection, as measured by hemagglutination inhibition assay (HAI).
 

Lower response rate

At day 28 post vaccination, the seroprotection rates for the overall cohort were 19/30 (63.3%) for A/H1N1, 21/23 (91.3%) for A/H3N2, and 13/30 (43.3%) for influenza B. Patients with MBL achieved significantly higher day 28 HAI geometric mean titers (GMT), compared with CLL patients (54.1 vs. 12.1]; P = .01), In addition, MBL patients achieved higher day 28 seroprotection rates against the influenza B vaccine strain virus than did those with CLL (76.9% vs. 17.6%; P = .002). Seroconversion rates for the overall cohort were 3/30 (10%) for A/H1N1; 5/23 (21.7%) for A/H3N2; and 3/30 (10%) for influenza B. No individual with CLL demonstrated seroconversion for influenza B, according to the researchers.

“Our studies reinforce rigorous adherence to vaccination strategies in patients with hematologic malignancy, including those with CLL, given the increased risk of serious complications among those experiencing influenza infection,” the authors stated.

“Even suboptimal responses to influenza vaccination can provide partial protection, reduce hospitalization rates, and/or prevent serious disease complications. Given the recent major issue with novel and aggressive viruses such COVID-19, we absolutely must continue with larger prospective studies to confirm these findings and evaluate vaccine effectiveness in preventing influenza or other novel viruses in these populations,” the researchers concluded.

This study was funded by the National Institutes of Health. Dr. Whitaker reported having no disclosures. Several of the coauthors reported financial relationships with a variety of pharmaceutical and biotechnology companies.

[email protected]

Immunogenicity of the high-dose influenza vaccine (HD IIV3) in patients with chronic lymphocytic leukemia (CLL) and monoclonal B-cell lymphocytosis (MBL, the precursor state to CLL) was found lower than reported in healthy adults according to a report in Vaccine.

In addition, immunogenicity to influenza B was found to be greater in those patients with MBL, compared with those with CLL.

“Acute and chronic leukemia patients hospitalized with influenza infection document a case fatality rate of 25%-37%,” according to Jennifer A. Whitaker, MD, of the Mayo Clinic, Rochester, Minn., and colleagues in pointing out the importance of their study.

The prospective pilot study assessed the humoral immune responses of patients to the 2013-2014 and 2014-2015 HD IIV3 (Fluzone High-Dose; Sanofi Pasteur), which was administered as part of routine clinical care in 30 patients (17 with previously untreated CLL and 13 with MBL). The median patient age was 69.5 years.

The primary outcomes were seroconversion and seroprotection, as measured by hemagglutination inhibition assay (HAI).
 

Lower response rate

At day 28 post vaccination, the seroprotection rates for the overall cohort were 19/30 (63.3%) for A/H1N1, 21/23 (91.3%) for A/H3N2, and 13/30 (43.3%) for influenza B. Patients with MBL achieved significantly higher day 28 HAI geometric mean titers (GMT), compared with CLL patients (54.1 vs. 12.1]; P = .01), In addition, MBL patients achieved higher day 28 seroprotection rates against the influenza B vaccine strain virus than did those with CLL (76.9% vs. 17.6%; P = .002). Seroconversion rates for the overall cohort were 3/30 (10%) for A/H1N1; 5/23 (21.7%) for A/H3N2; and 3/30 (10%) for influenza B. No individual with CLL demonstrated seroconversion for influenza B, according to the researchers.

“Our studies reinforce rigorous adherence to vaccination strategies in patients with hematologic malignancy, including those with CLL, given the increased risk of serious complications among those experiencing influenza infection,” the authors stated.

“Even suboptimal responses to influenza vaccination can provide partial protection, reduce hospitalization rates, and/or prevent serious disease complications. Given the recent major issue with novel and aggressive viruses such COVID-19, we absolutely must continue with larger prospective studies to confirm these findings and evaluate vaccine effectiveness in preventing influenza or other novel viruses in these populations,” the researchers concluded.

This study was funded by the National Institutes of Health. Dr. Whitaker reported having no disclosures. Several of the coauthors reported financial relationships with a variety of pharmaceutical and biotechnology companies.

[email protected]

Asymptomatic screening of cancer patients receiving anticancer therapy detected a very low rate of COVID-19 in a retrospective study.

Of more than 2,000 patients, less than 1% were found to be COVID-19 positive on asymptomatic screening, an investigator reported at the AACR Virtual Meeting: COVID-19 and Cancer (Abstract S09-04).

While several models have been proposed to screen for COVID-19 among cancer patients, the optimal strategy remains unknown, said investigator Justin A. Shaya, MD, of the University of California, San Diego.

The most commonly used approach is symptom/exposure-based screening and testing. However, other models have combined this method with polymerase chain reaction (PCR) testing for asymptomatic high-risk patients (such as those undergoing bone marrow transplant, receiving chemotherapy, or with hematologic malignancies) or with PCR testing for all asymptomatic cancer patients.

Dr. Shaya’s institution implemented a novel COVID-19 screening protocol for cancer patients receiving infusional anticancer therapy in May 2020.

The protocol required SARS-CoV-2 PCR testing for asymptomatic patients 24-96 hours prior to infusion. However, testing was only required before the administration of anticancer therapy. Infusion visits for supportive care interventions did not require previsit testing.

The researchers retrospectively analyzed data from patients with active cancer receiving infusional anticancer therapy who had at least one asymptomatic SARS-CoV-2 PCR test between June 1 and Dec. 1, 2020. The primary outcome was the rate of COVID-19 positivity among asymptomatic patients.

Results

Among 2,202 patients identified, 21 (0.95%) were found to be COVID-19 positive on asymptomatic screening. Most of these patients (90.5%) had solid tumors, but two (9.5%) had hematologic malignancies.

With respect to treatment, 16 patients (76.2%) received cytotoxic chemotherapy, 2 (9.5%) received targeted therapy, 1 (4.7%) received immunotherapy, and 2 (9.5%) were on a clinical trial.

At a median follow-up of 174 days from a positive PCR test (range, 55-223 days), only two patients (9.5%) developed COVID-related symptoms. Both patients had acute leukemia, and one required hospitalization for COVID-related complications.

In the COVID-19–positive cohort, 20 (95.2%) patients had their anticancer therapy delayed or deferred, with a median delay of 21 days (range, 7-77 days).

In the overall cohort, an additional 26 patients (1.2%) developed symptomatic COVID-19 during the study period.

“These results are particularly interesting because they come from a high-quality center that sees a large number of patients,” said Solange Peters, MD, PhD, of the University of Lausanne (Switzerland), who was not involved in this study.

“As they suggest, it is still a debate on how efficient routine screening is, asking the question whether we’re really detecting COVID-19 infection in our patients. Of course, it depends on the time and environment,” Dr. Peters added.

Dr. Shaya acknowledged that the small sample size was a key limitation of the study. Thus, the results may not be generalizable to other regions.

“One of the most striking things is that asymptomatic patients suffer very few consequences of COVID-19 infection, except for patients with hematologic malignancies,” Dr. Shaya said during a live discussion. “The majority of our patients had solid tumors and failed to develop any signs/symptoms of COVID infection.

“Routine screening provides a lot of security, and our institution is big enough to allow for it, and it seems our teams enjoy the fact of knowing the COVID status for each patient,” he continued.

Dr. Shaya and Dr. Peters disclosed no conflicts of interest. No funding sources were reported in the presentation.

Asymptomatic screening of cancer patients receiving anticancer therapy detected a very low rate of COVID-19 in a retrospective study.

Of more than 2,000 patients, less than 1% were found to be COVID-19 positive on asymptomatic screening, an investigator reported at the AACR Virtual Meeting: COVID-19 and Cancer (Abstract S09-04).

While several models have been proposed to screen for COVID-19 among cancer patients, the optimal strategy remains unknown, said investigator Justin A. Shaya, MD, of the University of California, San Diego.

The most commonly used approach is symptom/exposure-based screening and testing. However, other models have combined this method with polymerase chain reaction (PCR) testing for asymptomatic high-risk patients (such as those undergoing bone marrow transplant, receiving chemotherapy, or with hematologic malignancies) or with PCR testing for all asymptomatic cancer patients.

Dr. Shaya’s institution implemented a novel COVID-19 screening protocol for cancer patients receiving infusional anticancer therapy in May 2020.

The protocol required SARS-CoV-2 PCR testing for asymptomatic patients 24-96 hours prior to infusion. However, testing was only required before the administration of anticancer therapy. Infusion visits for supportive care interventions did not require previsit testing.

The researchers retrospectively analyzed data from patients with active cancer receiving infusional anticancer therapy who had at least one asymptomatic SARS-CoV-2 PCR test between June 1 and Dec. 1, 2020. The primary outcome was the rate of COVID-19 positivity among asymptomatic patients.

Results

Among 2,202 patients identified, 21 (0.95%) were found to be COVID-19 positive on asymptomatic screening. Most of these patients (90.5%) had solid tumors, but two (9.5%) had hematologic malignancies.

With respect to treatment, 16 patients (76.2%) received cytotoxic chemotherapy, 2 (9.5%) received targeted therapy, 1 (4.7%) received immunotherapy, and 2 (9.5%) were on a clinical trial.

At a median follow-up of 174 days from a positive PCR test (range, 55-223 days), only two patients (9.5%) developed COVID-related symptoms. Both patients had acute leukemia, and one required hospitalization for COVID-related complications.

In the COVID-19–positive cohort, 20 (95.2%) patients had their anticancer therapy delayed or deferred, with a median delay of 21 days (range, 7-77 days).

In the overall cohort, an additional 26 patients (1.2%) developed symptomatic COVID-19 during the study period.

“These results are particularly interesting because they come from a high-quality center that sees a large number of patients,” said Solange Peters, MD, PhD, of the University of Lausanne (Switzerland), who was not involved in this study.

“As they suggest, it is still a debate on how efficient routine screening is, asking the question whether we’re really detecting COVID-19 infection in our patients. Of course, it depends on the time and environment,” Dr. Peters added.

Dr. Shaya acknowledged that the small sample size was a key limitation of the study. Thus, the results may not be generalizable to other regions.

“One of the most striking things is that asymptomatic patients suffer very few consequences of COVID-19 infection, except for patients with hematologic malignancies,” Dr. Shaya said during a live discussion. “The majority of our patients had solid tumors and failed to develop any signs/symptoms of COVID infection.

“Routine screening provides a lot of security, and our institution is big enough to allow for it, and it seems our teams enjoy the fact of knowing the COVID status for each patient,” he continued.

Dr. Shaya and Dr. Peters disclosed no conflicts of interest. No funding sources were reported in the presentation.

Asymptomatic screening of cancer patients receiving anticancer therapy detected a very low rate of COVID-19 in a retrospective study.

Of more than 2,000 patients, less than 1% were found to be COVID-19 positive on asymptomatic screening, an investigator reported at the AACR Virtual Meeting: COVID-19 and Cancer (Abstract S09-04).

While several models have been proposed to screen for COVID-19 among cancer patients, the optimal strategy remains unknown, said investigator Justin A. Shaya, MD, of the University of California, San Diego.

The most commonly used approach is symptom/exposure-based screening and testing. However, other models have combined this method with polymerase chain reaction (PCR) testing for asymptomatic high-risk patients (such as those undergoing bone marrow transplant, receiving chemotherapy, or with hematologic malignancies) or with PCR testing for all asymptomatic cancer patients.

Dr. Shaya’s institution implemented a novel COVID-19 screening protocol for cancer patients receiving infusional anticancer therapy in May 2020.

The protocol required SARS-CoV-2 PCR testing for asymptomatic patients 24-96 hours prior to infusion. However, testing was only required before the administration of anticancer therapy. Infusion visits for supportive care interventions did not require previsit testing.

The researchers retrospectively analyzed data from patients with active cancer receiving infusional anticancer therapy who had at least one asymptomatic SARS-CoV-2 PCR test between June 1 and Dec. 1, 2020. The primary outcome was the rate of COVID-19 positivity among asymptomatic patients.

Results

Among 2,202 patients identified, 21 (0.95%) were found to be COVID-19 positive on asymptomatic screening. Most of these patients (90.5%) had solid tumors, but two (9.5%) had hematologic malignancies.

With respect to treatment, 16 patients (76.2%) received cytotoxic chemotherapy, 2 (9.5%) received targeted therapy, 1 (4.7%) received immunotherapy, and 2 (9.5%) were on a clinical trial.

At a median follow-up of 174 days from a positive PCR test (range, 55-223 days), only two patients (9.5%) developed COVID-related symptoms. Both patients had acute leukemia, and one required hospitalization for COVID-related complications.

In the COVID-19–positive cohort, 20 (95.2%) patients had their anticancer therapy delayed or deferred, with a median delay of 21 days (range, 7-77 days).

In the overall cohort, an additional 26 patients (1.2%) developed symptomatic COVID-19 during the study period.

“These results are particularly interesting because they come from a high-quality center that sees a large number of patients,” said Solange Peters, MD, PhD, of the University of Lausanne (Switzerland), who was not involved in this study.

“As they suggest, it is still a debate on how efficient routine screening is, asking the question whether we’re really detecting COVID-19 infection in our patients. Of course, it depends on the time and environment,” Dr. Peters added.

Dr. Shaya acknowledged that the small sample size was a key limitation of the study. Thus, the results may not be generalizable to other regions.

“One of the most striking things is that asymptomatic patients suffer very few consequences of COVID-19 infection, except for patients with hematologic malignancies,” Dr. Shaya said during a live discussion. “The majority of our patients had solid tumors and failed to develop any signs/symptoms of COVID infection.

“Routine screening provides a lot of security, and our institution is big enough to allow for it, and it seems our teams enjoy the fact of knowing the COVID status for each patient,” he continued.

Dr. Shaya and Dr. Peters disclosed no conflicts of interest. No funding sources were reported in the presentation.

States that implemented mask mandates in 2020 saw a decline in the growth of COVID-19 hospitalizations between March and October 2020, according to a new study published Feb. 5 in the CDC’s Morbidity and Mortality Weekly Report.

Hospitalization growth rates declined by 5.5 percentage points for adults between ages 18-64 about 3 weeks after the mandates were implemented, compared with climbing growth rates in the 4 weeks before mandates.

CDC Director Rochelle Walensky said she was pleased to see the results, but that it’s “too early” to tell whether President Joe Biden’s recent mask orders have had an effect on cases and hospitalizations in 2021.

“We’re going to be watching the mask data very carefully,” she said during a news briefing with the White House COVID-19 Response Team on Feb. 5. “I think it’s probably still a bit too early to tell, but I’m encouraged with the decrease in case rates right now.”

In another study published Feb. 5 in the Morbidity and Mortality Weekly Report, trained observers tracked mask use at six universities with mask mandates between September and November 2020. Overall, observers reported that about 92% of people wore masks correctly indoors, which varied based on the type of mask.

About 97% of people used N95 masks correctly, compared with 92% who used cloth masks, and 79% who used bandanas, scarves, or neck gaiters. Cloth masks were most common, and bandanas and scarves were least common.

The Biden administration is considering whether to send masks directly to American households to encourage people to wear them, according to NBC News. The White House COVID-19 Response Team is debating the logistics of mailing out masks, including how many to send and what the mask material would be, the news outlet reported.

Wisconsin Gov. Tony Evers reissued a new statewide mask mandate on Feb. 4, just an hour after the Republican-controlled legislature voted to repeal his previous mandate, according to The Associated Press. Gov. Evers said his priority is to keep people safe and that wearing a mask is the easiest way to do so.

“If the legislature keeps playing politics and we don’t keep wearing masks, we’re going to see more preventable deaths,” he said. “It’s going to take even longer to get our state and our economy back on track.”

A version of this article first appeared on WebMD.com.

States that implemented mask mandates in 2020 saw a decline in the growth of COVID-19 hospitalizations between March and October 2020, according to a new study published Feb. 5 in the CDC’s Morbidity and Mortality Weekly Report.

Hospitalization growth rates declined by 5.5 percentage points for adults between ages 18-64 about 3 weeks after the mandates were implemented, compared with climbing growth rates in the 4 weeks before mandates.

CDC Director Rochelle Walensky said she was pleased to see the results, but that it’s “too early” to tell whether President Joe Biden’s recent mask orders have had an effect on cases and hospitalizations in 2021.

“We’re going to be watching the mask data very carefully,” she said during a news briefing with the White House COVID-19 Response Team on Feb. 5. “I think it’s probably still a bit too early to tell, but I’m encouraged with the decrease in case rates right now.”

In another study published Feb. 5 in the Morbidity and Mortality Weekly Report, trained observers tracked mask use at six universities with mask mandates between September and November 2020. Overall, observers reported that about 92% of people wore masks correctly indoors, which varied based on the type of mask.

About 97% of people used N95 masks correctly, compared with 92% who used cloth masks, and 79% who used bandanas, scarves, or neck gaiters. Cloth masks were most common, and bandanas and scarves were least common.

The Biden administration is considering whether to send masks directly to American households to encourage people to wear them, according to NBC News. The White House COVID-19 Response Team is debating the logistics of mailing out masks, including how many to send and what the mask material would be, the news outlet reported.

Wisconsin Gov. Tony Evers reissued a new statewide mask mandate on Feb. 4, just an hour after the Republican-controlled legislature voted to repeal his previous mandate, according to The Associated Press. Gov. Evers said his priority is to keep people safe and that wearing a mask is the easiest way to do so.

“If the legislature keeps playing politics and we don’t keep wearing masks, we’re going to see more preventable deaths,” he said. “It’s going to take even longer to get our state and our economy back on track.”

A version of this article first appeared on WebMD.com.

States that implemented mask mandates in 2020 saw a decline in the growth of COVID-19 hospitalizations between March and October 2020, according to a new study published Feb. 5 in the CDC’s Morbidity and Mortality Weekly Report.

Hospitalization growth rates declined by 5.5 percentage points for adults between ages 18-64 about 3 weeks after the mandates were implemented, compared with climbing growth rates in the 4 weeks before mandates.

CDC Director Rochelle Walensky said she was pleased to see the results, but that it’s “too early” to tell whether President Joe Biden’s recent mask orders have had an effect on cases and hospitalizations in 2021.

“We’re going to be watching the mask data very carefully,” she said during a news briefing with the White House COVID-19 Response Team on Feb. 5. “I think it’s probably still a bit too early to tell, but I’m encouraged with the decrease in case rates right now.”

In another study published Feb. 5 in the Morbidity and Mortality Weekly Report, trained observers tracked mask use at six universities with mask mandates between September and November 2020. Overall, observers reported that about 92% of people wore masks correctly indoors, which varied based on the type of mask.

About 97% of people used N95 masks correctly, compared with 92% who used cloth masks, and 79% who used bandanas, scarves, or neck gaiters. Cloth masks were most common, and bandanas and scarves were least common.

The Biden administration is considering whether to send masks directly to American households to encourage people to wear them, according to NBC News. The White House COVID-19 Response Team is debating the logistics of mailing out masks, including how many to send and what the mask material would be, the news outlet reported.

Wisconsin Gov. Tony Evers reissued a new statewide mask mandate on Feb. 4, just an hour after the Republican-controlled legislature voted to repeal his previous mandate, according to The Associated Press. Gov. Evers said his priority is to keep people safe and that wearing a mask is the easiest way to do so.

“If the legislature keeps playing politics and we don’t keep wearing masks, we’re going to see more preventable deaths,” he said. “It’s going to take even longer to get our state and our economy back on track.”

A version of this article first appeared on WebMD.com.

Branching of the great vessels from the aorta normally progresses with the brachiocephalic trunk as the first takeoff followed by the left common carotid and left subclavian artery in approximately 85% of cases.¹ Variants of great vessel branching patterns include the so-called bovine arch, arteria lusoria or aberrant right subclavian artery (ARSA), aberrant origin of the vertebral arteries, and truncus bicaroticus, or common origin of the carotid arteries (COCA). These aberrancies are quite rare, some with an incidence of < 1%.^1,2

These vascular anomalies become clinically relevant when they pose difficulty for operators in surgical and interventional specialties, necessitating unique approaches, catheters, and techniques to overcome. We present a case of concomitant aortic arch abnormalities during a diagnostic workup for transcatheter aortic valve replacement (TAVR) in a patient with previous coronary artery bypass grafting (CABG).

Case Presentation

A 66-year-old woman with coronary artery disease (CAD) status post-CABG and stage D1 aortic stenosis (AS) presented with exertional dyspnea. She was referred for coronary angiography as part of a workup for TAVR. Echocardiography confirmed severe AS with a peak velocity of 4.1 m/s, mean pressure gradient of 50 mm Hg, and an aortic valve area of 0.7 cm². The patient was scheduled for cardiac catheterization with anticipated left radial artery approach for intubation and opacification of the left internal mammary artery (LIMA). However, this approach was abandoned during the procedure due to discovery of aberrant left radial artery anatomy, and the procedure was completed via femoral access.

Subsequent coronary angiography revealed 3-vessel CAD, patent saphenous vein grafts (SVG) to the right coronary artery (RCA) and a diagonal branch vessel with an occluded SVG to the left circumflex. Difficulty was encountered when engaging the left subclavian artery using a JR 4.0 diagnostic catheter for LIMA angiography. Nonselective angiography of the aortic arch was performed and demonstrated an uncommon anatomical variant (Figure 1, left). The right common carotid artery (CCA) [A] and the left CCA [B] arose from a single trunk, consistent with truncus bicaroticus or COCA [C]. The right subclavian artery [D] originated distal to the left subclavian artery otherwise known as arteria lusoria or ARSA forming an incomplete vascular ring [E]. Selective engagement of the left subclavian artery remained problematic even with the use of specialty arch catheters (Headhunter and LIMA catheters). The procedure concluded without confirming patency of the LIMA graft. A total of 145 mL of Omnipaque (iohexol injection) contrast was used for the procedure, and no adverse events occurred.

Same-day access of the ipsilateral ulnar artery was not pursued because of the risk of hand ischemia. The patient underwent repeat catheterization utilizing left ulnar artery access after adequate recovery time from the initial left radial approach. Selective LIMA angiography was achieved and demonstrated a patent LIMA to LAD graft. A computed tomography (CT) aorta for purposes of TAVR planning was able to reconstruct the aortic arch vasculature (Figure 1, right) confirming the presence of both ARSA and COCA. The patient went on to undergo successful TAVR with subsequent improvement of clinical symptoms.

Discussion

Arteria lusoria is defined as an anomalous right subclavian artery arising distal to the origin of the left subclavian artery on the aortic arch. It has an estimated incidence of 0.5 to 2% and occurs as a consequence of abnormal embryologic involution of the right fourth aortic arch and right proximal dorsal aorta. This causes the origin of the right subclavian artery to shift onto the descending aorta and cross the mediastinum from left to right, passing behind the esophagus and the trachea.^1,3-5

ARSA is often associated with other anatomic abnormalities, including COCA, right-sided aortic arch, interrupted aortic arch, aortic coarctation, tetralogy of Fallot, truncus arteriosus, transposition of the great arteries, atrial septal defects, and ventricular septal defects.Underlying genetic disorders, such as Edwards, Down, DiGeorge syndromes, aneurysms, and arterioesophageal fistulae can accompany these vascular malformations.⁶

COCA, such as we encountered, is the presence of a single branch from the aorta giving off both right and left common carotid arteries. It has an incidence of < 0.1% in isolation and is discovered most often in cadaveric dissections or incidentally on imaging.¹ Its embryologic origin results from the third pair of cervical aortic arches persisting as a common bicarotid trunk.^1,4,5 The combination of ARSA and COCA is rare. Of the 0.5 to 2% of ARSA cases discovered, only 20% of those cases present with associated COCA for a combined prevalence estimated at < 0.05%.⁷

The majority of patients with either anatomic abnormality are asymptomatic. However, a few classic clinical manifestations have been described. ARSA can rarely present with dysphagia lusoria, a condition resulting from an incomplete vascular ring formed by the abnormal course of the right subclavian compressing the esophagus. Although not seen in our patient, it should be considered in the differential diagnosis for dysphagia.^1,2,7 Ortner syndrome can result from right laryngeal nerve compression and palsy resultant from the aberrant course of the right subclavian artery.⁸ Another clinically relevant feature of ARSA is the presence of a diverticulum of Kommerell or dilatation at the origin of the right subclavian artery. It is a type of retroesophageal diverticulum resulting from persistence of a segment of the right sixth aortic arch.⁹ Finally, the spatial arrangement of ARSA increases risk for injury during head and neck surgical procedures, such as thyroidectomy, tracheotomy, and lymph node dissection of the right paratracheal fossa.⁶ Although the incidence is not well described, COCA has been described in several case reports as causing tracheal compression with dyspnea and in some cases, ischemic stroke.^4,5,10

Diagnosis

The diagnosis of ARSA and COCA is often made incidentally on diagnostic imaging studies such as endovascular imaging, CT angiography, magnetic resonance (MR) angiography, postmortem cadaveric dissections, or, as in our case, during cardiac catheterization.^11,12 A classification system for aortic arch branching patterns exists published by Adachi and Williams.⁶ The classification includes ARSA and differentiates it into 4 subtypes (Figure 2). Our patient exhibited type H-1, indicating ARSA as the distal most branch of the aortic arch with coexistence of COCA.⁶ The primary clinical implication of ARSA and COCA in our case was increased difficulty and complexity when performing coronary angiography. Available literature has well characterized the challenges operators encounter when cannulating aberrant great vessel anatomy, often electing to perform nonselective aortography to define a patient’s anatomy.^7,9,13 A comparison of diagnostic imaging techniques for vascular rings such as ARSA have shown MR, CT, and endovascular angiography to be the most reliable modalities to delineate vascular anatomy.¹⁴

Methods

Due to the presence of CABG in our patient, left radial and ulnar artery approaches were used rather than a right radial artery approach. Engagement of the LIMA is performed most commonly with left radial or femoral artery access using an internal mammary catheter that has a more steeply angled tip (80º-85º) compared with the standard JR catheter. An accessory left radial artery anatomic variant was encountered in our case precluding left radial approach. In addition, abnormal takeoffs of the great vessels thwarted multiple attempts at intubation of the LSA (Figure 1, right). Some data suggest CT imaging can be of assistance in establishing patency of bypass grafts in CABG patients.¹⁵ This can be considered an option if branch-vessel anatomy remains unclear. Our patient exhibited several risk factors for stroke, including female gender, hypertension, and prior CABG. These and other risk factors may influence clinical decisions such as continued catheter manipulation, choice of catheter type, and further contrast studies.¹⁶

Nonselective angiography in these cases often can require excessive iodinated contrast, exposing the patient to increased risk of contrast-induced nephropathy (CIN).^7,17 Although the amount of contrast used in our case was average for diagnostic catheterization,the patient went on to undergo a second catheterization and CT angiography to establish LIMA graft patency.¹⁷ CT imaging reconstruction elucidated her aberrant branch-vessel anatomy. Patients are at increased risk of CIN with contrast loads < 200 mL per study, and this effect is compounded when the patient is elderly, has diabetes mellitus, and/or antecedent renal disease.¹⁸ Attention to the patient’s preoperative glomerular filtration rate, avoidance of nephrotoxic agents, and intraoperative left ventricular end-diastolic pressure during cardiac catheterization with postcontrast administration of IV isotonic fluids have been shown to prevent CIN.^19,20 In the POSEIDON trial, fluid administration on a sliding scale based on the left ventricular end-diastolic pressure resulted in lower absolute risk of CIN postcatheterization vs standard postprocedure hydration in cardiac catheterization.²¹ Further, the now widespread use of low and iso-osmolar contrast agents further reduces the risk of CIN.²²

For cardiac catheter laboratory operators, it is important to note that ARSA is more frequently encountered due to increased use of the transradial approach to coronary angiography.¹¹ It should be suspected when accessing the ascending aorta proves exceptionally challenging and the catheter has a predilection for entering the descending aorta.¹¹ While more technically demanding, 2 cases described by Allen and colleagues exhibited safe and successful entry into the ascending aorta with catheter rotation and hydrophilic support wires indicating the right radial approach is feasible despite presence of ARSA.¹² Several patient-initiated maneuvers can be utilized to aid in accessing the ascending aorta. For example, deep inspiration to reduce the angulation between the aortic arch and ARSA. The use of curved catheters, such as Amplatz left, internal mammary catheter, or Simmons catheter may be considered to cannulate the ascending aorta if ARSA is encountered. Complications associated with a transradial approach include dissection and intramural hematoma. Minor bleeds and vasospasm also can occur secondary to increased procedural duration.^6,8

Treatment

ARSA and COCA are considered normal anatomic variants and no treatment is indicated if the patient is asymptomatic. If symptoms are present, they often arise from aneurysmal or occlusive complications of the vascular anatomy. In patients with isolated ARSA and mild dysphasia or reflux symptoms, the use of prokinetics and antireflux medications may provide relief. It is important to note the coexistence of ARSA and COCA is more likely to produce esophageal compression compared to ARSA alone due to formation of a more complete vascular ring. Surgical management has been described in severe cases of ARSA involving risk of aneurysm rupture, right upper limb ischemia, or compression of the esophagus or trachea.

Several surgical approaches have been described, including simple ligation and division of ARSA and reimplantation of the RSA into the right CCA or ascending aorta.⁵ A recent review of 180 cases of ARSA diagnosed on CT angiography with concomitant common carotid trunk in half of studied individuals focused on a hybrid open and intravascular procedure. This procedure involved a double transposition or bypass (LSA to left common carotid artery and ARSA to the right CCA) followed by implantation of a thoracic stent graft. Few cases are eligible for these procedures or require them for definitive treatment.²³

Conclusions

Recognition of aortic arch anatomical variants such as our case of ARSA with concomitant COCA may influence clinician decisions in various specialties, such as interventional cardiology, interventional neurology, cardiothoracic surgery, and gastroenterology. While most patients with these conditions are asymptomatic, some may present with dysphagia, dyspnea, and/or stroke symptoms. In our practice, discovery of such anomalies periprocedurally may affect cardiac catheterization access site, catheter selection, and additional imaging. The presence of arteria lusoria can be of critical importance when encountering a patient with myocardial infarction as switching from transradial to transfemoral approach may be required to gain access to the ascending aorta. Overall, transradial coronary angiography and percutaneous coronary intervention is not contraindicated in the setting of ARSA/COCA and can be safely performed by an experienced operator.

It is important for surgical specialists to be aware of the coexistence of anomalies where the discovery of one aberrancy can signal coexistent variant anatomy. If aortic arch anatomy is unclear, it is useful to perform nonselective angiography and/or further imaging with CT angiography. Knowledge of abnormal aortic arch anatomy can decrease fluoroscopy time and contrast load administered, thereby reducing potential periprocedural adverse events.

Branching of the great vessels from the aorta normally progresses with the brachiocephalic trunk as the first takeoff followed by the left common carotid and left subclavian artery in approximately 85% of cases.¹ Variants of great vessel branching patterns include the so-called bovine arch, arteria lusoria or aberrant right subclavian artery (ARSA), aberrant origin of the vertebral arteries, and truncus bicaroticus, or common origin of the carotid arteries (COCA). These aberrancies are quite rare, some with an incidence of < 1%.^1,2

These vascular anomalies become clinically relevant when they pose difficulty for operators in surgical and interventional specialties, necessitating unique approaches, catheters, and techniques to overcome. We present a case of concomitant aortic arch abnormalities during a diagnostic workup for transcatheter aortic valve replacement (TAVR) in a patient with previous coronary artery bypass grafting (CABG).

Case Presentation

A 66-year-old woman with coronary artery disease (CAD) status post-CABG and stage D1 aortic stenosis (AS) presented with exertional dyspnea. She was referred for coronary angiography as part of a workup for TAVR. Echocardiography confirmed severe AS with a peak velocity of 4.1 m/s, mean pressure gradient of 50 mm Hg, and an aortic valve area of 0.7 cm². The patient was scheduled for cardiac catheterization with anticipated left radial artery approach for intubation and opacification of the left internal mammary artery (LIMA). However, this approach was abandoned during the procedure due to discovery of aberrant left radial artery anatomy, and the procedure was completed via femoral access.

Subsequent coronary angiography revealed 3-vessel CAD, patent saphenous vein grafts (SVG) to the right coronary artery (RCA) and a diagonal branch vessel with an occluded SVG to the left circumflex. Difficulty was encountered when engaging the left subclavian artery using a JR 4.0 diagnostic catheter for LIMA angiography. Nonselective angiography of the aortic arch was performed and demonstrated an uncommon anatomical variant (Figure 1, left). The right common carotid artery (CCA) [A] and the left CCA [B] arose from a single trunk, consistent with truncus bicaroticus or COCA [C]. The right subclavian artery [D] originated distal to the left subclavian artery otherwise known as arteria lusoria or ARSA forming an incomplete vascular ring [E]. Selective engagement of the left subclavian artery remained problematic even with the use of specialty arch catheters (Headhunter and LIMA catheters). The procedure concluded without confirming patency of the LIMA graft. A total of 145 mL of Omnipaque (iohexol injection) contrast was used for the procedure, and no adverse events occurred.

Same-day access of the ipsilateral ulnar artery was not pursued because of the risk of hand ischemia. The patient underwent repeat catheterization utilizing left ulnar artery access after adequate recovery time from the initial left radial approach. Selective LIMA angiography was achieved and demonstrated a patent LIMA to LAD graft. A computed tomography (CT) aorta for purposes of TAVR planning was able to reconstruct the aortic arch vasculature (Figure 1, right) confirming the presence of both ARSA and COCA. The patient went on to undergo successful TAVR with subsequent improvement of clinical symptoms.

Discussion

Arteria lusoria is defined as an anomalous right subclavian artery arising distal to the origin of the left subclavian artery on the aortic arch. It has an estimated incidence of 0.5 to 2% and occurs as a consequence of abnormal embryologic involution of the right fourth aortic arch and right proximal dorsal aorta. This causes the origin of the right subclavian artery to shift onto the descending aorta and cross the mediastinum from left to right, passing behind the esophagus and the trachea.^1,3-5

ARSA is often associated with other anatomic abnormalities, including COCA, right-sided aortic arch, interrupted aortic arch, aortic coarctation, tetralogy of Fallot, truncus arteriosus, transposition of the great arteries, atrial septal defects, and ventricular septal defects.Underlying genetic disorders, such as Edwards, Down, DiGeorge syndromes, aneurysms, and arterioesophageal fistulae can accompany these vascular malformations.⁶

COCA, such as we encountered, is the presence of a single branch from the aorta giving off both right and left common carotid arteries. It has an incidence of < 0.1% in isolation and is discovered most often in cadaveric dissections or incidentally on imaging.¹ Its embryologic origin results from the third pair of cervical aortic arches persisting as a common bicarotid trunk.^1,4,5 The combination of ARSA and COCA is rare. Of the 0.5 to 2% of ARSA cases discovered, only 20% of those cases present with associated COCA for a combined prevalence estimated at < 0.05%.⁷

The majority of patients with either anatomic abnormality are asymptomatic. However, a few classic clinical manifestations have been described. ARSA can rarely present with dysphagia lusoria, a condition resulting from an incomplete vascular ring formed by the abnormal course of the right subclavian compressing the esophagus. Although not seen in our patient, it should be considered in the differential diagnosis for dysphagia.^1,2,7 Ortner syndrome can result from right laryngeal nerve compression and palsy resultant from the aberrant course of the right subclavian artery.⁸ Another clinically relevant feature of ARSA is the presence of a diverticulum of Kommerell or dilatation at the origin of the right subclavian artery. It is a type of retroesophageal diverticulum resulting from persistence of a segment of the right sixth aortic arch.⁹ Finally, the spatial arrangement of ARSA increases risk for injury during head and neck surgical procedures, such as thyroidectomy, tracheotomy, and lymph node dissection of the right paratracheal fossa.⁶ Although the incidence is not well described, COCA has been described in several case reports as causing tracheal compression with dyspnea and in some cases, ischemic stroke.^4,5,10

Diagnosis

The diagnosis of ARSA and COCA is often made incidentally on diagnostic imaging studies such as endovascular imaging, CT angiography, magnetic resonance (MR) angiography, postmortem cadaveric dissections, or, as in our case, during cardiac catheterization.^11,12 A classification system for aortic arch branching patterns exists published by Adachi and Williams.⁶ The classification includes ARSA and differentiates it into 4 subtypes (Figure 2). Our patient exhibited type H-1, indicating ARSA as the distal most branch of the aortic arch with coexistence of COCA.⁶ The primary clinical implication of ARSA and COCA in our case was increased difficulty and complexity when performing coronary angiography. Available literature has well characterized the challenges operators encounter when cannulating aberrant great vessel anatomy, often electing to perform nonselective aortography to define a patient’s anatomy.^7,9,13 A comparison of diagnostic imaging techniques for vascular rings such as ARSA have shown MR, CT, and endovascular angiography to be the most reliable modalities to delineate vascular anatomy.¹⁴

Methods

Due to the presence of CABG in our patient, left radial and ulnar artery approaches were used rather than a right radial artery approach. Engagement of the LIMA is performed most commonly with left radial or femoral artery access using an internal mammary catheter that has a more steeply angled tip (80º-85º) compared with the standard JR catheter. An accessory left radial artery anatomic variant was encountered in our case precluding left radial approach. In addition, abnormal takeoffs of the great vessels thwarted multiple attempts at intubation of the LSA (Figure 1, right). Some data suggest CT imaging can be of assistance in establishing patency of bypass grafts in CABG patients.¹⁵ This can be considered an option if branch-vessel anatomy remains unclear. Our patient exhibited several risk factors for stroke, including female gender, hypertension, and prior CABG. These and other risk factors may influence clinical decisions such as continued catheter manipulation, choice of catheter type, and further contrast studies.¹⁶

Nonselective angiography in these cases often can require excessive iodinated contrast, exposing the patient to increased risk of contrast-induced nephropathy (CIN).^7,17 Although the amount of contrast used in our case was average for diagnostic catheterization,the patient went on to undergo a second catheterization and CT angiography to establish LIMA graft patency.¹⁷ CT imaging reconstruction elucidated her aberrant branch-vessel anatomy. Patients are at increased risk of CIN with contrast loads < 200 mL per study, and this effect is compounded when the patient is elderly, has diabetes mellitus, and/or antecedent renal disease.¹⁸ Attention to the patient’s preoperative glomerular filtration rate, avoidance of nephrotoxic agents, and intraoperative left ventricular end-diastolic pressure during cardiac catheterization with postcontrast administration of IV isotonic fluids have been shown to prevent CIN.^19,20 In the POSEIDON trial, fluid administration on a sliding scale based on the left ventricular end-diastolic pressure resulted in lower absolute risk of CIN postcatheterization vs standard postprocedure hydration in cardiac catheterization.²¹ Further, the now widespread use of low and iso-osmolar contrast agents further reduces the risk of CIN.²²

For cardiac catheter laboratory operators, it is important to note that ARSA is more frequently encountered due to increased use of the transradial approach to coronary angiography.¹¹ It should be suspected when accessing the ascending aorta proves exceptionally challenging and the catheter has a predilection for entering the descending aorta.¹¹ While more technically demanding, 2 cases described by Allen and colleagues exhibited safe and successful entry into the ascending aorta with catheter rotation and hydrophilic support wires indicating the right radial approach is feasible despite presence of ARSA.¹² Several patient-initiated maneuvers can be utilized to aid in accessing the ascending aorta. For example, deep inspiration to reduce the angulation between the aortic arch and ARSA. The use of curved catheters, such as Amplatz left, internal mammary catheter, or Simmons catheter may be considered to cannulate the ascending aorta if ARSA is encountered. Complications associated with a transradial approach include dissection and intramural hematoma. Minor bleeds and vasospasm also can occur secondary to increased procedural duration.^6,8

Treatment

ARSA and COCA are considered normal anatomic variants and no treatment is indicated if the patient is asymptomatic. If symptoms are present, they often arise from aneurysmal or occlusive complications of the vascular anatomy. In patients with isolated ARSA and mild dysphasia or reflux symptoms, the use of prokinetics and antireflux medications may provide relief. It is important to note the coexistence of ARSA and COCA is more likely to produce esophageal compression compared to ARSA alone due to formation of a more complete vascular ring. Surgical management has been described in severe cases of ARSA involving risk of aneurysm rupture, right upper limb ischemia, or compression of the esophagus or trachea.

Several surgical approaches have been described, including simple ligation and division of ARSA and reimplantation of the RSA into the right CCA or ascending aorta.⁵ A recent review of 180 cases of ARSA diagnosed on CT angiography with concomitant common carotid trunk in half of studied individuals focused on a hybrid open and intravascular procedure. This procedure involved a double transposition or bypass (LSA to left common carotid artery and ARSA to the right CCA) followed by implantation of a thoracic stent graft. Few cases are eligible for these procedures or require them for definitive treatment.²³

Conclusions

Recognition of aortic arch anatomical variants such as our case of ARSA with concomitant COCA may influence clinician decisions in various specialties, such as interventional cardiology, interventional neurology, cardiothoracic surgery, and gastroenterology. While most patients with these conditions are asymptomatic, some may present with dysphagia, dyspnea, and/or stroke symptoms. In our practice, discovery of such anomalies periprocedurally may affect cardiac catheterization access site, catheter selection, and additional imaging. The presence of arteria lusoria can be of critical importance when encountering a patient with myocardial infarction as switching from transradial to transfemoral approach may be required to gain access to the ascending aorta. Overall, transradial coronary angiography and percutaneous coronary intervention is not contraindicated in the setting of ARSA/COCA and can be safely performed by an experienced operator.

It is important for surgical specialists to be aware of the coexistence of anomalies where the discovery of one aberrancy can signal coexistent variant anatomy. If aortic arch anatomy is unclear, it is useful to perform nonselective angiography and/or further imaging with CT angiography. Knowledge of abnormal aortic arch anatomy can decrease fluoroscopy time and contrast load administered, thereby reducing potential periprocedural adverse events.

Branching of the great vessels from the aorta normally progresses with the brachiocephalic trunk as the first takeoff followed by the left common carotid and left subclavian artery in approximately 85% of cases.¹ Variants of great vessel branching patterns include the so-called bovine arch, arteria lusoria or aberrant right subclavian artery (ARSA), aberrant origin of the vertebral arteries, and truncus bicaroticus, or common origin of the carotid arteries (COCA). These aberrancies are quite rare, some with an incidence of < 1%.^1,2

These vascular anomalies become clinically relevant when they pose difficulty for operators in surgical and interventional specialties, necessitating unique approaches, catheters, and techniques to overcome. We present a case of concomitant aortic arch abnormalities during a diagnostic workup for transcatheter aortic valve replacement (TAVR) in a patient with previous coronary artery bypass grafting (CABG).

Case Presentation

A 66-year-old woman with coronary artery disease (CAD) status post-CABG and stage D1 aortic stenosis (AS) presented with exertional dyspnea. She was referred for coronary angiography as part of a workup for TAVR. Echocardiography confirmed severe AS with a peak velocity of 4.1 m/s, mean pressure gradient of 50 mm Hg, and an aortic valve area of 0.7 cm². The patient was scheduled for cardiac catheterization with anticipated left radial artery approach for intubation and opacification of the left internal mammary artery (LIMA). However, this approach was abandoned during the procedure due to discovery of aberrant left radial artery anatomy, and the procedure was completed via femoral access.

Subsequent coronary angiography revealed 3-vessel CAD, patent saphenous vein grafts (SVG) to the right coronary artery (RCA) and a diagonal branch vessel with an occluded SVG to the left circumflex. Difficulty was encountered when engaging the left subclavian artery using a JR 4.0 diagnostic catheter for LIMA angiography. Nonselective angiography of the aortic arch was performed and demonstrated an uncommon anatomical variant (Figure 1, left). The right common carotid artery (CCA) [A] and the left CCA [B] arose from a single trunk, consistent with truncus bicaroticus or COCA [C]. The right subclavian artery [D] originated distal to the left subclavian artery otherwise known as arteria lusoria or ARSA forming an incomplete vascular ring [E]. Selective engagement of the left subclavian artery remained problematic even with the use of specialty arch catheters (Headhunter and LIMA catheters). The procedure concluded without confirming patency of the LIMA graft. A total of 145 mL of Omnipaque (iohexol injection) contrast was used for the procedure, and no adverse events occurred.

Same-day access of the ipsilateral ulnar artery was not pursued because of the risk of hand ischemia. The patient underwent repeat catheterization utilizing left ulnar artery access after adequate recovery time from the initial left radial approach. Selective LIMA angiography was achieved and demonstrated a patent LIMA to LAD graft. A computed tomography (CT) aorta for purposes of TAVR planning was able to reconstruct the aortic arch vasculature (Figure 1, right) confirming the presence of both ARSA and COCA. The patient went on to undergo successful TAVR with subsequent improvement of clinical symptoms.

Discussion

Arteria lusoria is defined as an anomalous right subclavian artery arising distal to the origin of the left subclavian artery on the aortic arch. It has an estimated incidence of 0.5 to 2% and occurs as a consequence of abnormal embryologic involution of the right fourth aortic arch and right proximal dorsal aorta. This causes the origin of the right subclavian artery to shift onto the descending aorta and cross the mediastinum from left to right, passing behind the esophagus and the trachea.^1,3-5

ARSA is often associated with other anatomic abnormalities, including COCA, right-sided aortic arch, interrupted aortic arch, aortic coarctation, tetralogy of Fallot, truncus arteriosus, transposition of the great arteries, atrial septal defects, and ventricular septal defects.Underlying genetic disorders, such as Edwards, Down, DiGeorge syndromes, aneurysms, and arterioesophageal fistulae can accompany these vascular malformations.⁶

COCA, such as we encountered, is the presence of a single branch from the aorta giving off both right and left common carotid arteries. It has an incidence of < 0.1% in isolation and is discovered most often in cadaveric dissections or incidentally on imaging.¹ Its embryologic origin results from the third pair of cervical aortic arches persisting as a common bicarotid trunk.^1,4,5 The combination of ARSA and COCA is rare. Of the 0.5 to 2% of ARSA cases discovered, only 20% of those cases present with associated COCA for a combined prevalence estimated at < 0.05%.⁷

The majority of patients with either anatomic abnormality are asymptomatic. However, a few classic clinical manifestations have been described. ARSA can rarely present with dysphagia lusoria, a condition resulting from an incomplete vascular ring formed by the abnormal course of the right subclavian compressing the esophagus. Although not seen in our patient, it should be considered in the differential diagnosis for dysphagia.^1,2,7 Ortner syndrome can result from right laryngeal nerve compression and palsy resultant from the aberrant course of the right subclavian artery.⁸ Another clinically relevant feature of ARSA is the presence of a diverticulum of Kommerell or dilatation at the origin of the right subclavian artery. It is a type of retroesophageal diverticulum resulting from persistence of a segment of the right sixth aortic arch.⁹ Finally, the spatial arrangement of ARSA increases risk for injury during head and neck surgical procedures, such as thyroidectomy, tracheotomy, and lymph node dissection of the right paratracheal fossa.⁶ Although the incidence is not well described, COCA has been described in several case reports as causing tracheal compression with dyspnea and in some cases, ischemic stroke.^4,5,10

Diagnosis

The diagnosis of ARSA and COCA is often made incidentally on diagnostic imaging studies such as endovascular imaging, CT angiography, magnetic resonance (MR) angiography, postmortem cadaveric dissections, or, as in our case, during cardiac catheterization.^11,12 A classification system for aortic arch branching patterns exists published by Adachi and Williams.⁶ The classification includes ARSA and differentiates it into 4 subtypes (Figure 2). Our patient exhibited type H-1, indicating ARSA as the distal most branch of the aortic arch with coexistence of COCA.⁶ The primary clinical implication of ARSA and COCA in our case was increased difficulty and complexity when performing coronary angiography. Available literature has well characterized the challenges operators encounter when cannulating aberrant great vessel anatomy, often electing to perform nonselective aortography to define a patient’s anatomy.^7,9,13 A comparison of diagnostic imaging techniques for vascular rings such as ARSA have shown MR, CT, and endovascular angiography to be the most reliable modalities to delineate vascular anatomy.¹⁴

Methods

Due to the presence of CABG in our patient, left radial and ulnar artery approaches were used rather than a right radial artery approach. Engagement of the LIMA is performed most commonly with left radial or femoral artery access using an internal mammary catheter that has a more steeply angled tip (80º-85º) compared with the standard JR catheter. An accessory left radial artery anatomic variant was encountered in our case precluding left radial approach. In addition, abnormal takeoffs of the great vessels thwarted multiple attempts at intubation of the LSA (Figure 1, right). Some data suggest CT imaging can be of assistance in establishing patency of bypass grafts in CABG patients.¹⁵ This can be considered an option if branch-vessel anatomy remains unclear. Our patient exhibited several risk factors for stroke, including female gender, hypertension, and prior CABG. These and other risk factors may influence clinical decisions such as continued catheter manipulation, choice of catheter type, and further contrast studies.¹⁶

Nonselective angiography in these cases often can require excessive iodinated contrast, exposing the patient to increased risk of contrast-induced nephropathy (CIN).^7,17 Although the amount of contrast used in our case was average for diagnostic catheterization,the patient went on to undergo a second catheterization and CT angiography to establish LIMA graft patency.¹⁷ CT imaging reconstruction elucidated her aberrant branch-vessel anatomy. Patients are at increased risk of CIN with contrast loads < 200 mL per study, and this effect is compounded when the patient is elderly, has diabetes mellitus, and/or antecedent renal disease.¹⁸ Attention to the patient’s preoperative glomerular filtration rate, avoidance of nephrotoxic agents, and intraoperative left ventricular end-diastolic pressure during cardiac catheterization with postcontrast administration of IV isotonic fluids have been shown to prevent CIN.^19,20 In the POSEIDON trial, fluid administration on a sliding scale based on the left ventricular end-diastolic pressure resulted in lower absolute risk of CIN postcatheterization vs standard postprocedure hydration in cardiac catheterization.²¹ Further, the now widespread use of low and iso-osmolar contrast agents further reduces the risk of CIN.²²

For cardiac catheter laboratory operators, it is important to note that ARSA is more frequently encountered due to increased use of the transradial approach to coronary angiography.¹¹ It should be suspected when accessing the ascending aorta proves exceptionally challenging and the catheter has a predilection for entering the descending aorta.¹¹ While more technically demanding, 2 cases described by Allen and colleagues exhibited safe and successful entry into the ascending aorta with catheter rotation and hydrophilic support wires indicating the right radial approach is feasible despite presence of ARSA.¹² Several patient-initiated maneuvers can be utilized to aid in accessing the ascending aorta. For example, deep inspiration to reduce the angulation between the aortic arch and ARSA. The use of curved catheters, such as Amplatz left, internal mammary catheter, or Simmons catheter may be considered to cannulate the ascending aorta if ARSA is encountered. Complications associated with a transradial approach include dissection and intramural hematoma. Minor bleeds and vasospasm also can occur secondary to increased procedural duration.^6,8

Treatment

ARSA and COCA are considered normal anatomic variants and no treatment is indicated if the patient is asymptomatic. If symptoms are present, they often arise from aneurysmal or occlusive complications of the vascular anatomy. In patients with isolated ARSA and mild dysphasia or reflux symptoms, the use of prokinetics and antireflux medications may provide relief. It is important to note the coexistence of ARSA and COCA is more likely to produce esophageal compression compared to ARSA alone due to formation of a more complete vascular ring. Surgical management has been described in severe cases of ARSA involving risk of aneurysm rupture, right upper limb ischemia, or compression of the esophagus or trachea.

Several surgical approaches have been described, including simple ligation and division of ARSA and reimplantation of the RSA into the right CCA or ascending aorta.⁵ A recent review of 180 cases of ARSA diagnosed on CT angiography with concomitant common carotid trunk in half of studied individuals focused on a hybrid open and intravascular procedure. This procedure involved a double transposition or bypass (LSA to left common carotid artery and ARSA to the right CCA) followed by implantation of a thoracic stent graft. Few cases are eligible for these procedures or require them for definitive treatment.²³

Conclusions

Recognition of aortic arch anatomical variants such as our case of ARSA with concomitant COCA may influence clinician decisions in various specialties, such as interventional cardiology, interventional neurology, cardiothoracic surgery, and gastroenterology. While most patients with these conditions are asymptomatic, some may present with dysphagia, dyspnea, and/or stroke symptoms. In our practice, discovery of such anomalies periprocedurally may affect cardiac catheterization access site, catheter selection, and additional imaging. The presence of arteria lusoria can be of critical importance when encountering a patient with myocardial infarction as switching from transradial to transfemoral approach may be required to gain access to the ascending aorta. Overall, transradial coronary angiography and percutaneous coronary intervention is not contraindicated in the setting of ARSA/COCA and can be safely performed by an experienced operator.

It is important for surgical specialists to be aware of the coexistence of anomalies where the discovery of one aberrancy can signal coexistent variant anatomy. If aortic arch anatomy is unclear, it is useful to perform nonselective angiography and/or further imaging with CT angiography. Knowledge of abnormal aortic arch anatomy can decrease fluoroscopy time and contrast load administered, thereby reducing potential periprocedural adverse events.

Suicide is a global phenomenon and a worldwide public health concern.¹ The World Health Organization estimates that > 800,000 people die by suicide every year. In the US, suicide is the 10th leading cause of death, and on average, 129 Americans die by suicide each day.² In 2018, the suicide rate for all veterans was 1.5 times higher than the rate for nonveterans, after adjusting for population differences in age and sex. Among female veterans, the rate of suicide was 2.1 times higher than the rate for female nonveterans.³

In light of this disparity, suicide prevention is one of the highest priorities for the US Department of Veterans Affairs (VA). In 2018, the VA developed and published the National Strategy for Preventing Veteran Suicide.⁴ One major goal of this strategy is to reduce access to lethal means (ie, firearms, medications, chemicals, or poisons) among veterans at high risk for suicide. Reducing access to lethal means has been found to decrease suicide rates.^4,5

Step 1: Determine Suicide Risk

Although it is impossible to predict with certainty an individual’s risk of suicide, several patient characteristics and life circumstances have been identified as risk factors. The strongest predictor of suicide is the presence of psychiatric disease.⁸ More than 90% of those who have had a death by suicide have a psychiatric diagnosis at the time of death, and suicide rates in those with mental illness are at least 10 times as high as in the general population.^9,10 Depression is the leading cause of death by suicide worldwide, followed by substance-related disorders (22.4%), personality disorders (11.6%), schizophrenia (10.6%), and anxiety/somatoform disorders (6.1%).^8,11-13

Clinicians also can use various risk assessment tools to identify patients at high risk for suicide. The Veterans Health Administration (VHA) Stratification Tool for Opioid Risk Mitigation (STORM) calculates patients’ risk based on data extracted from the electronic health record and is less time intensive, more easily refined, and may be more powerful than standard risk assessment tools because it can be deployed on a large scale.^14,15 The VHA also developed the Suicide Prevention Population Risk Identification and Tracking for Exigencies (SPPRITE) tool to assist clinicians in tracking patients with current (or recent) high levels of suicide risk. This tool unifies specific patient information gathered from the patient’s electronic health record and from other predictive model dashboards (such as STORM).

Step 2: Identify Substances Strongly Associated With Fatalities

According to the American Association of Poison Control Centers (AAPCC), the pharmaceutical classes associated with the largest number of fatalities are analgesics, followed by stimulants and street drugs, cardiovascular agents, antidepressants, antipsychotics, and sedatives/hypnotics (Table 1).¹⁶ Stimulants and street drugs accounted for 694 fatalities of 39,238 single-substance exposures (mortality rate: 1.8%).¹⁶ Drugs of abuse, including cocaine, hallucinogenic amphetamines, heroin, and kratom, have shown an increased trend in use.¹⁶

In 2018 there were 834 fatalities from 174,269 single-substance exposure to analgesics, which include opioids and acetaminophen, for a mortality rate of 0.5%.¹⁶ The opioid epidemic is one of the main drivers of the increase in drug overdose deaths in the US.^16,17 The opioid with the highest drug overdose fatality rate is illicitly manufactured fentanyl, which often is combined with other substances, such as heroin, to increase its potency at a low cost.¹⁸ These combinations also increase the risk of overdose fatality.

Acetaminophen is unique among the top substances associated with fatalities because it is obtained easily without a prescription. An acetaminophen overdose can cause hepatic injury, which may progress to fulminant hepatic failure and death.¹⁹ The recommended maximum dose of acetaminophen is 4 g/d in an adult and 50 to 75 mg/kg/d in children. A single acute ingestion of > 7.5 g in an adult or 150 mg/kg in children has been considered potentially toxic.^19,20 The use of combination analgesics that contain both an opioid and acetaminophen can pose an even greater risk due to the potential for respiratory depression and hepatotoxicity.

Cardiovascular drugs accounted for 232 fatalities from 46,499 single-substance exposures (mortality rate: 0.5%).¹⁶ According to the AAPCC, calcium channel blockers (CCB) and β-blockers accounted for 63% of overdose deaths by cardiovascular drugs because they can cause severe hypotension, bradycardia, and hemodynamic collapse.^16,21,22

In the past, the nondihydropyridine CCBs verapamil and diltiazem were associated with increased overdose fatalities. However, the most recent data show that dihydropyridine CCBs such as amlodipine also have significant risk for lethality.¹⁶ Metoprolol was associated with more overdose deaths in the past year among β-blockers. However, caution also should be used with agents such as propranolol and labetalol, which can antagonize sodium channels in overdose and may be associated with a higher risk of mortality than other β-blockers.²²

Step 3: Consider Potential Drug-Drug Interactions

Suicide attempts involving multiple substances carry increased risk. Only 12.1% of all fatal overdoses, according to AAPCC, involved single-substance exposure, whereas 56.3% were attributed to multiple substance exposures.¹⁶ It is important for clinicians to be aware of and avoid possibly fatal drug-drug interactions, such as the combination of opioids and sedative-hypnotics, like BZDs, which can lead to fatal respiratory depression. Clinicians also should be aware of a patient’s history of illicit opioid and alcohol use before prescribing opioids and BZDs. Clinicians can use various online databases to detect potential drug-drug interactions.

Step 4: Address Risks

If a patient is deemed to be at high risk for suicide, but it is not imminent and the patient will be managed as an outpatient, then it may be preferential to prescribe medications that are less lethal, such as SSRIs, instead of TCAs or MAOIs. If a potentially lethal medication is indicated, such as lithium or clozapine, both of which have been found to reduce suicidal behavior, then dispensing a limited quantity of pills and having more frequent follow-up visits are some ways to lessen risk.^24,25 A clinical pearl published in Current Psychiatry provided an equation to determine the lethality of a 30-day supply of medications.²⁶ This equation uses lethal dose 50 (LD50), which is the dose of a medication that results in the death of 50% of the animals used in a controlled experiment, and the maximum daily dose of the medication (D) to find the human equivalent dose (HED) relative lethality. The HED relative lethality calculation may help prescribers determine which medications should have a limited quantity dispensed to patients at risk of medication-related suicide. Any value for the HED relative lethality that is > 100% is considered a lethal dose for humans. Therefore, it would be appropriate to avoid or limit the quantity of medications with a HED relative lethality > 100%. Table 4 lists the psychotropic agents with the highest relative lethality for a 30-day supply. The psychotropic agents with the lowest HED relative lethality are SSRIs: desvenlafaxine, mirtazapine, topiramate, and aripiprazole.²⁶

Limiting drugs with a narrow therapeutic index should be considered when aiming to reduce the risk of medication-related suicide. These drugs present a high risk in the event of an overdose. Clinicians can monitor the levels of lithium, clozapine, or TCAs to ensure that a patient is taking the medication as prescribed rather than stockpiling it at home. If the patient is in a monitored setting, such as a partial hospital program or intensive outpatient program, then the medication can be given while under direct observation.

Clinicians should obtain an accurate and detailed medication and illicit drug use history from patients. It also is important to review the prescription drug monitoring program to limit access to potentially lethal combinations of medications.²⁷ Clinicians can additionally employ risk mitigation strategies (eg, providing naloxone kits) for patients who are prescribed or abuse opioids.

Finally, all patients with a high risk of suicide should receive lethal means counseling, which involves first determining whether patients have access to lethal means, such as firearms or medications with high lethality, then limiting their access to these lethal means. This includes advising patients and family members to safely dispose medications that are no longer in use and in some cases recommending that a family member keep medications locked and dispense them on a daily basis.

Conclusions

Suicide is a major public health concern that affects tens of thousands of Americans annually. Furthermore, veterans are more likely to die by suicide than those in the general population. Firearms continue to be the most lethal means for suicide. However, intentional poisoning with medications or substances also is a common method for suicide, especially in female veterans. Having knowledge of medications with high lethality and limiting access to these agents can be a successful strategy for reducing suicide deaths.

Suicide is a global phenomenon and a worldwide public health concern.¹ The World Health Organization estimates that > 800,000 people die by suicide every year. In the US, suicide is the 10th leading cause of death, and on average, 129 Americans die by suicide each day.² In 2018, the suicide rate for all veterans was 1.5 times higher than the rate for nonveterans, after adjusting for population differences in age and sex. Among female veterans, the rate of suicide was 2.1 times higher than the rate for female nonveterans.³

In light of this disparity, suicide prevention is one of the highest priorities for the US Department of Veterans Affairs (VA). In 2018, the VA developed and published the National Strategy for Preventing Veteran Suicide.⁴ One major goal of this strategy is to reduce access to lethal means (ie, firearms, medications, chemicals, or poisons) among veterans at high risk for suicide. Reducing access to lethal means has been found to decrease suicide rates.^4,5

Step 1: Determine Suicide Risk

Although it is impossible to predict with certainty an individual’s risk of suicide, several patient characteristics and life circumstances have been identified as risk factors. The strongest predictor of suicide is the presence of psychiatric disease.⁸ More than 90% of those who have had a death by suicide have a psychiatric diagnosis at the time of death, and suicide rates in those with mental illness are at least 10 times as high as in the general population.^9,10 Depression is the leading cause of death by suicide worldwide, followed by substance-related disorders (22.4%), personality disorders (11.6%), schizophrenia (10.6%), and anxiety/somatoform disorders (6.1%).^8,11-13

Clinicians also can use various risk assessment tools to identify patients at high risk for suicide. The Veterans Health Administration (VHA) Stratification Tool for Opioid Risk Mitigation (STORM) calculates patients’ risk based on data extracted from the electronic health record and is less time intensive, more easily refined, and may be more powerful than standard risk assessment tools because it can be deployed on a large scale.^14,15 The VHA also developed the Suicide Prevention Population Risk Identification and Tracking for Exigencies (SPPRITE) tool to assist clinicians in tracking patients with current (or recent) high levels of suicide risk. This tool unifies specific patient information gathered from the patient’s electronic health record and from other predictive model dashboards (such as STORM).

Step 2: Identify Substances Strongly Associated With Fatalities

According to the American Association of Poison Control Centers (AAPCC), the pharmaceutical classes associated with the largest number of fatalities are analgesics, followed by stimulants and street drugs, cardiovascular agents, antidepressants, antipsychotics, and sedatives/hypnotics (Table 1).¹⁶ Stimulants and street drugs accounted for 694 fatalities of 39,238 single-substance exposures (mortality rate: 1.8%).¹⁶ Drugs of abuse, including cocaine, hallucinogenic amphetamines, heroin, and kratom, have shown an increased trend in use.¹⁶

In 2018 there were 834 fatalities from 174,269 single-substance exposure to analgesics, which include opioids and acetaminophen, for a mortality rate of 0.5%.¹⁶ The opioid epidemic is one of the main drivers of the increase in drug overdose deaths in the US.^16,17 The opioid with the highest drug overdose fatality rate is illicitly manufactured fentanyl, which often is combined with other substances, such as heroin, to increase its potency at a low cost.¹⁸ These combinations also increase the risk of overdose fatality.

Acetaminophen is unique among the top substances associated with fatalities because it is obtained easily without a prescription. An acetaminophen overdose can cause hepatic injury, which may progress to fulminant hepatic failure and death.¹⁹ The recommended maximum dose of acetaminophen is 4 g/d in an adult and 50 to 75 mg/kg/d in children. A single acute ingestion of > 7.5 g in an adult or 150 mg/kg in children has been considered potentially toxic.^19,20 The use of combination analgesics that contain both an opioid and acetaminophen can pose an even greater risk due to the potential for respiratory depression and hepatotoxicity.

Cardiovascular drugs accounted for 232 fatalities from 46,499 single-substance exposures (mortality rate: 0.5%).¹⁶ According to the AAPCC, calcium channel blockers (CCB) and β-blockers accounted for 63% of overdose deaths by cardiovascular drugs because they can cause severe hypotension, bradycardia, and hemodynamic collapse.^16,21,22

In the past, the nondihydropyridine CCBs verapamil and diltiazem were associated with increased overdose fatalities. However, the most recent data show that dihydropyridine CCBs such as amlodipine also have significant risk for lethality.¹⁶ Metoprolol was associated with more overdose deaths in the past year among β-blockers. However, caution also should be used with agents such as propranolol and labetalol, which can antagonize sodium channels in overdose and may be associated with a higher risk of mortality than other β-blockers.²²

Step 3: Consider Potential Drug-Drug Interactions

Suicide attempts involving multiple substances carry increased risk. Only 12.1% of all fatal overdoses, according to AAPCC, involved single-substance exposure, whereas 56.3% were attributed to multiple substance exposures.¹⁶ It is important for clinicians to be aware of and avoid possibly fatal drug-drug interactions, such as the combination of opioids and sedative-hypnotics, like BZDs, which can lead to fatal respiratory depression. Clinicians also should be aware of a patient’s history of illicit opioid and alcohol use before prescribing opioids and BZDs. Clinicians can use various online databases to detect potential drug-drug interactions.

Step 4: Address Risks

If a patient is deemed to be at high risk for suicide, but it is not imminent and the patient will be managed as an outpatient, then it may be preferential to prescribe medications that are less lethal, such as SSRIs, instead of TCAs or MAOIs. If a potentially lethal medication is indicated, such as lithium or clozapine, both of which have been found to reduce suicidal behavior, then dispensing a limited quantity of pills and having more frequent follow-up visits are some ways to lessen risk.^24,25 A clinical pearl published in Current Psychiatry provided an equation to determine the lethality of a 30-day supply of medications.²⁶ This equation uses lethal dose 50 (LD50), which is the dose of a medication that results in the death of 50% of the animals used in a controlled experiment, and the maximum daily dose of the medication (D) to find the human equivalent dose (HED) relative lethality. The HED relative lethality calculation may help prescribers determine which medications should have a limited quantity dispensed to patients at risk of medication-related suicide. Any value for the HED relative lethality that is > 100% is considered a lethal dose for humans. Therefore, it would be appropriate to avoid or limit the quantity of medications with a HED relative lethality > 100%. Table 4 lists the psychotropic agents with the highest relative lethality for a 30-day supply. The psychotropic agents with the lowest HED relative lethality are SSRIs: desvenlafaxine, mirtazapine, topiramate, and aripiprazole.²⁶

Limiting drugs with a narrow therapeutic index should be considered when aiming to reduce the risk of medication-related suicide. These drugs present a high risk in the event of an overdose. Clinicians can monitor the levels of lithium, clozapine, or TCAs to ensure that a patient is taking the medication as prescribed rather than stockpiling it at home. If the patient is in a monitored setting, such as a partial hospital program or intensive outpatient program, then the medication can be given while under direct observation.

Clinicians should obtain an accurate and detailed medication and illicit drug use history from patients. It also is important to review the prescription drug monitoring program to limit access to potentially lethal combinations of medications.²⁷ Clinicians can additionally employ risk mitigation strategies (eg, providing naloxone kits) for patients who are prescribed or abuse opioids.

Finally, all patients with a high risk of suicide should receive lethal means counseling, which involves first determining whether patients have access to lethal means, such as firearms or medications with high lethality, then limiting their access to these lethal means. This includes advising patients and family members to safely dispose medications that are no longer in use and in some cases recommending that a family member keep medications locked and dispense them on a daily basis.

Conclusions

Suicide is a major public health concern that affects tens of thousands of Americans annually. Furthermore, veterans are more likely to die by suicide than those in the general population. Firearms continue to be the most lethal means for suicide. However, intentional poisoning with medications or substances also is a common method for suicide, especially in female veterans. Having knowledge of medications with high lethality and limiting access to these agents can be a successful strategy for reducing suicide deaths.

Suicide is a global phenomenon and a worldwide public health concern.¹ The World Health Organization estimates that > 800,000 people die by suicide every year. In the US, suicide is the 10th leading cause of death, and on average, 129 Americans die by suicide each day.² In 2018, the suicide rate for all veterans was 1.5 times higher than the rate for nonveterans, after adjusting for population differences in age and sex. Among female veterans, the rate of suicide was 2.1 times higher than the rate for female nonveterans.³

In light of this disparity, suicide prevention is one of the highest priorities for the US Department of Veterans Affairs (VA). In 2018, the VA developed and published the National Strategy for Preventing Veteran Suicide.⁴ One major goal of this strategy is to reduce access to lethal means (ie, firearms, medications, chemicals, or poisons) among veterans at high risk for suicide. Reducing access to lethal means has been found to decrease suicide rates.^4,5

Step 1: Determine Suicide Risk

Although it is impossible to predict with certainty an individual’s risk of suicide, several patient characteristics and life circumstances have been identified as risk factors. The strongest predictor of suicide is the presence of psychiatric disease.⁸ More than 90% of those who have had a death by suicide have a psychiatric diagnosis at the time of death, and suicide rates in those with mental illness are at least 10 times as high as in the general population.^9,10 Depression is the leading cause of death by suicide worldwide, followed by substance-related disorders (22.4%), personality disorders (11.6%), schizophrenia (10.6%), and anxiety/somatoform disorders (6.1%).^8,11-13

Clinicians also can use various risk assessment tools to identify patients at high risk for suicide. The Veterans Health Administration (VHA) Stratification Tool for Opioid Risk Mitigation (STORM) calculates patients’ risk based on data extracted from the electronic health record and is less time intensive, more easily refined, and may be more powerful than standard risk assessment tools because it can be deployed on a large scale.^14,15 The VHA also developed the Suicide Prevention Population Risk Identification and Tracking for Exigencies (SPPRITE) tool to assist clinicians in tracking patients with current (or recent) high levels of suicide risk. This tool unifies specific patient information gathered from the patient’s electronic health record and from other predictive model dashboards (such as STORM).

Step 2: Identify Substances Strongly Associated With Fatalities

According to the American Association of Poison Control Centers (AAPCC), the pharmaceutical classes associated with the largest number of fatalities are analgesics, followed by stimulants and street drugs, cardiovascular agents, antidepressants, antipsychotics, and sedatives/hypnotics (Table 1).¹⁶ Stimulants and street drugs accounted for 694 fatalities of 39,238 single-substance exposures (mortality rate: 1.8%).¹⁶ Drugs of abuse, including cocaine, hallucinogenic amphetamines, heroin, and kratom, have shown an increased trend in use.¹⁶

In 2018 there were 834 fatalities from 174,269 single-substance exposure to analgesics, which include opioids and acetaminophen, for a mortality rate of 0.5%.¹⁶ The opioid epidemic is one of the main drivers of the increase in drug overdose deaths in the US.^16,17 The opioid with the highest drug overdose fatality rate is illicitly manufactured fentanyl, which often is combined with other substances, such as heroin, to increase its potency at a low cost.¹⁸ These combinations also increase the risk of overdose fatality.

Acetaminophen is unique among the top substances associated with fatalities because it is obtained easily without a prescription. An acetaminophen overdose can cause hepatic injury, which may progress to fulminant hepatic failure and death.¹⁹ The recommended maximum dose of acetaminophen is 4 g/d in an adult and 50 to 75 mg/kg/d in children. A single acute ingestion of > 7.5 g in an adult or 150 mg/kg in children has been considered potentially toxic.^19,20 The use of combination analgesics that contain both an opioid and acetaminophen can pose an even greater risk due to the potential for respiratory depression and hepatotoxicity.

Cardiovascular drugs accounted for 232 fatalities from 46,499 single-substance exposures (mortality rate: 0.5%).¹⁶ According to the AAPCC, calcium channel blockers (CCB) and β-blockers accounted for 63% of overdose deaths by cardiovascular drugs because they can cause severe hypotension, bradycardia, and hemodynamic collapse.^16,21,22

In the past, the nondihydropyridine CCBs verapamil and diltiazem were associated with increased overdose fatalities. However, the most recent data show that dihydropyridine CCBs such as amlodipine also have significant risk for lethality.¹⁶ Metoprolol was associated with more overdose deaths in the past year among β-blockers. However, caution also should be used with agents such as propranolol and labetalol, which can antagonize sodium channels in overdose and may be associated with a higher risk of mortality than other β-blockers.²²

Step 3: Consider Potential Drug-Drug Interactions

Suicide attempts involving multiple substances carry increased risk. Only 12.1% of all fatal overdoses, according to AAPCC, involved single-substance exposure, whereas 56.3% were attributed to multiple substance exposures.¹⁶ It is important for clinicians to be aware of and avoid possibly fatal drug-drug interactions, such as the combination of opioids and sedative-hypnotics, like BZDs, which can lead to fatal respiratory depression. Clinicians also should be aware of a patient’s history of illicit opioid and alcohol use before prescribing opioids and BZDs. Clinicians can use various online databases to detect potential drug-drug interactions.

Step 4: Address Risks

If a patient is deemed to be at high risk for suicide, but it is not imminent and the patient will be managed as an outpatient, then it may be preferential to prescribe medications that are less lethal, such as SSRIs, instead of TCAs or MAOIs. If a potentially lethal medication is indicated, such as lithium or clozapine, both of which have been found to reduce suicidal behavior, then dispensing a limited quantity of pills and having more frequent follow-up visits are some ways to lessen risk.^24,25 A clinical pearl published in Current Psychiatry provided an equation to determine the lethality of a 30-day supply of medications.²⁶ This equation uses lethal dose 50 (LD50), which is the dose of a medication that results in the death of 50% of the animals used in a controlled experiment, and the maximum daily dose of the medication (D) to find the human equivalent dose (HED) relative lethality. The HED relative lethality calculation may help prescribers determine which medications should have a limited quantity dispensed to patients at risk of medication-related suicide. Any value for the HED relative lethality that is > 100% is considered a lethal dose for humans. Therefore, it would be appropriate to avoid or limit the quantity of medications with a HED relative lethality > 100%. Table 4 lists the psychotropic agents with the highest relative lethality for a 30-day supply. The psychotropic agents with the lowest HED relative lethality are SSRIs: desvenlafaxine, mirtazapine, topiramate, and aripiprazole.²⁶

Limiting drugs with a narrow therapeutic index should be considered when aiming to reduce the risk of medication-related suicide. These drugs present a high risk in the event of an overdose. Clinicians can monitor the levels of lithium, clozapine, or TCAs to ensure that a patient is taking the medication as prescribed rather than stockpiling it at home. If the patient is in a monitored setting, such as a partial hospital program or intensive outpatient program, then the medication can be given while under direct observation.

Clinicians should obtain an accurate and detailed medication and illicit drug use history from patients. It also is important to review the prescription drug monitoring program to limit access to potentially lethal combinations of medications.²⁷ Clinicians can additionally employ risk mitigation strategies (eg, providing naloxone kits) for patients who are prescribed or abuse opioids.

Finally, all patients with a high risk of suicide should receive lethal means counseling, which involves first determining whether patients have access to lethal means, such as firearms or medications with high lethality, then limiting their access to these lethal means. This includes advising patients and family members to safely dispose medications that are no longer in use and in some cases recommending that a family member keep medications locked and dispense them on a daily basis.

Conclusions

Suicide is a major public health concern that affects tens of thousands of Americans annually. Furthermore, veterans are more likely to die by suicide than those in the general population. Firearms continue to be the most lethal means for suicide. However, intentional poisoning with medications or substances also is a common method for suicide, especially in female veterans. Having knowledge of medications with high lethality and limiting access to these agents can be a successful strategy for reducing suicide deaths.

Deep vein thrombosis (DVT) is a frequently encountered medical condition with about 1 in 1,000 adults diagnosed annually.^1,2 Up to one-half of patients who receive a diagnosis will experience long-term complications in the affected limb.¹ Anticoagulation is the treatment of choice for DVT in the absence of any contraindications.³ Thrombolytic therapies (eg, systemic thrombolysis, catheter-directed thrombolysis with or without thrombectomy) historically have been reserved for patients who present with phlegmasia cerulea dolens (PCD), a severe condition involving venous obstruction within the extremities that causes impaired arterial blood supply and cyanosis that can lead to limb loss and death.⁴

The role of thrombolytic therapy is less clear in patients without PCD who present with extensive or symptomatic lower extremity DVT that causes significant pain, edema, and functional disability. Proximal lower extremity DVT (thrombus above the knee and above the popliteal vein) and particularly those involving the iliac or common femoral vein (ie, iliofemoral DVT) carry a significant risk of recurrent thromboembolism as well as postthrombotic syndrome (PTS), a complication of DVT resulting in chronic leg pain, edema, skin discoloration, and venous ulcers.⁵There is a lack of established standards of care for treating severely symptomatic or extensive proximal DVT without PCD. There are currently no specific treatment recommendations in the major guidelines for this subset of patients.

The goal of thrombolytic therapy is to prevent thrombus propagation, recurrent thromboembolism, and PTS, in addition to providing more rapid pain relief and improvement in limb function. Catheter-directed thrombolysis is preferred over systemic thrombolysis when used for DVT treatment because it is associated with less major bleeding complications and noninferior clinical outcomes.⁶ Catheter-directed thrombolysis is a minimally invasive endovascular treatment using a wire catheter combination to traverse the thrombus under fluoroscopic guidance through which a thrombolytic drug is infused over a specified duration (usually 24 to 72 hours).⁷

Catheter-directed thrombolysis can be combined with catheter-directed thrombectomy using the same endovascular technique. This combination is called a pharmacomechanical thrombectomy or a pharmacomechanical thromobolysis and can offer more rapid removal of thrombus and decreased infusion times of thrombolytic drug.⁸ Pharmacomechanical thrombolysis is a relatively new technique, so the choice of thrombolytic therapy will depend on procedural expertise and resource availability. Early interventional radiology consultation (or vascular surgery in some centers) can assist in determining appropriate candidates for thrombolytic therapies. Here we present 2 cases of extensive symptomatic DVT successfully treated with catheter-directed pharmacomechanical thrombolysis.

Case 1

A 61-year-old male current smoker with a history of obesity and hypertension presented to the West Los Angeles Veterans Affairs Medical Center emergency department (ED) with 2 days of progressive pain and swelling in the right lower extremity (RLE) after sustaining a calf injury the preceding week. The patient rated pain as 9 on a 10-point scale and reported no other symptoms. He reported no prior history of venous thromboembolism (VTE) or family history of thrombophilia.

A physical examination was notable for stable vital signs and normal cardiopulmonary examination. There was extensive RLE edema below the knee with tenderness to palpation and shiny taut skin. The neurovascular examination of the RLE was normal. Laboratory studies were notable only for a mild leukocytosis. Compression ultrasound with Doppler of the RLE demonstrated an acute thrombus of the right femoral vein extending to the popliteal vein.

The patient was prescribed enoxaparin 90 mg every 12 hours for anticoagulation. After 36 hours of anticoagulation, he continued to experience severe RLE pain and swelling limiting ambulation. Interventional radiology was consulted, and catheter-directed pharmacomechanical thrombolysis of the RLE was pursued given the persistence of significant symptoms. Intraprocedure venogram demonstrated thrombi filling the entirety of the right femoral and popliteal veins (Figure 1A). This was treated with catheter-directed pulse-spray thrombolysis with 12 mg of tissue plasminogen activator (tPA).

Case 2

A male aged 78 years with a history of hypertension, hyperlipidemia, and benign prostatic hypertrophy presented to the ED with 10 days of progressive pain and swelling in the left lower extremity (LLE). The patient noted decreased mobility over recent months and was using a front wheel walker while recovering from surgical repair of a hamstring tendon injury. He reported taking a transcontinental flight around the same time that his LLE pain began. The patient reported no prior history of VTE or family history of thrombophilia.

A physical examination was notable for stable vital signs with a normal cardiopulmonary examination. There was extensive LLE edema up to the proximal thigh without erythema or cyanosis, and his skin was taut and tender. Neurovascular examination of the LLE was normal. Laboratory studies were unremarkable. Compression ultrasonography with Doppler of the LLE demonstrated an extensive acute occlusive thrombus within the left common femoral, entire left femoral, and left popliteal veins.

After evaluating the patient, the Vascular Surgery service did not feel there was evidence of compartment syndrome nor PCD. The patient received unfractionated heparin anticoagulation therapy and the LLE was elevated continuously. After 24 hours of anticoagulation therapy, the patient continued to have significant pain and was unable to ambulate. The case was presented in a joint Interventional Radiology/Vascular Surgery conference and the decision was made to pursue pharmacomechanic thrombolysis given the significant extent of thrombotic burden.

Discussion

Anticoagulation is the preferred therapy for most patients with acute uncomplicated lower extremity DVT. PCD is the only widely accepted indication for thrombolytic therapy in patients with acute lower extremity DVT. However, in the absence of PCD, management of complicated DVT where there are either significant symptoms, extensive clot burden, or proximal location is less clear due to the paucity of clinical data. For example, in the case of iliofemoral DVT, thrombosis of the iliofemoral region is associated with an increased risk of pulmonary embolism, limb malperfusion, and PTS when compared with other types of DVT.^5,6Furthermore, despite the use of anticoagulant therapy, PTS develops within 2 years in about half of patients with proximal DVT, which can progress to major disability and impaired quality of life.⁹

Earlier retrospective observational studies in patients with acute DVT found that the addition of either systemic thrombolysis or catheter-directed thrombolysis to anticoagulation increased rates of clot lysis but did not lead to a reduction in clinical outcomes such as recurrent thromboembolism, mortality, or the rate of PTS.^10-12 Additionally, both systemic thrombolytic therapy and catheter-directed thrombolytic therapy were associated with higher rates of major bleeding. However, these studies included all patients with acute DVT without selecting for criteria, such as proximal location of DVT, severe symptoms, or extensive clot burden. Because thrombolytic therapy is proven to provide more rapid and immediate clot lysis (whereas conventional anticoagulation prevents thrombus extension and recurrence but does not dissolve the clot), it is reasonable to suggest that a subpopulation of patients with extensive or symptomatic DVT may benefit from immediate clot lysis, thereby restoring limb perfusion and avoiding limb gangrene while preserving venous function and preventing PTS.

Mixed Study Results

The 2012 CaVenT study is one of the few randomized controlled trials to assess outcomes comparing conventional anticoagulation alone to anticoagulation with catheter-directed thrombolysis in patients with acute lower extremity DVT.¹³ Study patients did not undergo catheter-directed mechanical thrombectomy. Patients in this study consisted solely of those with first-time iliofemoral DVT. Long-term outcomes at 24-month follow-up showed that additional catheter-directed thrombolysis reduced the risk of PTS when compared with those who were treated with anticoagulation alone (41.1% vs 55.6%, P = .047). The difference in PTS corresponded to an absolute risk reduction of 14.4% (95% CI, 0.2-27.9), and the number needed to treat was 7 (95% CI, 4-502). There was a clinically relevant bleeding complication rate of 8.9% in the thrombolysis group with none leading to a permanently impaired outcome.

These results could not be confirmed by a more recent randomized control trial in 2017 conducted by Vedantham and colleagues.¹⁴ In this trial, patients with acute proximal DVT (femoral and iliofemoral DVT) were randomized to receive either anticoagulation alone or anticoagulation plus pharmacomechanical thrombolysis. In the pharmacomechanic thrombolysis group, the overall incidence of PTS and recurrent VTE was not reduced over the 24-month follow-up period. Those who developed PTS in the pharmacomechanical thrombolysis group had lower severity scores, as there was a significant reduction in moderate-to-severe PTS in this group. There also were more early major bleeds in the pharmacomechanic thrombolysis group (1.7%, with no fatal or intracranial bleeds) when compared with the control group; however, this bleeding complication rate was much less than what was noted in the CaVenT study. Additionally, there was a significant decrease in both lower extremity pain and edema in the pharmacomechanical thrombolysis group at 10 days and 30 days postintervention.

Given the mixed results of these 2 randomized controlled trials, further studies are warranted to clarify the role of thrombolytic therapies in preventing major events such as recurrent VTE and PTS, especially given the increased risk of bleeding observed with thrombolytic therapies. The 2016 American College of Chest Physicians guidelines recommend anticoagulation as monotherapy vs thrombolytics, systemic or catheter-directed thrombolysis as designated treatment modalities.³ These guidelines are rated “Grade 2C”, which reflect a weak recommendation based on low-quality evidence. While these recommendations do not comment on additional considerations, such as DVT clot burden, location, or severity of symptoms, the guidelines do state that patients who attach a high value to the prevention of PTS and a lower value to the risk of bleeding with catheter-directed therapy are likely to choose catheter-directed therapy over anticoagulation alone.

Case Studies Analyses

In our first case presentation, pharma-comechanic thrombolysis was pursued because the patient presented with severesymptoms and did not experience any symptomatic improvement after 36 hours of anticoagulation. It is unclear whether a longer duration of anticoagulation might have improved the severity of his symptoms. When considering the level of pain, edema, and inability to ambulate, thrombolytic therapy was considered the most appropriate choice for treatment. Pharmacomechanic thrombolysis was successful, resulting in complete clot lysis, significant decrease in pain and edema with total recovery of ambulatory abilities, no bleeding complications, and prevention of any potential clinical deterioration, such as phlegmasia cerulea dolens. The patient is now 12 months postprocedure without symptoms of PTS or recurrent thromboembolic events. Continued follow-up that monitors the development of PTS will be necessary for at least 2 years postprocedure.

In the second case, our patient experienced some improvement in pain after 24 hours of anticoagulation alone. However, considering the extensive proximal clot burden involving the entire femoral and common femoral veins, the treatment teams believed it was likely that this patient would experience a prolonged recovery time and increased morbidity on anticoagulant therapy alone. Pharmacomechanic thrombolysis was again successful with almost immediate resolution of pain and edema, and recovery of ambulatory abilities on postprocedure day 1. The patient is now 6 months postprocedure without any symptoms of PTS or recurrent thromboembolic events.

In both case presentations, the presenting symptoms, methods of treatment, and immediate symptomatic improvement postintervention were similar. The patient in Case 2 had more extensive clot burden, a more proximal location of clot, and was classified as having an iliofemoral DVT because the thrombus included the common femoral vein; the decision for intervention in this case was more weighted on clot burden and location rather than on the significant symptoms of severe pain and difficulty with ambulation seen in Case 1. However, it is noteworthy that in Case 2 our patient also experienced significant improvement in pain, swelling, and ambulation postintervention. Complications were minimal and limited to Case 2 where our patient experienced mild asymptomatic hematuria likely related to the catheter-directed tPA that resolved spontaneously within hours and did not cause further complications. Additionally, it is likely that the length of hospital stay was decreased significantly in both cases given the rapid improvement in symptoms and recovery of ambulatory abilities.

High-Risk Patients

Given the successful treatment results in these 2 cases, we believe that there is a subset of higher-risk patients with severe symptomatic proximal DVT but without PCD that may benefit from the addition of thrombolytic therapies to anticoagulation. These patients may present with significant pain, difficulty ambulating, and will likely have extensive proximal clot burden. Immediate thrombolytic intervention can achieve rapid symptom relief, which, in turn, can decrease morbidity by decreasing length of hospitalization, improving ambulation, and possibly decreasing the incidence or severity of future PTS. Positive outcomes may be easier to predict for those with obvious features of pain, edema, and difficulty ambulating, which may be more readily reversed by rapid clot reversal/removal.

These patients should be considered on a case-by-case basis. For example, the severity of pain can be balanced against the patient’s risk factors for bleeding because rapid thrombus lysis or immediate thrombus removal will likely reduce the pain. Patients who attach a high value to functional quality (eg, both patients in this case study experienced significant difficulty ambulating), quicker recovery, and decreased hospitalization duration may be more likely to choose the addition of thrombolytic therapies over anticoagulation alone and accept the higher risk of bleed. A scoring system with inclusion/exclusion criteria such as location of clot, bleeding history, age, and pain can create an individualized approach for each patient. Future studies also could consider using a detailed pretreatment symptom-severity score (similar to the Likert pain scale and calf circumference measurements used by Vedantham and colleagues¹⁴) and assess whether higher symptom-severity patients are more likely to benefit from the addition of thrombolytic therapies to anticoagulation. Positive outcomes can be assessed for the short-term such as pain severity, ability to ambulate, and length of hospitalization. Additionally, it would be important to determine whether there is a correlation with severity of pain on presentation and future PTS incidence or severity—a positive correlation would lend further support toward using thrombolytic therapies in those with severe symptomatic DVT.

Finally, additional studies involving variations in methodology should be examined, including whether pharmacomechanic thrombolysis may be safer in terms of bleeding than catheter-directed thrombolysis alone, as suggested by the lower bleeding rates seen in the pharmacomechanic study by Vedantham and colleagues when compared with the CaVenT study.^13,14 Patients in the CaVenT study received an infusion of 20 mg of alteplase over a maximum of 96 hours. Patients in the pharmacomechanic study by Vedanthem and colleagues received either a rapid pulsed delivery of alteplase over a single procedural session (as in our 2 cases) or a maximum of 30 hours of alteplase infusion (total alteplase dose < 35 mg) followed by thrombus removal. It is possible that the lower incidence of major bleeds observed in the study by Vedanthem and colleagues is a result of the decreased exposure to thrombolytic agents.

Conclusions

There is a relative lack of high-quality data examining thrombolytic therapies in the setting of acute lower extremity DVT. Recent studies have prioritized evaluation of the posttreatment incidence of PTS, recurrent thromboembolism, and risk of bleeding caused by thrombolytic therapies. Results are mixed thus far, and further studies are necessary to clarify a more definitive role for thrombolytic therapies, particularly in established higher-risk populations with proximal DVT. In this case series, we highlighted 2 patients with extensive proximal DVT burden with significant symptoms who experienced almost complete resolution of symptoms immediately following thrombolytic therapies. We postulate that even in the absence of PCD, there is a subset of patients with severe symptoms in the setting of acute proximal lower extremity DVT that clearly benefit from thrombolytic therapies.

Deep vein thrombosis (DVT) is a frequently encountered medical condition with about 1 in 1,000 adults diagnosed annually.^1,2 Up to one-half of patients who receive a diagnosis will experience long-term complications in the affected limb.¹ Anticoagulation is the treatment of choice for DVT in the absence of any contraindications.³ Thrombolytic therapies (eg, systemic thrombolysis, catheter-directed thrombolysis with or without thrombectomy) historically have been reserved for patients who present with phlegmasia cerulea dolens (PCD), a severe condition involving venous obstruction within the extremities that causes impaired arterial blood supply and cyanosis that can lead to limb loss and death.⁴

The role of thrombolytic therapy is less clear in patients without PCD who present with extensive or symptomatic lower extremity DVT that causes significant pain, edema, and functional disability. Proximal lower extremity DVT (thrombus above the knee and above the popliteal vein) and particularly those involving the iliac or common femoral vein (ie, iliofemoral DVT) carry a significant risk of recurrent thromboembolism as well as postthrombotic syndrome (PTS), a complication of DVT resulting in chronic leg pain, edema, skin discoloration, and venous ulcers.⁵There is a lack of established standards of care for treating severely symptomatic or extensive proximal DVT without PCD. There are currently no specific treatment recommendations in the major guidelines for this subset of patients.

The goal of thrombolytic therapy is to prevent thrombus propagation, recurrent thromboembolism, and PTS, in addition to providing more rapid pain relief and improvement in limb function. Catheter-directed thrombolysis is preferred over systemic thrombolysis when used for DVT treatment because it is associated with less major bleeding complications and noninferior clinical outcomes.⁶ Catheter-directed thrombolysis is a minimally invasive endovascular treatment using a wire catheter combination to traverse the thrombus under fluoroscopic guidance through which a thrombolytic drug is infused over a specified duration (usually 24 to 72 hours).⁷

Catheter-directed thrombolysis can be combined with catheter-directed thrombectomy using the same endovascular technique. This combination is called a pharmacomechanical thrombectomy or a pharmacomechanical thromobolysis and can offer more rapid removal of thrombus and decreased infusion times of thrombolytic drug.⁸ Pharmacomechanical thrombolysis is a relatively new technique, so the choice of thrombolytic therapy will depend on procedural expertise and resource availability. Early interventional radiology consultation (or vascular surgery in some centers) can assist in determining appropriate candidates for thrombolytic therapies. Here we present 2 cases of extensive symptomatic DVT successfully treated with catheter-directed pharmacomechanical thrombolysis.

Case 1

A 61-year-old male current smoker with a history of obesity and hypertension presented to the West Los Angeles Veterans Affairs Medical Center emergency department (ED) with 2 days of progressive pain and swelling in the right lower extremity (RLE) after sustaining a calf injury the preceding week. The patient rated pain as 9 on a 10-point scale and reported no other symptoms. He reported no prior history of venous thromboembolism (VTE) or family history of thrombophilia.

A physical examination was notable for stable vital signs and normal cardiopulmonary examination. There was extensive RLE edema below the knee with tenderness to palpation and shiny taut skin. The neurovascular examination of the RLE was normal. Laboratory studies were notable only for a mild leukocytosis. Compression ultrasound with Doppler of the RLE demonstrated an acute thrombus of the right femoral vein extending to the popliteal vein.

The patient was prescribed enoxaparin 90 mg every 12 hours for anticoagulation. After 36 hours of anticoagulation, he continued to experience severe RLE pain and swelling limiting ambulation. Interventional radiology was consulted, and catheter-directed pharmacomechanical thrombolysis of the RLE was pursued given the persistence of significant symptoms. Intraprocedure venogram demonstrated thrombi filling the entirety of the right femoral and popliteal veins (Figure 1A). This was treated with catheter-directed pulse-spray thrombolysis with 12 mg of tissue plasminogen activator (tPA).

Case 2

A male aged 78 years with a history of hypertension, hyperlipidemia, and benign prostatic hypertrophy presented to the ED with 10 days of progressive pain and swelling in the left lower extremity (LLE). The patient noted decreased mobility over recent months and was using a front wheel walker while recovering from surgical repair of a hamstring tendon injury. He reported taking a transcontinental flight around the same time that his LLE pain began. The patient reported no prior history of VTE or family history of thrombophilia.

A physical examination was notable for stable vital signs with a normal cardiopulmonary examination. There was extensive LLE edema up to the proximal thigh without erythema or cyanosis, and his skin was taut and tender. Neurovascular examination of the LLE was normal. Laboratory studies were unremarkable. Compression ultrasonography with Doppler of the LLE demonstrated an extensive acute occlusive thrombus within the left common femoral, entire left femoral, and left popliteal veins.

After evaluating the patient, the Vascular Surgery service did not feel there was evidence of compartment syndrome nor PCD. The patient received unfractionated heparin anticoagulation therapy and the LLE was elevated continuously. After 24 hours of anticoagulation therapy, the patient continued to have significant pain and was unable to ambulate. The case was presented in a joint Interventional Radiology/Vascular Surgery conference and the decision was made to pursue pharmacomechanic thrombolysis given the significant extent of thrombotic burden.

Discussion

Anticoagulation is the preferred therapy for most patients with acute uncomplicated lower extremity DVT. PCD is the only widely accepted indication for thrombolytic therapy in patients with acute lower extremity DVT. However, in the absence of PCD, management of complicated DVT where there are either significant symptoms, extensive clot burden, or proximal location is less clear due to the paucity of clinical data. For example, in the case of iliofemoral DVT, thrombosis of the iliofemoral region is associated with an increased risk of pulmonary embolism, limb malperfusion, and PTS when compared with other types of DVT.^5,6Furthermore, despite the use of anticoagulant therapy, PTS develops within 2 years in about half of patients with proximal DVT, which can progress to major disability and impaired quality of life.⁹

Earlier retrospective observational studies in patients with acute DVT found that the addition of either systemic thrombolysis or catheter-directed thrombolysis to anticoagulation increased rates of clot lysis but did not lead to a reduction in clinical outcomes such as recurrent thromboembolism, mortality, or the rate of PTS.^10-12 Additionally, both systemic thrombolytic therapy and catheter-directed thrombolytic therapy were associated with higher rates of major bleeding. However, these studies included all patients with acute DVT without selecting for criteria, such as proximal location of DVT, severe symptoms, or extensive clot burden. Because thrombolytic therapy is proven to provide more rapid and immediate clot lysis (whereas conventional anticoagulation prevents thrombus extension and recurrence but does not dissolve the clot), it is reasonable to suggest that a subpopulation of patients with extensive or symptomatic DVT may benefit from immediate clot lysis, thereby restoring limb perfusion and avoiding limb gangrene while preserving venous function and preventing PTS.

Mixed Study Results

The 2012 CaVenT study is one of the few randomized controlled trials to assess outcomes comparing conventional anticoagulation alone to anticoagulation with catheter-directed thrombolysis in patients with acute lower extremity DVT.¹³ Study patients did not undergo catheter-directed mechanical thrombectomy. Patients in this study consisted solely of those with first-time iliofemoral DVT. Long-term outcomes at 24-month follow-up showed that additional catheter-directed thrombolysis reduced the risk of PTS when compared with those who were treated with anticoagulation alone (41.1% vs 55.6%, P = .047). The difference in PTS corresponded to an absolute risk reduction of 14.4% (95% CI, 0.2-27.9), and the number needed to treat was 7 (95% CI, 4-502). There was a clinically relevant bleeding complication rate of 8.9% in the thrombolysis group with none leading to a permanently impaired outcome.

These results could not be confirmed by a more recent randomized control trial in 2017 conducted by Vedantham and colleagues.¹⁴ In this trial, patients with acute proximal DVT (femoral and iliofemoral DVT) were randomized to receive either anticoagulation alone or anticoagulation plus pharmacomechanical thrombolysis. In the pharmacomechanic thrombolysis group, the overall incidence of PTS and recurrent VTE was not reduced over the 24-month follow-up period. Those who developed PTS in the pharmacomechanical thrombolysis group had lower severity scores, as there was a significant reduction in moderate-to-severe PTS in this group. There also were more early major bleeds in the pharmacomechanic thrombolysis group (1.7%, with no fatal or intracranial bleeds) when compared with the control group; however, this bleeding complication rate was much less than what was noted in the CaVenT study. Additionally, there was a significant decrease in both lower extremity pain and edema in the pharmacomechanical thrombolysis group at 10 days and 30 days postintervention.

Given the mixed results of these 2 randomized controlled trials, further studies are warranted to clarify the role of thrombolytic therapies in preventing major events such as recurrent VTE and PTS, especially given the increased risk of bleeding observed with thrombolytic therapies. The 2016 American College of Chest Physicians guidelines recommend anticoagulation as monotherapy vs thrombolytics, systemic or catheter-directed thrombolysis as designated treatment modalities.³ These guidelines are rated “Grade 2C”, which reflect a weak recommendation based on low-quality evidence. While these recommendations do not comment on additional considerations, such as DVT clot burden, location, or severity of symptoms, the guidelines do state that patients who attach a high value to the prevention of PTS and a lower value to the risk of bleeding with catheter-directed therapy are likely to choose catheter-directed therapy over anticoagulation alone.

Case Studies Analyses

In our first case presentation, pharma-comechanic thrombolysis was pursued because the patient presented with severesymptoms and did not experience any symptomatic improvement after 36 hours of anticoagulation. It is unclear whether a longer duration of anticoagulation might have improved the severity of his symptoms. When considering the level of pain, edema, and inability to ambulate, thrombolytic therapy was considered the most appropriate choice for treatment. Pharmacomechanic thrombolysis was successful, resulting in complete clot lysis, significant decrease in pain and edema with total recovery of ambulatory abilities, no bleeding complications, and prevention of any potential clinical deterioration, such as phlegmasia cerulea dolens. The patient is now 12 months postprocedure without symptoms of PTS or recurrent thromboembolic events. Continued follow-up that monitors the development of PTS will be necessary for at least 2 years postprocedure.

In the second case, our patient experienced some improvement in pain after 24 hours of anticoagulation alone. However, considering the extensive proximal clot burden involving the entire femoral and common femoral veins, the treatment teams believed it was likely that this patient would experience a prolonged recovery time and increased morbidity on anticoagulant therapy alone. Pharmacomechanic thrombolysis was again successful with almost immediate resolution of pain and edema, and recovery of ambulatory abilities on postprocedure day 1. The patient is now 6 months postprocedure without any symptoms of PTS or recurrent thromboembolic events.

In both case presentations, the presenting symptoms, methods of treatment, and immediate symptomatic improvement postintervention were similar. The patient in Case 2 had more extensive clot burden, a more proximal location of clot, and was classified as having an iliofemoral DVT because the thrombus included the common femoral vein; the decision for intervention in this case was more weighted on clot burden and location rather than on the significant symptoms of severe pain and difficulty with ambulation seen in Case 1. However, it is noteworthy that in Case 2 our patient also experienced significant improvement in pain, swelling, and ambulation postintervention. Complications were minimal and limited to Case 2 where our patient experienced mild asymptomatic hematuria likely related to the catheter-directed tPA that resolved spontaneously within hours and did not cause further complications. Additionally, it is likely that the length of hospital stay was decreased significantly in both cases given the rapid improvement in symptoms and recovery of ambulatory abilities.

High-Risk Patients

Given the successful treatment results in these 2 cases, we believe that there is a subset of higher-risk patients with severe symptomatic proximal DVT but without PCD that may benefit from the addition of thrombolytic therapies to anticoagulation. These patients may present with significant pain, difficulty ambulating, and will likely have extensive proximal clot burden. Immediate thrombolytic intervention can achieve rapid symptom relief, which, in turn, can decrease morbidity by decreasing length of hospitalization, improving ambulation, and possibly decreasing the incidence or severity of future PTS. Positive outcomes may be easier to predict for those with obvious features of pain, edema, and difficulty ambulating, which may be more readily reversed by rapid clot reversal/removal.

These patients should be considered on a case-by-case basis. For example, the severity of pain can be balanced against the patient’s risk factors for bleeding because rapid thrombus lysis or immediate thrombus removal will likely reduce the pain. Patients who attach a high value to functional quality (eg, both patients in this case study experienced significant difficulty ambulating), quicker recovery, and decreased hospitalization duration may be more likely to choose the addition of thrombolytic therapies over anticoagulation alone and accept the higher risk of bleed. A scoring system with inclusion/exclusion criteria such as location of clot, bleeding history, age, and pain can create an individualized approach for each patient. Future studies also could consider using a detailed pretreatment symptom-severity score (similar to the Likert pain scale and calf circumference measurements used by Vedantham and colleagues¹⁴) and assess whether higher symptom-severity patients are more likely to benefit from the addition of thrombolytic therapies to anticoagulation. Positive outcomes can be assessed for the short-term such as pain severity, ability to ambulate, and length of hospitalization. Additionally, it would be important to determine whether there is a correlation with severity of pain on presentation and future PTS incidence or severity—a positive correlation would lend further support toward using thrombolytic therapies in those with severe symptomatic DVT.

Finally, additional studies involving variations in methodology should be examined, including whether pharmacomechanic thrombolysis may be safer in terms of bleeding than catheter-directed thrombolysis alone, as suggested by the lower bleeding rates seen in the pharmacomechanic study by Vedantham and colleagues when compared with the CaVenT study.^13,14 Patients in the CaVenT study received an infusion of 20 mg of alteplase over a maximum of 96 hours. Patients in the pharmacomechanic study by Vedanthem and colleagues received either a rapid pulsed delivery of alteplase over a single procedural session (as in our 2 cases) or a maximum of 30 hours of alteplase infusion (total alteplase dose < 35 mg) followed by thrombus removal. It is possible that the lower incidence of major bleeds observed in the study by Vedanthem and colleagues is a result of the decreased exposure to thrombolytic agents.

Conclusions

There is a relative lack of high-quality data examining thrombolytic therapies in the setting of acute lower extremity DVT. Recent studies have prioritized evaluation of the posttreatment incidence of PTS, recurrent thromboembolism, and risk of bleeding caused by thrombolytic therapies. Results are mixed thus far, and further studies are necessary to clarify a more definitive role for thrombolytic therapies, particularly in established higher-risk populations with proximal DVT. In this case series, we highlighted 2 patients with extensive proximal DVT burden with significant symptoms who experienced almost complete resolution of symptoms immediately following thrombolytic therapies. We postulate that even in the absence of PCD, there is a subset of patients with severe symptoms in the setting of acute proximal lower extremity DVT that clearly benefit from thrombolytic therapies.

Deep vein thrombosis (DVT) is a frequently encountered medical condition with about 1 in 1,000 adults diagnosed annually.^1,2 Up to one-half of patients who receive a diagnosis will experience long-term complications in the affected limb.¹ Anticoagulation is the treatment of choice for DVT in the absence of any contraindications.³ Thrombolytic therapies (eg, systemic thrombolysis, catheter-directed thrombolysis with or without thrombectomy) historically have been reserved for patients who present with phlegmasia cerulea dolens (PCD), a severe condition involving venous obstruction within the extremities that causes impaired arterial blood supply and cyanosis that can lead to limb loss and death.⁴

The role of thrombolytic therapy is less clear in patients without PCD who present with extensive or symptomatic lower extremity DVT that causes significant pain, edema, and functional disability. Proximal lower extremity DVT (thrombus above the knee and above the popliteal vein) and particularly those involving the iliac or common femoral vein (ie, iliofemoral DVT) carry a significant risk of recurrent thromboembolism as well as postthrombotic syndrome (PTS), a complication of DVT resulting in chronic leg pain, edema, skin discoloration, and venous ulcers.⁵There is a lack of established standards of care for treating severely symptomatic or extensive proximal DVT without PCD. There are currently no specific treatment recommendations in the major guidelines for this subset of patients.

The goal of thrombolytic therapy is to prevent thrombus propagation, recurrent thromboembolism, and PTS, in addition to providing more rapid pain relief and improvement in limb function. Catheter-directed thrombolysis is preferred over systemic thrombolysis when used for DVT treatment because it is associated with less major bleeding complications and noninferior clinical outcomes.⁶ Catheter-directed thrombolysis is a minimally invasive endovascular treatment using a wire catheter combination to traverse the thrombus under fluoroscopic guidance through which a thrombolytic drug is infused over a specified duration (usually 24 to 72 hours).⁷

Catheter-directed thrombolysis can be combined with catheter-directed thrombectomy using the same endovascular technique. This combination is called a pharmacomechanical thrombectomy or a pharmacomechanical thromobolysis and can offer more rapid removal of thrombus and decreased infusion times of thrombolytic drug.⁸ Pharmacomechanical thrombolysis is a relatively new technique, so the choice of thrombolytic therapy will depend on procedural expertise and resource availability. Early interventional radiology consultation (or vascular surgery in some centers) can assist in determining appropriate candidates for thrombolytic therapies. Here we present 2 cases of extensive symptomatic DVT successfully treated with catheter-directed pharmacomechanical thrombolysis.

Case 1

A 61-year-old male current smoker with a history of obesity and hypertension presented to the West Los Angeles Veterans Affairs Medical Center emergency department (ED) with 2 days of progressive pain and swelling in the right lower extremity (RLE) after sustaining a calf injury the preceding week. The patient rated pain as 9 on a 10-point scale and reported no other symptoms. He reported no prior history of venous thromboembolism (VTE) or family history of thrombophilia.

A physical examination was notable for stable vital signs and normal cardiopulmonary examination. There was extensive RLE edema below the knee with tenderness to palpation and shiny taut skin. The neurovascular examination of the RLE was normal. Laboratory studies were notable only for a mild leukocytosis. Compression ultrasound with Doppler of the RLE demonstrated an acute thrombus of the right femoral vein extending to the popliteal vein.

The patient was prescribed enoxaparin 90 mg every 12 hours for anticoagulation. After 36 hours of anticoagulation, he continued to experience severe RLE pain and swelling limiting ambulation. Interventional radiology was consulted, and catheter-directed pharmacomechanical thrombolysis of the RLE was pursued given the persistence of significant symptoms. Intraprocedure venogram demonstrated thrombi filling the entirety of the right femoral and popliteal veins (Figure 1A). This was treated with catheter-directed pulse-spray thrombolysis with 12 mg of tissue plasminogen activator (tPA).

Case 2

A male aged 78 years with a history of hypertension, hyperlipidemia, and benign prostatic hypertrophy presented to the ED with 10 days of progressive pain and swelling in the left lower extremity (LLE). The patient noted decreased mobility over recent months and was using a front wheel walker while recovering from surgical repair of a hamstring tendon injury. He reported taking a transcontinental flight around the same time that his LLE pain began. The patient reported no prior history of VTE or family history of thrombophilia.

A physical examination was notable for stable vital signs with a normal cardiopulmonary examination. There was extensive LLE edema up to the proximal thigh without erythema or cyanosis, and his skin was taut and tender. Neurovascular examination of the LLE was normal. Laboratory studies were unremarkable. Compression ultrasonography with Doppler of the LLE demonstrated an extensive acute occlusive thrombus within the left common femoral, entire left femoral, and left popliteal veins.

After evaluating the patient, the Vascular Surgery service did not feel there was evidence of compartment syndrome nor PCD. The patient received unfractionated heparin anticoagulation therapy and the LLE was elevated continuously. After 24 hours of anticoagulation therapy, the patient continued to have significant pain and was unable to ambulate. The case was presented in a joint Interventional Radiology/Vascular Surgery conference and the decision was made to pursue pharmacomechanic thrombolysis given the significant extent of thrombotic burden.

Discussion

Anticoagulation is the preferred therapy for most patients with acute uncomplicated lower extremity DVT. PCD is the only widely accepted indication for thrombolytic therapy in patients with acute lower extremity DVT. However, in the absence of PCD, management of complicated DVT where there are either significant symptoms, extensive clot burden, or proximal location is less clear due to the paucity of clinical data. For example, in the case of iliofemoral DVT, thrombosis of the iliofemoral region is associated with an increased risk of pulmonary embolism, limb malperfusion, and PTS when compared with other types of DVT.^5,6Furthermore, despite the use of anticoagulant therapy, PTS develops within 2 years in about half of patients with proximal DVT, which can progress to major disability and impaired quality of life.⁹

Earlier retrospective observational studies in patients with acute DVT found that the addition of either systemic thrombolysis or catheter-directed thrombolysis to anticoagulation increased rates of clot lysis but did not lead to a reduction in clinical outcomes such as recurrent thromboembolism, mortality, or the rate of PTS.^10-12 Additionally, both systemic thrombolytic therapy and catheter-directed thrombolytic therapy were associated with higher rates of major bleeding. However, these studies included all patients with acute DVT without selecting for criteria, such as proximal location of DVT, severe symptoms, or extensive clot burden. Because thrombolytic therapy is proven to provide more rapid and immediate clot lysis (whereas conventional anticoagulation prevents thrombus extension and recurrence but does not dissolve the clot), it is reasonable to suggest that a subpopulation of patients with extensive or symptomatic DVT may benefit from immediate clot lysis, thereby restoring limb perfusion and avoiding limb gangrene while preserving venous function and preventing PTS.

Mixed Study Results

The 2012 CaVenT study is one of the few randomized controlled trials to assess outcomes comparing conventional anticoagulation alone to anticoagulation with catheter-directed thrombolysis in patients with acute lower extremity DVT.¹³ Study patients did not undergo catheter-directed mechanical thrombectomy. Patients in this study consisted solely of those with first-time iliofemoral DVT. Long-term outcomes at 24-month follow-up showed that additional catheter-directed thrombolysis reduced the risk of PTS when compared with those who were treated with anticoagulation alone (41.1% vs 55.6%, P = .047). The difference in PTS corresponded to an absolute risk reduction of 14.4% (95% CI, 0.2-27.9), and the number needed to treat was 7 (95% CI, 4-502). There was a clinically relevant bleeding complication rate of 8.9% in the thrombolysis group with none leading to a permanently impaired outcome.

These results could not be confirmed by a more recent randomized control trial in 2017 conducted by Vedantham and colleagues.¹⁴ In this trial, patients with acute proximal DVT (femoral and iliofemoral DVT) were randomized to receive either anticoagulation alone or anticoagulation plus pharmacomechanical thrombolysis. In the pharmacomechanic thrombolysis group, the overall incidence of PTS and recurrent VTE was not reduced over the 24-month follow-up period. Those who developed PTS in the pharmacomechanical thrombolysis group had lower severity scores, as there was a significant reduction in moderate-to-severe PTS in this group. There also were more early major bleeds in the pharmacomechanic thrombolysis group (1.7%, with no fatal or intracranial bleeds) when compared with the control group; however, this bleeding complication rate was much less than what was noted in the CaVenT study. Additionally, there was a significant decrease in both lower extremity pain and edema in the pharmacomechanical thrombolysis group at 10 days and 30 days postintervention.

Given the mixed results of these 2 randomized controlled trials, further studies are warranted to clarify the role of thrombolytic therapies in preventing major events such as recurrent VTE and PTS, especially given the increased risk of bleeding observed with thrombolytic therapies. The 2016 American College of Chest Physicians guidelines recommend anticoagulation as monotherapy vs thrombolytics, systemic or catheter-directed thrombolysis as designated treatment modalities.³ These guidelines are rated “Grade 2C”, which reflect a weak recommendation based on low-quality evidence. While these recommendations do not comment on additional considerations, such as DVT clot burden, location, or severity of symptoms, the guidelines do state that patients who attach a high value to the prevention of PTS and a lower value to the risk of bleeding with catheter-directed therapy are likely to choose catheter-directed therapy over anticoagulation alone.

Case Studies Analyses

In our first case presentation, pharma-comechanic thrombolysis was pursued because the patient presented with severesymptoms and did not experience any symptomatic improvement after 36 hours of anticoagulation. It is unclear whether a longer duration of anticoagulation might have improved the severity of his symptoms. When considering the level of pain, edema, and inability to ambulate, thrombolytic therapy was considered the most appropriate choice for treatment. Pharmacomechanic thrombolysis was successful, resulting in complete clot lysis, significant decrease in pain and edema with total recovery of ambulatory abilities, no bleeding complications, and prevention of any potential clinical deterioration, such as phlegmasia cerulea dolens. The patient is now 12 months postprocedure without symptoms of PTS or recurrent thromboembolic events. Continued follow-up that monitors the development of PTS will be necessary for at least 2 years postprocedure.

In the second case, our patient experienced some improvement in pain after 24 hours of anticoagulation alone. However, considering the extensive proximal clot burden involving the entire femoral and common femoral veins, the treatment teams believed it was likely that this patient would experience a prolonged recovery time and increased morbidity on anticoagulant therapy alone. Pharmacomechanic thrombolysis was again successful with almost immediate resolution of pain and edema, and recovery of ambulatory abilities on postprocedure day 1. The patient is now 6 months postprocedure without any symptoms of PTS or recurrent thromboembolic events.

In both case presentations, the presenting symptoms, methods of treatment, and immediate symptomatic improvement postintervention were similar. The patient in Case 2 had more extensive clot burden, a more proximal location of clot, and was classified as having an iliofemoral DVT because the thrombus included the common femoral vein; the decision for intervention in this case was more weighted on clot burden and location rather than on the significant symptoms of severe pain and difficulty with ambulation seen in Case 1. However, it is noteworthy that in Case 2 our patient also experienced significant improvement in pain, swelling, and ambulation postintervention. Complications were minimal and limited to Case 2 where our patient experienced mild asymptomatic hematuria likely related to the catheter-directed tPA that resolved spontaneously within hours and did not cause further complications. Additionally, it is likely that the length of hospital stay was decreased significantly in both cases given the rapid improvement in symptoms and recovery of ambulatory abilities.

High-Risk Patients

Given the successful treatment results in these 2 cases, we believe that there is a subset of higher-risk patients with severe symptomatic proximal DVT but without PCD that may benefit from the addition of thrombolytic therapies to anticoagulation. These patients may present with significant pain, difficulty ambulating, and will likely have extensive proximal clot burden. Immediate thrombolytic intervention can achieve rapid symptom relief, which, in turn, can decrease morbidity by decreasing length of hospitalization, improving ambulation, and possibly decreasing the incidence or severity of future PTS. Positive outcomes may be easier to predict for those with obvious features of pain, edema, and difficulty ambulating, which may be more readily reversed by rapid clot reversal/removal.

These patients should be considered on a case-by-case basis. For example, the severity of pain can be balanced against the patient’s risk factors for bleeding because rapid thrombus lysis or immediate thrombus removal will likely reduce the pain. Patients who attach a high value to functional quality (eg, both patients in this case study experienced significant difficulty ambulating), quicker recovery, and decreased hospitalization duration may be more likely to choose the addition of thrombolytic therapies over anticoagulation alone and accept the higher risk of bleed. A scoring system with inclusion/exclusion criteria such as location of clot, bleeding history, age, and pain can create an individualized approach for each patient. Future studies also could consider using a detailed pretreatment symptom-severity score (similar to the Likert pain scale and calf circumference measurements used by Vedantham and colleagues¹⁴) and assess whether higher symptom-severity patients are more likely to benefit from the addition of thrombolytic therapies to anticoagulation. Positive outcomes can be assessed for the short-term such as pain severity, ability to ambulate, and length of hospitalization. Additionally, it would be important to determine whether there is a correlation with severity of pain on presentation and future PTS incidence or severity—a positive correlation would lend further support toward using thrombolytic therapies in those with severe symptomatic DVT.

Finally, additional studies involving variations in methodology should be examined, including whether pharmacomechanic thrombolysis may be safer in terms of bleeding than catheter-directed thrombolysis alone, as suggested by the lower bleeding rates seen in the pharmacomechanic study by Vedantham and colleagues when compared with the CaVenT study.^13,14 Patients in the CaVenT study received an infusion of 20 mg of alteplase over a maximum of 96 hours. Patients in the pharmacomechanic study by Vedanthem and colleagues received either a rapid pulsed delivery of alteplase over a single procedural session (as in our 2 cases) or a maximum of 30 hours of alteplase infusion (total alteplase dose < 35 mg) followed by thrombus removal. It is possible that the lower incidence of major bleeds observed in the study by Vedanthem and colleagues is a result of the decreased exposure to thrombolytic agents.

Conclusions

There is a relative lack of high-quality data examining thrombolytic therapies in the setting of acute lower extremity DVT. Recent studies have prioritized evaluation of the posttreatment incidence of PTS, recurrent thromboembolism, and risk of bleeding caused by thrombolytic therapies. Results are mixed thus far, and further studies are necessary to clarify a more definitive role for thrombolytic therapies, particularly in established higher-risk populations with proximal DVT. In this case series, we highlighted 2 patients with extensive proximal DVT burden with significant symptoms who experienced almost complete resolution of symptoms immediately following thrombolytic therapies. We postulate that even in the absence of PCD, there is a subset of patients with severe symptoms in the setting of acute proximal lower extremity DVT that clearly benefit from thrombolytic therapies.

In January 2017, the US Department of Veterans Affairs (VA), led by the National Center of Ethics in Health Care, created the Life-Sustaining Treatment Decisions Initiative (LSTDI). The VA gradually implemented the LSTDI in its facilities nationwide. In a format similar to the standardized form of portable medical orders, provider orders for life-sustaining treatments (POLST), the initiative promotes discussions with veterans and encourages but does not require health care professionals (HCPs) to complete a template for documentation (life-sustaining treatment [LST] note) of a patient’s preferences.¹ The HCP enters a code status into the electronic health record (EHR), creating a portable and durable note and order.

With a new durable code status, the HCPs performing these procedures (eg, colonoscopies, coronary catheterization, or percutaneous biopsies) need to acknowledge and can potentially rescind a do not resuscitate (DNR) order. Although the risk of cardiac arrest or intubation is low, all invasive procedures carry these risks to some degree.^2,3 Some HCPs advocate the automatic discontinuation of DNR orders before any procedure, but multiple professional societies recommend that patients be included in these discussions to honor their wishes.^4-7 Although no procedures at the VA require the suspension of a DNR status, it is important to establish which life-sustaining measures are acceptable to patients.

As part of the informed consent process, proceduralists (HCPs who perform a procedure) should discuss the option of temporary suspension of DNR in the periprocedural period and document the outcome of this discussion (eg, rescinded DNR, acknowledgment of continued DNR status). These discussions need to be documented clearly to ensure accurate communication with other HCPs, particularly those caring for the patient postprocedure. Without the documentation, the risk that the patient’s wishes will not be honored is high.⁸ Code status is usually addressed before intubation of general anesthesia; however, nonsurgical procedures have a lower likelihood of DNR acknowledgment.

Methods

This was a single center, before/after quasi-experimental study. The study was considered clinical operations and institutional review board approval was unnecessary.

A retrospective chart review was performed of patients who underwent an inpatient or outpatient, nonsurgical invasive procedure at the Minneapolis VA Medical Center in Minnesota. The preintervention period was defined as the first 6 months after implementation of the LSTDI between May 8, 2018 and October 31, 2018. The intervention was presented in December 2018 and January 2019. The postintervention period was from February 1, 2019 to April 30, 2019.

Patients who underwent a nonsurgical invasive procedure were reviewed in 3 procedural areas. These areas were chosen based on high patient volumes and the need for rapid patient turnover, including gastroenterology, cardiology, and interventional radiology. An invasive procedure was defined as any procedure requiring patient consent. Those patients who had a completed LST note and who had a DNR order were recorded.

Outcomes

The primary outcome of the study was proceduralist acknowledgment of DNR status before nonsurgical invasive procedures. DNR status was considered acknowledged if the proceduralist provided any type of documentation.

Statistical Analysis

Model predicted percentages of DNR acknowledgment are reported from a logistic regression model with both procedural area, time (before vs after) and the interaction between these 2 variables in the model. The simple main effects comparing before vs after within the procedural area based on post hoc contrasts of the interaction term also are shown.

Results

During the first 6 months following LSTDI implementation (the preintervention phase), 5,362 invasive procedures were performed in gastroenterology, interventional radiology, and cardiology. A total of 211 procedures were performed on patients who had a prior LST note indicating DNR. Of those, 68 (32.2%) had documentation acknowledging their DNR status. The educational presentation was given to each of the 3 departments with about 75% faculty attendance in each department. After the intervention, 1,932 invasive procedures were performed, identifying 143 LST notes with a DNR status. Sixty-five (45.5%) had documentation of a discussion regarding their DNR status.

The interaction between procedural areas and time (before, after) was examined. Of the 3 procedural areas, only interventional radiology had significant differences before vs after, 7.5% vs 26.3%, respectively (P = .01). Model-adjusted percentages before vs after for cardiology were 75.6% vs 91.7% (P = .12) and for gastroenterology were 46% vs 53.5% (P = .40) (Table). When all 3 procedural areas were combined, there was a significant improvement in the overall percentage of DNR acknowledgment postintervention from 38.6% to 61.1.% (P = .01).

Discussion

With the LSTDI, DNR orders remain in place and are valid in the inpatient and outpatient setting until reversed by the patient. This creates new challenges for proceduralists. Before our intervention, only about one-third of proceduralists’ recognized DNR status before procedures. This low rate of preprocedural DNR acknowledgments is not unique to the VA. A pilot study assessing rate of documentation of code status discussions in patients undergoing venting gastrostomy tube for malignant bowel obstruction showed documentation in only 22% of cases before the procedure.¹⁰ Another simulation-based study of anesthesiologist showed only 57% of subjects addressed resuscitation before starting the procedure.¹¹

Despite the low initial rates of DNR acknowledgment, our intervention successfully improved these rates, although with variation between procedural areas. Prior studies looking at improving adherence to guidelines have shown the benefit of physician education.^12,13 Improving code status acknowledgment before an invasive procedure not only involves increasing awareness of a preexisting code status, but also developing a system to incorporate the documentation process efficiently into the procedural workflow and ensuring that providers are aware of the appropriate process. Although the largest improvement was in interventional radiology, many patients postintervention still did not have their DNR orders acknowledged. Confusion is created when the patient is cared for by a different HCP or when the resuscitation team is called during a cardiac arrest. Cardiopulmonary resuscitation may be started or withheld incorrectly if the patient’s most recent wishes for resuscitation are unclear.¹⁴

Limitations

Our single-center results may not be generalizable. Although the interaction between procedural area and time was tested, it is possible that improvement in DNR acknowledgment was attributable to secular trends and not the intervention. Other limitations included the decreased generalizability of a VA health care initiative and its unique electronic health record, incomplete attendance rates at our educational sessions, and a lack of patient-centered outcomes.

Conclusions

A templated addendum combined with targeted staff education improved the percentage of DNR acknowledgments before nonsurgical invasive procedures, an important step in establishing patient preferences for life-sustaining treatment in procedures with potential complications. Further research is needed to assess whether these improvements also lead to improved patient-centered outcomes.

Acknowledgments

The authors would like to acknowledge the invaluable help of Dr. Kathryn Rice and Dr. Anne Melzer for their guidance in the manuscript revision process

In January 2017, the US Department of Veterans Affairs (VA), led by the National Center of Ethics in Health Care, created the Life-Sustaining Treatment Decisions Initiative (LSTDI). The VA gradually implemented the LSTDI in its facilities nationwide. In a format similar to the standardized form of portable medical orders, provider orders for life-sustaining treatments (POLST), the initiative promotes discussions with veterans and encourages but does not require health care professionals (HCPs) to complete a template for documentation (life-sustaining treatment [LST] note) of a patient’s preferences.¹ The HCP enters a code status into the electronic health record (EHR), creating a portable and durable note and order.

With a new durable code status, the HCPs performing these procedures (eg, colonoscopies, coronary catheterization, or percutaneous biopsies) need to acknowledge and can potentially rescind a do not resuscitate (DNR) order. Although the risk of cardiac arrest or intubation is low, all invasive procedures carry these risks to some degree.^2,3 Some HCPs advocate the automatic discontinuation of DNR orders before any procedure, but multiple professional societies recommend that patients be included in these discussions to honor their wishes.^4-7 Although no procedures at the VA require the suspension of a DNR status, it is important to establish which life-sustaining measures are acceptable to patients.

As part of the informed consent process, proceduralists (HCPs who perform a procedure) should discuss the option of temporary suspension of DNR in the periprocedural period and document the outcome of this discussion (eg, rescinded DNR, acknowledgment of continued DNR status). These discussions need to be documented clearly to ensure accurate communication with other HCPs, particularly those caring for the patient postprocedure. Without the documentation, the risk that the patient’s wishes will not be honored is high.⁸ Code status is usually addressed before intubation of general anesthesia; however, nonsurgical procedures have a lower likelihood of DNR acknowledgment.

Methods

This was a single center, before/after quasi-experimental study. The study was considered clinical operations and institutional review board approval was unnecessary.

A retrospective chart review was performed of patients who underwent an inpatient or outpatient, nonsurgical invasive procedure at the Minneapolis VA Medical Center in Minnesota. The preintervention period was defined as the first 6 months after implementation of the LSTDI between May 8, 2018 and October 31, 2018. The intervention was presented in December 2018 and January 2019. The postintervention period was from February 1, 2019 to April 30, 2019.

Patients who underwent a nonsurgical invasive procedure were reviewed in 3 procedural areas. These areas were chosen based on high patient volumes and the need for rapid patient turnover, including gastroenterology, cardiology, and interventional radiology. An invasive procedure was defined as any procedure requiring patient consent. Those patients who had a completed LST note and who had a DNR order were recorded.

Outcomes

The primary outcome of the study was proceduralist acknowledgment of DNR status before nonsurgical invasive procedures. DNR status was considered acknowledged if the proceduralist provided any type of documentation.

Statistical Analysis

Model predicted percentages of DNR acknowledgment are reported from a logistic regression model with both procedural area, time (before vs after) and the interaction between these 2 variables in the model. The simple main effects comparing before vs after within the procedural area based on post hoc contrasts of the interaction term also are shown.

Results

During the first 6 months following LSTDI implementation (the preintervention phase), 5,362 invasive procedures were performed in gastroenterology, interventional radiology, and cardiology. A total of 211 procedures were performed on patients who had a prior LST note indicating DNR. Of those, 68 (32.2%) had documentation acknowledging their DNR status. The educational presentation was given to each of the 3 departments with about 75% faculty attendance in each department. After the intervention, 1,932 invasive procedures were performed, identifying 143 LST notes with a DNR status. Sixty-five (45.5%) had documentation of a discussion regarding their DNR status.

The interaction between procedural areas and time (before, after) was examined. Of the 3 procedural areas, only interventional radiology had significant differences before vs after, 7.5% vs 26.3%, respectively (P = .01). Model-adjusted percentages before vs after for cardiology were 75.6% vs 91.7% (P = .12) and for gastroenterology were 46% vs 53.5% (P = .40) (Table). When all 3 procedural areas were combined, there was a significant improvement in the overall percentage of DNR acknowledgment postintervention from 38.6% to 61.1.% (P = .01).

Discussion

With the LSTDI, DNR orders remain in place and are valid in the inpatient and outpatient setting until reversed by the patient. This creates new challenges for proceduralists. Before our intervention, only about one-third of proceduralists’ recognized DNR status before procedures. This low rate of preprocedural DNR acknowledgments is not unique to the VA. A pilot study assessing rate of documentation of code status discussions in patients undergoing venting gastrostomy tube for malignant bowel obstruction showed documentation in only 22% of cases before the procedure.¹⁰ Another simulation-based study of anesthesiologist showed only 57% of subjects addressed resuscitation before starting the procedure.¹¹

Despite the low initial rates of DNR acknowledgment, our intervention successfully improved these rates, although with variation between procedural areas. Prior studies looking at improving adherence to guidelines have shown the benefit of physician education.^12,13 Improving code status acknowledgment before an invasive procedure not only involves increasing awareness of a preexisting code status, but also developing a system to incorporate the documentation process efficiently into the procedural workflow and ensuring that providers are aware of the appropriate process. Although the largest improvement was in interventional radiology, many patients postintervention still did not have their DNR orders acknowledged. Confusion is created when the patient is cared for by a different HCP or when the resuscitation team is called during a cardiac arrest. Cardiopulmonary resuscitation may be started or withheld incorrectly if the patient’s most recent wishes for resuscitation are unclear.¹⁴

Limitations

Our single-center results may not be generalizable. Although the interaction between procedural area and time was tested, it is possible that improvement in DNR acknowledgment was attributable to secular trends and not the intervention. Other limitations included the decreased generalizability of a VA health care initiative and its unique electronic health record, incomplete attendance rates at our educational sessions, and a lack of patient-centered outcomes.

Conclusions

A templated addendum combined with targeted staff education improved the percentage of DNR acknowledgments before nonsurgical invasive procedures, an important step in establishing patient preferences for life-sustaining treatment in procedures with potential complications. Further research is needed to assess whether these improvements also lead to improved patient-centered outcomes.

Acknowledgments

The authors would like to acknowledge the invaluable help of Dr. Kathryn Rice and Dr. Anne Melzer for their guidance in the manuscript revision process

In January 2017, the US Department of Veterans Affairs (VA), led by the National Center of Ethics in Health Care, created the Life-Sustaining Treatment Decisions Initiative (LSTDI). The VA gradually implemented the LSTDI in its facilities nationwide. In a format similar to the standardized form of portable medical orders, provider orders for life-sustaining treatments (POLST), the initiative promotes discussions with veterans and encourages but does not require health care professionals (HCPs) to complete a template for documentation (life-sustaining treatment [LST] note) of a patient’s preferences.¹ The HCP enters a code status into the electronic health record (EHR), creating a portable and durable note and order.

With a new durable code status, the HCPs performing these procedures (eg, colonoscopies, coronary catheterization, or percutaneous biopsies) need to acknowledge and can potentially rescind a do not resuscitate (DNR) order. Although the risk of cardiac arrest or intubation is low, all invasive procedures carry these risks to some degree.^2,3 Some HCPs advocate the automatic discontinuation of DNR orders before any procedure, but multiple professional societies recommend that patients be included in these discussions to honor their wishes.^4-7 Although no procedures at the VA require the suspension of a DNR status, it is important to establish which life-sustaining measures are acceptable to patients.

As part of the informed consent process, proceduralists (HCPs who perform a procedure) should discuss the option of temporary suspension of DNR in the periprocedural period and document the outcome of this discussion (eg, rescinded DNR, acknowledgment of continued DNR status). These discussions need to be documented clearly to ensure accurate communication with other HCPs, particularly those caring for the patient postprocedure. Without the documentation, the risk that the patient’s wishes will not be honored is high.⁸ Code status is usually addressed before intubation of general anesthesia; however, nonsurgical procedures have a lower likelihood of DNR acknowledgment.

Methods

This was a single center, before/after quasi-experimental study. The study was considered clinical operations and institutional review board approval was unnecessary.

A retrospective chart review was performed of patients who underwent an inpatient or outpatient, nonsurgical invasive procedure at the Minneapolis VA Medical Center in Minnesota. The preintervention period was defined as the first 6 months after implementation of the LSTDI between May 8, 2018 and October 31, 2018. The intervention was presented in December 2018 and January 2019. The postintervention period was from February 1, 2019 to April 30, 2019.

Patients who underwent a nonsurgical invasive procedure were reviewed in 3 procedural areas. These areas were chosen based on high patient volumes and the need for rapid patient turnover, including gastroenterology, cardiology, and interventional radiology. An invasive procedure was defined as any procedure requiring patient consent. Those patients who had a completed LST note and who had a DNR order were recorded.

Outcomes

The primary outcome of the study was proceduralist acknowledgment of DNR status before nonsurgical invasive procedures. DNR status was considered acknowledged if the proceduralist provided any type of documentation.

Statistical Analysis

Model predicted percentages of DNR acknowledgment are reported from a logistic regression model with both procedural area, time (before vs after) and the interaction between these 2 variables in the model. The simple main effects comparing before vs after within the procedural area based on post hoc contrasts of the interaction term also are shown.

Results

During the first 6 months following LSTDI implementation (the preintervention phase), 5,362 invasive procedures were performed in gastroenterology, interventional radiology, and cardiology. A total of 211 procedures were performed on patients who had a prior LST note indicating DNR. Of those, 68 (32.2%) had documentation acknowledging their DNR status. The educational presentation was given to each of the 3 departments with about 75% faculty attendance in each department. After the intervention, 1,932 invasive procedures were performed, identifying 143 LST notes with a DNR status. Sixty-five (45.5%) had documentation of a discussion regarding their DNR status.

The interaction between procedural areas and time (before, after) was examined. Of the 3 procedural areas, only interventional radiology had significant differences before vs after, 7.5% vs 26.3%, respectively (P = .01). Model-adjusted percentages before vs after for cardiology were 75.6% vs 91.7% (P = .12) and for gastroenterology were 46% vs 53.5% (P = .40) (Table). When all 3 procedural areas were combined, there was a significant improvement in the overall percentage of DNR acknowledgment postintervention from 38.6% to 61.1.% (P = .01).

Discussion

With the LSTDI, DNR orders remain in place and are valid in the inpatient and outpatient setting until reversed by the patient. This creates new challenges for proceduralists. Before our intervention, only about one-third of proceduralists’ recognized DNR status before procedures. This low rate of preprocedural DNR acknowledgments is not unique to the VA. A pilot study assessing rate of documentation of code status discussions in patients undergoing venting gastrostomy tube for malignant bowel obstruction showed documentation in only 22% of cases before the procedure.¹⁰ Another simulation-based study of anesthesiologist showed only 57% of subjects addressed resuscitation before starting the procedure.¹¹

Despite the low initial rates of DNR acknowledgment, our intervention successfully improved these rates, although with variation between procedural areas. Prior studies looking at improving adherence to guidelines have shown the benefit of physician education.^12,13 Improving code status acknowledgment before an invasive procedure not only involves increasing awareness of a preexisting code status, but also developing a system to incorporate the documentation process efficiently into the procedural workflow and ensuring that providers are aware of the appropriate process. Although the largest improvement was in interventional radiology, many patients postintervention still did not have their DNR orders acknowledged. Confusion is created when the patient is cared for by a different HCP or when the resuscitation team is called during a cardiac arrest. Cardiopulmonary resuscitation may be started or withheld incorrectly if the patient’s most recent wishes for resuscitation are unclear.¹⁴

Limitations

Our single-center results may not be generalizable. Although the interaction between procedural area and time was tested, it is possible that improvement in DNR acknowledgment was attributable to secular trends and not the intervention. Other limitations included the decreased generalizability of a VA health care initiative and its unique electronic health record, incomplete attendance rates at our educational sessions, and a lack of patient-centered outcomes.

Conclusions

A templated addendum combined with targeted staff education improved the percentage of DNR acknowledgments before nonsurgical invasive procedures, an important step in establishing patient preferences for life-sustaining treatment in procedures with potential complications. Further research is needed to assess whether these improvements also lead to improved patient-centered outcomes.

Acknowledgments

The authors would like to acknowledge the invaluable help of Dr. Kathryn Rice and Dr. Anne Melzer for their guidance in the manuscript revision process

Best practices for managing cancer outpatients continue to evolve during the COVID-19 pandemic, with recent innovations in technology, operations, and communication.

“We’ve tried a lot of new things to ensure optimal care for our patients,” said Tiffany A. Traina, MD, of Memorial Sloan Kettering Cancer Center (MSKCC) in New York. “We need to effectively utilize all resources at our disposal to keep in touch with our patients during this time.”

Dr. Traina described the approach to outpatient management used at MSKCC during a presentation at the AACR Virtual Meeting: COVID-19 and Cancer.
 

Four guiding principles

MSKCC has established four guiding principles on how to manage cancer patients during the pandemic: openness, safety, technology, and staffing.

Openness ensures that decisions are guided by clinical priorities to provide optimal patient care and allow for prioritization of clinical research and education, Dr. Traina said.

The safety of patients and staff is of the utmost importance, she added. To ensure safety in the context of outpatient care, several operational levers were developed, including COVID surge planning, universal masking and personal protective equipment guidelines, remote work, clinical levers, and new dashboards and communications.

Dr. Traina said data analytics and dashboards have been key technological tools used to support evidence-based decision-making and deliver care remotely for patients during the pandemic.

Staffing resources have also shifted to support demand at different health system locations.
 

Screening, cohorting, and telemedicine

One measure MSKCC adopted is the MSK Engage Questionnaire, a COVID-19 screening questionnaire assigned to every patient with a scheduled outpatient visit. After completing the questionnaire, patients receive a response denoting whether they need to come into the outpatient setting.

On the staffing side, clinic coordinators prepare appointments accordingly, based on the risk level for each patient.

“We also try to cohort COVID-positive patients into particular areas within the outpatient setting,” Dr. Traina explained. “In addition, we control flow through ambulatory care locations by having separate patient entrances and use other tools to make flow as efficient as possible.”

On the technology side, interactive dashboards are being used to model traffic through different buildings.

“These data and analytics are useful for operational engineering, answering questions such as (1) Are there backups in chemotherapy? and (2) Are patients seeing one particular physician?” Dr. Traina explained. “One important key takeaway is the importance of frequently communicating simple messages through multiple mechanisms, including signage, websites, and dedicated resources.”

Other key technological measures are leveraging telemedicine to convert inpatient appointments to a virtual setting, as well as developing and deploying a system for centralized outpatient follow-up of COVID-19-positive patients.

“We saw a 3,000% increase in telemedicine utilization from February 2020 to June 2020,” Dr. Traina reported. “In a given month, we have approximately 230,000 outpatient visits, and a substantial proportion of these are now done via telemedicine.”

Dr. Traina also noted that multiple organizations have released guidelines addressing when to resume anticancer therapy in patients who have been COVID-19 positive. Adherence is important, as unnecessary COVID-19 testing may delay cancer therapy and is not recommended.

During a live discussion, Louis P. Voigt, MD, of MSKCC, said Dr. Traina’s presentation provided “a lot of good ideas for other institutions who may be facing similar challenges.”

Dr. Traina and Dr. Voigt disclosed no conflicts of interest. No funding sources were reported.

Best practices for managing cancer outpatients continue to evolve during the COVID-19 pandemic, with recent innovations in technology, operations, and communication.

“We’ve tried a lot of new things to ensure optimal care for our patients,” said Tiffany A. Traina, MD, of Memorial Sloan Kettering Cancer Center (MSKCC) in New York. “We need to effectively utilize all resources at our disposal to keep in touch with our patients during this time.”

Dr. Traina described the approach to outpatient management used at MSKCC during a presentation at the AACR Virtual Meeting: COVID-19 and Cancer.
 

Four guiding principles

MSKCC has established four guiding principles on how to manage cancer patients during the pandemic: openness, safety, technology, and staffing.

Openness ensures that decisions are guided by clinical priorities to provide optimal patient care and allow for prioritization of clinical research and education, Dr. Traina said.

The safety of patients and staff is of the utmost importance, she added. To ensure safety in the context of outpatient care, several operational levers were developed, including COVID surge planning, universal masking and personal protective equipment guidelines, remote work, clinical levers, and new dashboards and communications.

Dr. Traina said data analytics and dashboards have been key technological tools used to support evidence-based decision-making and deliver care remotely for patients during the pandemic.

Staffing resources have also shifted to support demand at different health system locations.
 

Screening, cohorting, and telemedicine

One measure MSKCC adopted is the MSK Engage Questionnaire, a COVID-19 screening questionnaire assigned to every patient with a scheduled outpatient visit. After completing the questionnaire, patients receive a response denoting whether they need to come into the outpatient setting.

On the staffing side, clinic coordinators prepare appointments accordingly, based on the risk level for each patient.

“We also try to cohort COVID-positive patients into particular areas within the outpatient setting,” Dr. Traina explained. “In addition, we control flow through ambulatory care locations by having separate patient entrances and use other tools to make flow as efficient as possible.”

On the technology side, interactive dashboards are being used to model traffic through different buildings.

“These data and analytics are useful for operational engineering, answering questions such as (1) Are there backups in chemotherapy? and (2) Are patients seeing one particular physician?” Dr. Traina explained. “One important key takeaway is the importance of frequently communicating simple messages through multiple mechanisms, including signage, websites, and dedicated resources.”

Other key technological measures are leveraging telemedicine to convert inpatient appointments to a virtual setting, as well as developing and deploying a system for centralized outpatient follow-up of COVID-19-positive patients.

“We saw a 3,000% increase in telemedicine utilization from February 2020 to June 2020,” Dr. Traina reported. “In a given month, we have approximately 230,000 outpatient visits, and a substantial proportion of these are now done via telemedicine.”

Dr. Traina also noted that multiple organizations have released guidelines addressing when to resume anticancer therapy in patients who have been COVID-19 positive. Adherence is important, as unnecessary COVID-19 testing may delay cancer therapy and is not recommended.

During a live discussion, Louis P. Voigt, MD, of MSKCC, said Dr. Traina’s presentation provided “a lot of good ideas for other institutions who may be facing similar challenges.”

Dr. Traina and Dr. Voigt disclosed no conflicts of interest. No funding sources were reported.

Best practices for managing cancer outpatients continue to evolve during the COVID-19 pandemic, with recent innovations in technology, operations, and communication.

“We’ve tried a lot of new things to ensure optimal care for our patients,” said Tiffany A. Traina, MD, of Memorial Sloan Kettering Cancer Center (MSKCC) in New York. “We need to effectively utilize all resources at our disposal to keep in touch with our patients during this time.”

Dr. Traina described the approach to outpatient management used at MSKCC during a presentation at the AACR Virtual Meeting: COVID-19 and Cancer.
 

Four guiding principles

MSKCC has established four guiding principles on how to manage cancer patients during the pandemic: openness, safety, technology, and staffing.

Openness ensures that decisions are guided by clinical priorities to provide optimal patient care and allow for prioritization of clinical research and education, Dr. Traina said.

The safety of patients and staff is of the utmost importance, she added. To ensure safety in the context of outpatient care, several operational levers were developed, including COVID surge planning, universal masking and personal protective equipment guidelines, remote work, clinical levers, and new dashboards and communications.

Dr. Traina said data analytics and dashboards have been key technological tools used to support evidence-based decision-making and deliver care remotely for patients during the pandemic.

Staffing resources have also shifted to support demand at different health system locations.
 

Screening, cohorting, and telemedicine

One measure MSKCC adopted is the MSK Engage Questionnaire, a COVID-19 screening questionnaire assigned to every patient with a scheduled outpatient visit. After completing the questionnaire, patients receive a response denoting whether they need to come into the outpatient setting.

On the staffing side, clinic coordinators prepare appointments accordingly, based on the risk level for each patient.

“We also try to cohort COVID-positive patients into particular areas within the outpatient setting,” Dr. Traina explained. “In addition, we control flow through ambulatory care locations by having separate patient entrances and use other tools to make flow as efficient as possible.”

On the technology side, interactive dashboards are being used to model traffic through different buildings.

“These data and analytics are useful for operational engineering, answering questions such as (1) Are there backups in chemotherapy? and (2) Are patients seeing one particular physician?” Dr. Traina explained. “One important key takeaway is the importance of frequently communicating simple messages through multiple mechanisms, including signage, websites, and dedicated resources.”

Other key technological measures are leveraging telemedicine to convert inpatient appointments to a virtual setting, as well as developing and deploying a system for centralized outpatient follow-up of COVID-19-positive patients.

“We saw a 3,000% increase in telemedicine utilization from February 2020 to June 2020,” Dr. Traina reported. “In a given month, we have approximately 230,000 outpatient visits, and a substantial proportion of these are now done via telemedicine.”

Dr. Traina also noted that multiple organizations have released guidelines addressing when to resume anticancer therapy in patients who have been COVID-19 positive. Adherence is important, as unnecessary COVID-19 testing may delay cancer therapy and is not recommended.

During a live discussion, Louis P. Voigt, MD, of MSKCC, said Dr. Traina’s presentation provided “a lot of good ideas for other institutions who may be facing similar challenges.”

Dr. Traina and Dr. Voigt disclosed no conflicts of interest. No funding sources were reported.

Patients with complex medical and psychosocial needs are at the highest risk for fragmented care and adverse health outcomes.^1,2 Although these high-risk patients make up only about 5% of the US patient population, they can account for as much as half of total health care costs.¹ High-risk patients are complicated to treat because most have multiple chronic medical conditions, and many have a wide variety of psychological and social needs. Thus, physician, physician assistant, and nurse practitioner primary care providers (PCPs), and nurses (registered nurses, licensed vocational nurses, and licensed practical nurses) must address the complexity of the human condition in conjunction with health problems.²

Background

Caring for high-risk patients within a tight clinic schedule geared to the provision of comprehensive care to large panels of less complex patients can be a source of stress for PCPs and nurses.^3-5 These conditions may lead to reduced well-being among primary care team members and to potential turnover.⁶ Furthermore, primary care staff may feel uncomfortable or lack the ability to address nonmedical concerns because of “person-specific factors that interfere with the delivery of usual care and decision making for whatever condition the patient has.”^7,8 Having additional support for complex patients, such as intensive outpatient management teams, may be protective both by reducing health care provider (HCP) stress and improving patient outcomes.^3,4

Caring for high-risk patients is challenging.^9-11 High-risk patient care may require additional, often unpaid, work hoursand may be discouraging because these patients can be difficult to engage in care.^7,12 Furthermore, high-risk patient care is challenging for primary care teams, since these complex patients may fall through the cracks and experience potentially preventable hospitalization or even death. Avoiding these negative consequences typically requires substantial time for the primary care team to engage and counsel the patient, family, and caregiver, through more frequent visits and additional communication. Furthermore, the primary care team typically must coordinate with other HCPs and resources—as many as 16 in a single year and as much as 12 for a single patient over an 80-day period.^13,14 Not surprisingly, primary care teams identify help with care coordination as a critical need that may be addressed with intensive management support.

Primary care at the US Department of Veterans Affairs (VA) Veterans Health Administration (VHA) provides care for a large proportion of high-risk patients.¹⁵ Accordingly, VHA provides a variety of intensive management options for equipping primary care teams with expanded resources for caring for high-risk patients, including those offered in a few sites by a pilot intensive management program.¹⁶ As part of the pilot’s evaluation, we studied the work experiences of PCPs and nurses, some of whom had experienced the pilot program and some of whom only had access to typical VHA intensive management resources, such as telehealth and specialty medical homes (referred to in the VA as patient aligned care teams, or PACT), eg, for women patients, for patients who are homeless, or for older adults.¹⁷ Surveys assessed whether HCPs who indicated they were likely to seek help from PACT intensive management (PIM) teams to care for high-risk patients had higher job satisfaction and intention to stay at VHA compared with those who were not likely to seek help.

While substantial research on high-risk patients’ intensive management needs has focused on patient-level outcomes of interventions for meeting those needs,little research has examined links between primary care team access to intensive management resources and experiences, such as job satisfaction and job retention.¹⁸ In the work presented here, our objectives were to (1) assess the likelihood that a PCP or nurse intent to manage high-risk patients by seeking care coordination help from or transferring care to an intensive management team; and (2) evaluate the relationship between PCP or nurse intentions regarding using intensive management help for high-risk patients and their job satisfaction and likelihood of leaving VA primary care. We hypothesized that the accessibility of intensive management resources and PCP and nurse receptivity to accessing those resources may affect job-related experiences.

Methods

This study was conducted as part of the evaluation of a VA pilot project to provide general primary care teams with intensive management support from interdisciplinary teams for high-risk patients in 5 VHA systems in 5 states (Ohio, Georgia, North Carolina, Wisconsin, and California).⁶ We sampled primary care staff at 39 primary care clinics within those systems, all of whom had access to VA intensive management resources. These included telehealth, health coaches, integrated mental health providers, and specialty PACTs for specific populations (eg, those who are women, elderly, homeless, HIV-positive, or who have serious mental illness). Of the 39 primary care clinics that participated in the survey, 8 also participated in the pilot program offering an intensive management team to support general primary care in their care of high-risk patients.

Data are from PCPs and nurses who completed 2 cross-sectional surveys (online or hard copy). We invited 1,000 PCPs and nurses to complete the first survey (fielded December 2014 to May 2015) and 863 to complete the second survey (fielded October 2016 to January 2017). A total of 436 completed the first survey for a response rate of 44%, and 313 completed the second survey for a response rate of 36%. We constructed a longitudinal cohort of 144 PCPs and nurses who completed both surveys and had data at 2 timepoints. This longitudinal cohort represents 33% of the 442 unique respondents who completed either the first or second survey. Overlap across surveys was low because of high staff turnover between survey waves.

Measures

Outcomes. We examined 2 single-item outcome measures to assess job satisfaction and retention (ie, intent to stay in primary care at the VA) measured in both surveys. These items were worded “Overall, I am satisfied with my job.” and “I intend to continue working in primary care at the VA for the next two years.” Both items were rated on a 5-point Likert scale.

Independent Variable. We assessed proclivity to seek assistance in caring for high-risk patients based on PCPs or nurses indicating that they are likely to either “manage these patients with ongoing care coordination assistance from an intensive management team” and/or “transfer these patients from primary care to another intensive management team or program specializing in high-risk patients.” These 2 items were rated on a 5-point Likert scale; we dichotomized the scale with likely or very likely indicating high proclivity (likelihood) for ease of interpretation of the combined items.

Covariates. We also controlled for indicators of staff demographic and practice characteristics in multivariate analyses. These included gender, staff type (PCP vs nurse), years practicing at a VA clinic, team staffing level (full vs partial), proportion of the panel consisting of high-risk patients (using binary indicators: 11 to 20% or > 20% compared with 0 to 10% as the reference group), and whether or not the site participated in the pilot program offering an intensive management team to support primary care for high-risk patients to distinguish the 8 pilot sites from nonpilot sites.

Statistical Analysis

We used ordinary least squares regression analysis to examine associations between the independent variable measured at time 1 and outcomes measured at time 2, controlling for time 1 outcomes among staff who completed both surveys (eg, the longitudinal cohort). We adjusted for time 1 covariates and clustering of staff within clinics, assuming a random effect with robust standard errors, and conducted multiple imputations for item-level missing data. Poststratification weights were used to adjust for survey nonresponse by staff type, gender, facilities participating in the innovations, and type of specialty PACT. We calculated weights based on the sampling frame of all PCPs and nurses for each survey.

Results

Table 1 shows the proportion of primary care staff responding to the surveys. For the longitudinal cohort, the response by staff type was similar to the sample of staff that responded only to a single survey, but the sample that did not respond to either survey included more physicians. There was also some variation by medical center. For example, a smaller proportion of the cohort was from site D and more was from site E compared with the other samples. The proportion of primary care staff in facilities that participated in the intensive management pilot was higher than the proportion in other facilities. More women (81.9%) were in the longitudinal cohort compared with 77.4% in the single-survey sample and 69.2% in the sample that responded to neither survey.

Both surveys were completed by 144 respondents while 442 completed 1 survey and 645 did not respond to either survey. The cohort was predominantly nurses (64.6%); Of the PCPs, 25% were physicians. Most staff were women (81.9%) and aged > 45 years (72.2%). Staff had practiced at their current VA clinics for a mean of 7.4 years, and most reported being on a fully-staffed primary care team (70%).

Multivariate Analyses

In the multivariable regression analyses, we found that the primary care staff, which reported being more likely to use intensive management teams to help care for high-risk patients at time 1, reported significantly higher satisfaction (0.63 points higher on a 5-point scale) and intention to stay (0.41 points higher) at VA primary care (both P < .05) at time 2, 18 months later (Table 2). These effect sizes are equivalent to nearly two-thirds and half of a standard deviation, respectively. Among our control variables, years practicing in the VA was significantly associated with a lower likelihood of intent to stay at the VA. Models account for 28% of the variation in satisfaction and 22% of the variation in retention. The Figure shows the adjusted means based on parameters from the regression models for job satisfaction and intent to stay at the VA as well as likelihood of using an intensive management team for high-risk patients. Job satisfaction is nearly 1 point higher among those who report being likely to draw on support from an intensive management team to care for high-risk patients compared with those who reported that they were unlikely to use such a team. The pattern for intent to stay at the VA, while less pronounced, is similar to that for satisfaction.

Discussion

Our findings are consistent with our hypothesis that augmenting primary care with high-risk patient intensive management assistance would improve primary care staff job satisfaction and retention. Findings also mirror recent qualitative studies, which have found that systemic approaches to augment primary care of high-risk patients are likely needed to maintain well-being.^7,19 We found a positive relationship between the likelihood of using intensive management teams to help care for their high-risk patients and reported job satisfaction and intent to continue to work within VA primary care 18 months later. To our knowledge, this study is the first to examine the potential impact on PCPs and nurses of using intensive management teams to help care for high-risk patients.

Our study suggests that this approach has the potential to alleviate PCP and nurse stress by incorporating intensive management teams as an extension of the medical home. Even high-functioning medical homes may find it challenging to meet the needs of their high-risk patients.^3,7,8 Time constraints and a structured clinic schedule may limit the ability of medical homes to balance the needs of the general panel vs the individual needs of high-risk patients who might benefit from intensive services. Limited knowledge and lack of training to address the broad array of problems faced by high-risk patients also makes care challenging.²

Intensive management services often include interdisciplinary and comprehensive assessments, care coordination, health care system navigation, and linkages to social and home care services.²⁰ Medical homes may benefit from these services, especially resources to support care coordination and communication with specialists and social services in large medical neighborhoods.²¹ For example, including a social worker on the intensive patient care team can help primary care staff by focusing specialized resources on nonmedical issues, such as chronic homelessness, substance use disorders, food insecurity, access to transportation, and poverty.¹⁸

Limitations

This study is subject to some limitations, including those typical of surveys, such as reliance on self-reported data. The longitudinal sample we studied had response rates that varied by site, participation in the pilot program, and gender relative to those who did not respond to both surveys; selection bias is possible. While we use a longitudinal cohort, we cannot attribute causality; it is possible that more satisfied staff are more likely to use intensive management teams rather than the use of intensive management teams contributing to higher satisfaction. Although each study site includes at least 1 type of intensive management resource, we cannot ascertain which intensive management resource primary care staff accessed, if any. While our sample size for the longitudinal cohort responders was limited, focusing on our longitudinal cohort provides more valid and reliable estimates than does using 2 cross-sectional samples with all responders. In addition, our models do not completely explain variation in the outcomes (R²= 0.28 and 0.22), although we included major explanatory factors, such as team staffing and professional type; other unmeasured factors may explain our outcomes. Finally, our provider sample may not generalize to HCPs in non-VA settings.

Conclusions

Our study expands on the limited data regarding the primary care staff experience of caring for high-risk patients and the potential impact of using interdisciplinary assistance to help care for this population. A strength of this study is the longitudinal cohort design that allowed us to understand staff receptivity to having access to intensive management resources to help care for high-risk patients over time among the same group of primary care staff. Given that an economic analysis has determined that the addition of the pilot intensive management program has been cost neutral to the VA, the possibility of its benefit, as suggested by our study findings, would support further implementation and evaluation of intensive management teams as a resource for PCPs caring for high-risk patients.²²

Understanding the mechanisms by which primary care staff benefit most from high-risk patient assistance, and how to optimize communication and coordination between primary care staff and intensive management teams for high-risk patients might further increase primary care satisfaction and retention.

Patients with complex medical and psychosocial needs are at the highest risk for fragmented care and adverse health outcomes.^1,2 Although these high-risk patients make up only about 5% of the US patient population, they can account for as much as half of total health care costs.¹ High-risk patients are complicated to treat because most have multiple chronic medical conditions, and many have a wide variety of psychological and social needs. Thus, physician, physician assistant, and nurse practitioner primary care providers (PCPs), and nurses (registered nurses, licensed vocational nurses, and licensed practical nurses) must address the complexity of the human condition in conjunction with health problems.²

Background

Caring for high-risk patients within a tight clinic schedule geared to the provision of comprehensive care to large panels of less complex patients can be a source of stress for PCPs and nurses.^3-5 These conditions may lead to reduced well-being among primary care team members and to potential turnover.⁶ Furthermore, primary care staff may feel uncomfortable or lack the ability to address nonmedical concerns because of “person-specific factors that interfere with the delivery of usual care and decision making for whatever condition the patient has.”^7,8 Having additional support for complex patients, such as intensive outpatient management teams, may be protective both by reducing health care provider (HCP) stress and improving patient outcomes.^3,4

Caring for high-risk patients is challenging.^9-11 High-risk patient care may require additional, often unpaid, work hoursand may be discouraging because these patients can be difficult to engage in care.^7,12 Furthermore, high-risk patient care is challenging for primary care teams, since these complex patients may fall through the cracks and experience potentially preventable hospitalization or even death. Avoiding these negative consequences typically requires substantial time for the primary care team to engage and counsel the patient, family, and caregiver, through more frequent visits and additional communication. Furthermore, the primary care team typically must coordinate with other HCPs and resources—as many as 16 in a single year and as much as 12 for a single patient over an 80-day period.^13,14 Not surprisingly, primary care teams identify help with care coordination as a critical need that may be addressed with intensive management support.

Primary care at the US Department of Veterans Affairs (VA) Veterans Health Administration (VHA) provides care for a large proportion of high-risk patients.¹⁵ Accordingly, VHA provides a variety of intensive management options for equipping primary care teams with expanded resources for caring for high-risk patients, including those offered in a few sites by a pilot intensive management program.¹⁶ As part of the pilot’s evaluation, we studied the work experiences of PCPs and nurses, some of whom had experienced the pilot program and some of whom only had access to typical VHA intensive management resources, such as telehealth and specialty medical homes (referred to in the VA as patient aligned care teams, or PACT), eg, for women patients, for patients who are homeless, or for older adults.¹⁷ Surveys assessed whether HCPs who indicated they were likely to seek help from PACT intensive management (PIM) teams to care for high-risk patients had higher job satisfaction and intention to stay at VHA compared with those who were not likely to seek help.

While substantial research on high-risk patients’ intensive management needs has focused on patient-level outcomes of interventions for meeting those needs,little research has examined links between primary care team access to intensive management resources and experiences, such as job satisfaction and job retention.¹⁸ In the work presented here, our objectives were to (1) assess the likelihood that a PCP or nurse intent to manage high-risk patients by seeking care coordination help from or transferring care to an intensive management team; and (2) evaluate the relationship between PCP or nurse intentions regarding using intensive management help for high-risk patients and their job satisfaction and likelihood of leaving VA primary care. We hypothesized that the accessibility of intensive management resources and PCP and nurse receptivity to accessing those resources may affect job-related experiences.

Methods

This study was conducted as part of the evaluation of a VA pilot project to provide general primary care teams with intensive management support from interdisciplinary teams for high-risk patients in 5 VHA systems in 5 states (Ohio, Georgia, North Carolina, Wisconsin, and California).⁶ We sampled primary care staff at 39 primary care clinics within those systems, all of whom had access to VA intensive management resources. These included telehealth, health coaches, integrated mental health providers, and specialty PACTs for specific populations (eg, those who are women, elderly, homeless, HIV-positive, or who have serious mental illness). Of the 39 primary care clinics that participated in the survey, 8 also participated in the pilot program offering an intensive management team to support general primary care in their care of high-risk patients.

Data are from PCPs and nurses who completed 2 cross-sectional surveys (online or hard copy). We invited 1,000 PCPs and nurses to complete the first survey (fielded December 2014 to May 2015) and 863 to complete the second survey (fielded October 2016 to January 2017). A total of 436 completed the first survey for a response rate of 44%, and 313 completed the second survey for a response rate of 36%. We constructed a longitudinal cohort of 144 PCPs and nurses who completed both surveys and had data at 2 timepoints. This longitudinal cohort represents 33% of the 442 unique respondents who completed either the first or second survey. Overlap across surveys was low because of high staff turnover between survey waves.

Measures

Outcomes. We examined 2 single-item outcome measures to assess job satisfaction and retention (ie, intent to stay in primary care at the VA) measured in both surveys. These items were worded “Overall, I am satisfied with my job.” and “I intend to continue working in primary care at the VA for the next two years.” Both items were rated on a 5-point Likert scale.

Independent Variable. We assessed proclivity to seek assistance in caring for high-risk patients based on PCPs or nurses indicating that they are likely to either “manage these patients with ongoing care coordination assistance from an intensive management team” and/or “transfer these patients from primary care to another intensive management team or program specializing in high-risk patients.” These 2 items were rated on a 5-point Likert scale; we dichotomized the scale with likely or very likely indicating high proclivity (likelihood) for ease of interpretation of the combined items.

Covariates. We also controlled for indicators of staff demographic and practice characteristics in multivariate analyses. These included gender, staff type (PCP vs nurse), years practicing at a VA clinic, team staffing level (full vs partial), proportion of the panel consisting of high-risk patients (using binary indicators: 11 to 20% or > 20% compared with 0 to 10% as the reference group), and whether or not the site participated in the pilot program offering an intensive management team to support primary care for high-risk patients to distinguish the 8 pilot sites from nonpilot sites.

Statistical Analysis

We used ordinary least squares regression analysis to examine associations between the independent variable measured at time 1 and outcomes measured at time 2, controlling for time 1 outcomes among staff who completed both surveys (eg, the longitudinal cohort). We adjusted for time 1 covariates and clustering of staff within clinics, assuming a random effect with robust standard errors, and conducted multiple imputations for item-level missing data. Poststratification weights were used to adjust for survey nonresponse by staff type, gender, facilities participating in the innovations, and type of specialty PACT. We calculated weights based on the sampling frame of all PCPs and nurses for each survey.

Results

Table 1 shows the proportion of primary care staff responding to the surveys. For the longitudinal cohort, the response by staff type was similar to the sample of staff that responded only to a single survey, but the sample that did not respond to either survey included more physicians. There was also some variation by medical center. For example, a smaller proportion of the cohort was from site D and more was from site E compared with the other samples. The proportion of primary care staff in facilities that participated in the intensive management pilot was higher than the proportion in other facilities. More women (81.9%) were in the longitudinal cohort compared with 77.4% in the single-survey sample and 69.2% in the sample that responded to neither survey.

Both surveys were completed by 144 respondents while 442 completed 1 survey and 645 did not respond to either survey. The cohort was predominantly nurses (64.6%); Of the PCPs, 25% were physicians. Most staff were women (81.9%) and aged > 45 years (72.2%). Staff had practiced at their current VA clinics for a mean of 7.4 years, and most reported being on a fully-staffed primary care team (70%).

Multivariate Analyses

In the multivariable regression analyses, we found that the primary care staff, which reported being more likely to use intensive management teams to help care for high-risk patients at time 1, reported significantly higher satisfaction (0.63 points higher on a 5-point scale) and intention to stay (0.41 points higher) at VA primary care (both P < .05) at time 2, 18 months later (Table 2). These effect sizes are equivalent to nearly two-thirds and half of a standard deviation, respectively. Among our control variables, years practicing in the VA was significantly associated with a lower likelihood of intent to stay at the VA. Models account for 28% of the variation in satisfaction and 22% of the variation in retention. The Figure shows the adjusted means based on parameters from the regression models for job satisfaction and intent to stay at the VA as well as likelihood of using an intensive management team for high-risk patients. Job satisfaction is nearly 1 point higher among those who report being likely to draw on support from an intensive management team to care for high-risk patients compared with those who reported that they were unlikely to use such a team. The pattern for intent to stay at the VA, while less pronounced, is similar to that for satisfaction.

Discussion

Our findings are consistent with our hypothesis that augmenting primary care with high-risk patient intensive management assistance would improve primary care staff job satisfaction and retention. Findings also mirror recent qualitative studies, which have found that systemic approaches to augment primary care of high-risk patients are likely needed to maintain well-being.^7,19 We found a positive relationship between the likelihood of using intensive management teams to help care for their high-risk patients and reported job satisfaction and intent to continue to work within VA primary care 18 months later. To our knowledge, this study is the first to examine the potential impact on PCPs and nurses of using intensive management teams to help care for high-risk patients.

Our study suggests that this approach has the potential to alleviate PCP and nurse stress by incorporating intensive management teams as an extension of the medical home. Even high-functioning medical homes may find it challenging to meet the needs of their high-risk patients.^3,7,8 Time constraints and a structured clinic schedule may limit the ability of medical homes to balance the needs of the general panel vs the individual needs of high-risk patients who might benefit from intensive services. Limited knowledge and lack of training to address the broad array of problems faced by high-risk patients also makes care challenging.²

Intensive management services often include interdisciplinary and comprehensive assessments, care coordination, health care system navigation, and linkages to social and home care services.²⁰ Medical homes may benefit from these services, especially resources to support care coordination and communication with specialists and social services in large medical neighborhoods.²¹ For example, including a social worker on the intensive patient care team can help primary care staff by focusing specialized resources on nonmedical issues, such as chronic homelessness, substance use disorders, food insecurity, access to transportation, and poverty.¹⁸

Limitations

This study is subject to some limitations, including those typical of surveys, such as reliance on self-reported data. The longitudinal sample we studied had response rates that varied by site, participation in the pilot program, and gender relative to those who did not respond to both surveys; selection bias is possible. While we use a longitudinal cohort, we cannot attribute causality; it is possible that more satisfied staff are more likely to use intensive management teams rather than the use of intensive management teams contributing to higher satisfaction. Although each study site includes at least 1 type of intensive management resource, we cannot ascertain which intensive management resource primary care staff accessed, if any. While our sample size for the longitudinal cohort responders was limited, focusing on our longitudinal cohort provides more valid and reliable estimates than does using 2 cross-sectional samples with all responders. In addition, our models do not completely explain variation in the outcomes (R²= 0.28 and 0.22), although we included major explanatory factors, such as team staffing and professional type; other unmeasured factors may explain our outcomes. Finally, our provider sample may not generalize to HCPs in non-VA settings.

Conclusions

Our study expands on the limited data regarding the primary care staff experience of caring for high-risk patients and the potential impact of using interdisciplinary assistance to help care for this population. A strength of this study is the longitudinal cohort design that allowed us to understand staff receptivity to having access to intensive management resources to help care for high-risk patients over time among the same group of primary care staff. Given that an economic analysis has determined that the addition of the pilot intensive management program has been cost neutral to the VA, the possibility of its benefit, as suggested by our study findings, would support further implementation and evaluation of intensive management teams as a resource for PCPs caring for high-risk patients.²²

Understanding the mechanisms by which primary care staff benefit most from high-risk patient assistance, and how to optimize communication and coordination between primary care staff and intensive management teams for high-risk patients might further increase primary care satisfaction and retention.

Patients with complex medical and psychosocial needs are at the highest risk for fragmented care and adverse health outcomes.^1,2 Although these high-risk patients make up only about 5% of the US patient population, they can account for as much as half of total health care costs.¹ High-risk patients are complicated to treat because most have multiple chronic medical conditions, and many have a wide variety of psychological and social needs. Thus, physician, physician assistant, and nurse practitioner primary care providers (PCPs), and nurses (registered nurses, licensed vocational nurses, and licensed practical nurses) must address the complexity of the human condition in conjunction with health problems.²

Background

Caring for high-risk patients within a tight clinic schedule geared to the provision of comprehensive care to large panels of less complex patients can be a source of stress for PCPs and nurses.^3-5 These conditions may lead to reduced well-being among primary care team members and to potential turnover.⁶ Furthermore, primary care staff may feel uncomfortable or lack the ability to address nonmedical concerns because of “person-specific factors that interfere with the delivery of usual care and decision making for whatever condition the patient has.”^7,8 Having additional support for complex patients, such as intensive outpatient management teams, may be protective both by reducing health care provider (HCP) stress and improving patient outcomes.^3,4

Caring for high-risk patients is challenging.^9-11 High-risk patient care may require additional, often unpaid, work hoursand may be discouraging because these patients can be difficult to engage in care.^7,12 Furthermore, high-risk patient care is challenging for primary care teams, since these complex patients may fall through the cracks and experience potentially preventable hospitalization or even death. Avoiding these negative consequences typically requires substantial time for the primary care team to engage and counsel the patient, family, and caregiver, through more frequent visits and additional communication. Furthermore, the primary care team typically must coordinate with other HCPs and resources—as many as 16 in a single year and as much as 12 for a single patient over an 80-day period.^13,14 Not surprisingly, primary care teams identify help with care coordination as a critical need that may be addressed with intensive management support.

Primary care at the US Department of Veterans Affairs (VA) Veterans Health Administration (VHA) provides care for a large proportion of high-risk patients.¹⁵ Accordingly, VHA provides a variety of intensive management options for equipping primary care teams with expanded resources for caring for high-risk patients, including those offered in a few sites by a pilot intensive management program.¹⁶ As part of the pilot’s evaluation, we studied the work experiences of PCPs and nurses, some of whom had experienced the pilot program and some of whom only had access to typical VHA intensive management resources, such as telehealth and specialty medical homes (referred to in the VA as patient aligned care teams, or PACT), eg, for women patients, for patients who are homeless, or for older adults.¹⁷ Surveys assessed whether HCPs who indicated they were likely to seek help from PACT intensive management (PIM) teams to care for high-risk patients had higher job satisfaction and intention to stay at VHA compared with those who were not likely to seek help.

While substantial research on high-risk patients’ intensive management needs has focused on patient-level outcomes of interventions for meeting those needs,little research has examined links between primary care team access to intensive management resources and experiences, such as job satisfaction and job retention.¹⁸ In the work presented here, our objectives were to (1) assess the likelihood that a PCP or nurse intent to manage high-risk patients by seeking care coordination help from or transferring care to an intensive management team; and (2) evaluate the relationship between PCP or nurse intentions regarding using intensive management help for high-risk patients and their job satisfaction and likelihood of leaving VA primary care. We hypothesized that the accessibility of intensive management resources and PCP and nurse receptivity to accessing those resources may affect job-related experiences.

Methods

This study was conducted as part of the evaluation of a VA pilot project to provide general primary care teams with intensive management support from interdisciplinary teams for high-risk patients in 5 VHA systems in 5 states (Ohio, Georgia, North Carolina, Wisconsin, and California).⁶ We sampled primary care staff at 39 primary care clinics within those systems, all of whom had access to VA intensive management resources. These included telehealth, health coaches, integrated mental health providers, and specialty PACTs for specific populations (eg, those who are women, elderly, homeless, HIV-positive, or who have serious mental illness). Of the 39 primary care clinics that participated in the survey, 8 also participated in the pilot program offering an intensive management team to support general primary care in their care of high-risk patients.

Data are from PCPs and nurses who completed 2 cross-sectional surveys (online or hard copy). We invited 1,000 PCPs and nurses to complete the first survey (fielded December 2014 to May 2015) and 863 to complete the second survey (fielded October 2016 to January 2017). A total of 436 completed the first survey for a response rate of 44%, and 313 completed the second survey for a response rate of 36%. We constructed a longitudinal cohort of 144 PCPs and nurses who completed both surveys and had data at 2 timepoints. This longitudinal cohort represents 33% of the 442 unique respondents who completed either the first or second survey. Overlap across surveys was low because of high staff turnover between survey waves.

Measures

Outcomes. We examined 2 single-item outcome measures to assess job satisfaction and retention (ie, intent to stay in primary care at the VA) measured in both surveys. These items were worded “Overall, I am satisfied with my job.” and “I intend to continue working in primary care at the VA for the next two years.” Both items were rated on a 5-point Likert scale.

Independent Variable. We assessed proclivity to seek assistance in caring for high-risk patients based on PCPs or nurses indicating that they are likely to either “manage these patients with ongoing care coordination assistance from an intensive management team” and/or “transfer these patients from primary care to another intensive management team or program specializing in high-risk patients.” These 2 items were rated on a 5-point Likert scale; we dichotomized the scale with likely or very likely indicating high proclivity (likelihood) for ease of interpretation of the combined items.

Covariates. We also controlled for indicators of staff demographic and practice characteristics in multivariate analyses. These included gender, staff type (PCP vs nurse), years practicing at a VA clinic, team staffing level (full vs partial), proportion of the panel consisting of high-risk patients (using binary indicators: 11 to 20% or > 20% compared with 0 to 10% as the reference group), and whether or not the site participated in the pilot program offering an intensive management team to support primary care for high-risk patients to distinguish the 8 pilot sites from nonpilot sites.

Statistical Analysis

We used ordinary least squares regression analysis to examine associations between the independent variable measured at time 1 and outcomes measured at time 2, controlling for time 1 outcomes among staff who completed both surveys (eg, the longitudinal cohort). We adjusted for time 1 covariates and clustering of staff within clinics, assuming a random effect with robust standard errors, and conducted multiple imputations for item-level missing data. Poststratification weights were used to adjust for survey nonresponse by staff type, gender, facilities participating in the innovations, and type of specialty PACT. We calculated weights based on the sampling frame of all PCPs and nurses for each survey.

Results

Table 1 shows the proportion of primary care staff responding to the surveys. For the longitudinal cohort, the response by staff type was similar to the sample of staff that responded only to a single survey, but the sample that did not respond to either survey included more physicians. There was also some variation by medical center. For example, a smaller proportion of the cohort was from site D and more was from site E compared with the other samples. The proportion of primary care staff in facilities that participated in the intensive management pilot was higher than the proportion in other facilities. More women (81.9%) were in the longitudinal cohort compared with 77.4% in the single-survey sample and 69.2% in the sample that responded to neither survey.

Both surveys were completed by 144 respondents while 442 completed 1 survey and 645 did not respond to either survey. The cohort was predominantly nurses (64.6%); Of the PCPs, 25% were physicians. Most staff were women (81.9%) and aged > 45 years (72.2%). Staff had practiced at their current VA clinics for a mean of 7.4 years, and most reported being on a fully-staffed primary care team (70%).

Multivariate Analyses

In the multivariable regression analyses, we found that the primary care staff, which reported being more likely to use intensive management teams to help care for high-risk patients at time 1, reported significantly higher satisfaction (0.63 points higher on a 5-point scale) and intention to stay (0.41 points higher) at VA primary care (both P < .05) at time 2, 18 months later (Table 2). These effect sizes are equivalent to nearly two-thirds and half of a standard deviation, respectively. Among our control variables, years practicing in the VA was significantly associated with a lower likelihood of intent to stay at the VA. Models account for 28% of the variation in satisfaction and 22% of the variation in retention. The Figure shows the adjusted means based on parameters from the regression models for job satisfaction and intent to stay at the VA as well as likelihood of using an intensive management team for high-risk patients. Job satisfaction is nearly 1 point higher among those who report being likely to draw on support from an intensive management team to care for high-risk patients compared with those who reported that they were unlikely to use such a team. The pattern for intent to stay at the VA, while less pronounced, is similar to that for satisfaction.

Discussion

Our findings are consistent with our hypothesis that augmenting primary care with high-risk patient intensive management assistance would improve primary care staff job satisfaction and retention. Findings also mirror recent qualitative studies, which have found that systemic approaches to augment primary care of high-risk patients are likely needed to maintain well-being.^7,19 We found a positive relationship between the likelihood of using intensive management teams to help care for their high-risk patients and reported job satisfaction and intent to continue to work within VA primary care 18 months later. To our knowledge, this study is the first to examine the potential impact on PCPs and nurses of using intensive management teams to help care for high-risk patients.

Our study suggests that this approach has the potential to alleviate PCP and nurse stress by incorporating intensive management teams as an extension of the medical home. Even high-functioning medical homes may find it challenging to meet the needs of their high-risk patients.^3,7,8 Time constraints and a structured clinic schedule may limit the ability of medical homes to balance the needs of the general panel vs the individual needs of high-risk patients who might benefit from intensive services. Limited knowledge and lack of training to address the broad array of problems faced by high-risk patients also makes care challenging.²

Intensive management services often include interdisciplinary and comprehensive assessments, care coordination, health care system navigation, and linkages to social and home care services.²⁰ Medical homes may benefit from these services, especially resources to support care coordination and communication with specialists and social services in large medical neighborhoods.²¹ For example, including a social worker on the intensive patient care team can help primary care staff by focusing specialized resources on nonmedical issues, such as chronic homelessness, substance use disorders, food insecurity, access to transportation, and poverty.¹⁸

Limitations

This study is subject to some limitations, including those typical of surveys, such as reliance on self-reported data. The longitudinal sample we studied had response rates that varied by site, participation in the pilot program, and gender relative to those who did not respond to both surveys; selection bias is possible. While we use a longitudinal cohort, we cannot attribute causality; it is possible that more satisfied staff are more likely to use intensive management teams rather than the use of intensive management teams contributing to higher satisfaction. Although each study site includes at least 1 type of intensive management resource, we cannot ascertain which intensive management resource primary care staff accessed, if any. While our sample size for the longitudinal cohort responders was limited, focusing on our longitudinal cohort provides more valid and reliable estimates than does using 2 cross-sectional samples with all responders. In addition, our models do not completely explain variation in the outcomes (R²= 0.28 and 0.22), although we included major explanatory factors, such as team staffing and professional type; other unmeasured factors may explain our outcomes. Finally, our provider sample may not generalize to HCPs in non-VA settings.

Conclusions

Our study expands on the limited data regarding the primary care staff experience of caring for high-risk patients and the potential impact of using interdisciplinary assistance to help care for this population. A strength of this study is the longitudinal cohort design that allowed us to understand staff receptivity to having access to intensive management resources to help care for high-risk patients over time among the same group of primary care staff. Given that an economic analysis has determined that the addition of the pilot intensive management program has been cost neutral to the VA, the possibility of its benefit, as suggested by our study findings, would support further implementation and evaluation of intensive management teams as a resource for PCPs caring for high-risk patients.²²

Understanding the mechanisms by which primary care staff benefit most from high-risk patient assistance, and how to optimize communication and coordination between primary care staff and intensive management teams for high-risk patients might further increase primary care satisfaction and retention.