ABSTRACT

Purpose To determine the characteristics and clinical course of Rhus dermatitis in patients who seek assistance from primary care clinicians, as well as treatment approaches used by patients and recommended by clinicians, and treatment approaches associated with better outcomes.

Methods This was a prospective cohort study with standardized baseline data collection on patients and their rashes, followed by examination of patient-completed diaries of signs, symptoms, and treatments.

Results Thirty-six clinicians identified 186 interested patients, of which 89 completed and returned diaries and consent forms. Of those 89 patients, 92% reported pruritus; 91%, erythema; 87%, papules; and 49%, vesicles or bullae at baseline. Their rashes involved the head/face/neck, 61%; trunk, 56%; legs, 54%; and arms, 22%.

Patients seeking help for poison ivy can expect the rash to last an additional 2 weeks on average, regardless of the treatment prescribed.From the date of clinical consultation, the mean (standard deviation [SD]; range) duration of any symptom or sign was 14.4 days (8.0; 1-43). Patients most often had tried a topical antipruritic, astringent, or low-potency corticosteroid before seeking care. Clinicians prescribed oral or parenteral corticosteroids 81% of the time, sometimes in combination with a high-potency topical corticosteroid (25%) or oral antihistamine (31%). Only systemic corticosteroids plus high-potency topical corticosteroids were associated with a significantly shorter duration of itching (P=.005). No treatment was associated with reduced duration of erythema, papules, or vesicles.

Conclusions Patients who visit a primary care clinician for Rhus dermatitis can expect the rash to last another 2 weeks on average (total duration: one day to 6 weeks) regardless of what treatment is prescribed. Parenteral corticosteroids plus high-potency topical corticosteroids may reduce the duration of the itching.

Rhus dermatitis (poison ivy, oak, and sumac) is a common cause of contact dermatitis throughout the United States. The condition is usually mild and often not brought to the attention of primary care clinicians. Some patients, however, do see a health care provider for treatment, most often because of pruritus. This form of contact dermatitis results from a type IV hypersensitivity reaction to urushiol, a colorless oil in the leaves, stem, root, and fruit of poison ivy, poison oak, and poison sumac. The reaction, which occurs 24 to 72 hours following contact with the skin, can be prevented by washing the skin promptly with a detergent soap after exposure. By the age of 8, most people are sensitized to urushiol.¹

According to most standard texts and clinical reviews, untreated Rhus dermatitis usually resolves in one to 3 weeks. What is not known is whether particular patient or rash characteristics might affect prognosis and thereby influence treatment recommendations—eg, age, gender, race, location of the rash, prior episodes, chronic illnesses such as diabetes, or chronic use of medications such as nonsteroidal anti-inflammatory drugs and corticosteroids.

Impetus for our study. An informal survey of 10 clinician members of the Oklahoma Physicians Resource/Research Network (OKPRN), a statewide practice-based research network, suggested that primary care clinicians treat between one and 10 patients with poison ivy each week during the spring, summer, and fall (median 2.5). Their reported armamentarium included more than 15 different over-the-counter topical agents, several oral antihistamines, and a variety of topical, oral, and parenteral corticosteroids.

Systemic corticosteroids plus high-potency topical corticosteroids reduced the duration of itching.Surprisingly, there is very little published evidence on which to base treatment decisions. Using PubMed and the search terms, Rhus dermatitis, poison ivy, and poison oak, we found only 3 placebo-controlled clinical trials of Rhus dermatitis treatments in the English language literature after 1966. Based on these studies, Zanfel, a mixture of alcohol-soluble and anionic surfactant, may be somewhat effective, but pimecrolimus and jewelweed extract were no more effective than placebo.^2-4 There is some evidence that topical corticosteroids are effective only before vesicles appear.⁵ In one uncontrolled study, intramuscular injection of betamethasone and dexamethasone yielded about a 30% reduction in symptoms within 48 hours.⁶ Assuming that systemic corticosteroids do produce benefit, however, the most effective dose and duration of treatment have not been determined.^7,8

To address some of these gaps in our knowledge base, OKPRN members asked that we undertake a longitudinal cohort study of patients reporting to primary care practices.

 

 

METHODS

We conducted this study between May 2010 and October 2014. The project was approved by the University of Oklahoma Health Sciences Center Institutional Review Board. Clinician members of OKPRN were invited to participate in the study via listserv, fax, or letter. We instructed clinicians and office staff to ask patients with Rhus dermatitis if they might be interested in participating in a study, which would require that they keep a symptom diary and would earn them a $20 gift card. Interested patients were given a packet of information, and a member of the research team later called the patients with additional information, including an explanation of informed consent and instructions on completing and returning the diary and written consent form.

Clinicians recorded information about the patient and the rash on a customized template, releasing it to the team after written consent was obtained from the patient. Categories for characterizing the rash were head/face, arms/hands, trunk, and legs/feet. A subset of 5 participating clinicians, selected to include a variety of practice types and patient populations, were also asked to produce, from their billing software, the number of patients and encounters in which poison ivy was addressed in each month of 2013.

On the diary, patients were instructed to record the presence or absence of pruritus, erythema, raised lesions, and vesicles/bullae at the end of each day until the rash resolved, or for 6 weeks following onset of the rash, whichever came first. Patients were asked to mail their diaries to the principal investigator once they were free of symptoms for one week or after 6 weeks from the onset of symptoms, whichever came first.

We asked both patients and clinicians to report medications used before and after the primary care encounter. A member of the research team assigned these medications to one of 12 categories: topical antihistamines, topical soaps (eg, Zanfel or Tecnu), topical astringents, other topical antipruritics, topical aloe vera, topical bleach, low-potency topical corticosteroids, moderate-potency topical corticosteroids, high-potency topical corticosteroids, oral antihistamines, oral corticosteroids, and parenteral corticosteroids.

We used independent T-tests to evaluate associations between baseline variables, patient-initiated treatments, and clinician-initiated treatments and the time to complete resolution of individual signs and symptoms and complete resolution of all signs and symptoms following the clinical encounter. We created additional outcome variables for initial resolution followed by recurrence of itching, erythema, papules, and vesicles. The purpose of these variables was to determine if some treatments were initially effective but without lasting effect.

We used the chi square test to assess associations between clinician-initiated treatments and recurrence of signs or symptoms following initial resolution. To account for chance associations resulting from multiple analyses, we chose to set the level of statistical significance at P=.01. However, because of the lower-than-projected sample size, we chose to also report variables with P<.05 so that the reader could judge the likelihood that a larger sample might have disclosed other important associations.

We assumed that an average of 4 categories of treatment would be tried (eg, topical corticosteroids, systemic corticosteroids, topical antihistamines, and other topical agents), and that the mean number of days until resolution would be 21, with a standard deviation (SD) of 4 days. Setting power at 80% and alpha at .05, we calculated it would take 105 patients per group (N=420) to detect a difference of 2 days in time until resolution.

RESULTS

Over the 5-year study period, 36 clinicians identified 186 patients who expressed an interest in the study, and they transmitted the patient contact information to the research team. Patients were seen in a traditional primary care setting. All 186 patients were enrolled by phone. However, only 89 completed and returned their diaries and signed consent forms; of these, 60% were female, 92% were white, 4% were black, 4% were American Indians, 2% were Hispanic, and 7% had diabetes mellitus.

Five practices contributed data on numbers of poison ivy encounters per month and total encounters per month for the year 2013. They included an inner city academic practice in central Oklahoma and a rural community health center, a suburban private practice, and 2 private practices in a town of 30,000 in eastern Oklahoma. The largest average number of encounters occurred between April and August.

The distribution of enrolled-patient visits by month and season corresponded roughly to the proportions of all patient visits for poison ivy, with 1% occurring in the winter, 35% in the spring, 55% during the summer, and 9% in the fall. Virtually all study participants (92%) complained of pruritus and had erythema (91%) and papules (87%). Forty-nine percent had vesicles or bullae. The area of the body most often affected was the head/face/­­neck, 61%, followed by the trunk, 56%; legs, 54%; and arms, 22%.

From the date of initial clinical consultation, the mean/median (SD; range) duration of symptoms and signs were: pruritus, 10.9/9 days (7.1; 0-43); erythema, 13.7/13 days (7.7; 0-42); papules, 10.1/9.5 days (6.5; 0-37); and vesicles, 5.3/5 days (4.1; 0-15). The mean/median (SD; range) duration of any symptom or sign was 14.4/13.5 days (8; 1-43). Rashes with vesicles tended to last longer (16.1 vs 12.9 days), but this difference did not reach statistical significance.

Treatments used by patients before and after their primary care visit are shown in TABLE 1. Seventy-three percent of patients had tried something from one treatment category before consulting a clinician, and 31% had tried something from more than one category. They were most likely to have used a topical antipruritic, astringent, or low-potency corticosteroid, or a combination of these. Clinicians always recommended some treatment and, in 76% of cases, treatments from more than one category. They most often prescribed oral or parenteral corticosteroids (81% of the time), sometimes in combination with a high-potency topical corticosteroid (25% of the time) or oral antihistamine (31%). Oral corticosteroids were used for an average of 11 days; parenteral corticosteroids were given once. Oral antihistamines were recommended for 30% of patients, with an average course duration of 13 days. Clinicians did not prescribe systemic corticosteroids or any other treatment type more often based on location of the rash or presence of vesicles.

No statistically significant associations were found between the baseline non-treatment variables and duration of symptoms and signs. Patient-initiated treatments were also not associated with duration of symptoms and signs following the initial clinician visit.

Of the treatments prescribed by clinicians or independently chosen by patients following their initial office visit, only systemic corticosteroids plus high-potency topical corticosteroids were associated with a significantly shorter duration of itching (P=.005). No treatment was associated with reduced duration of erythema, papules, or vesicles. Use of topical soaps was associated with a longer duration of papules (P<.0001) and of total duration of signs or symptoms (P=.0004) compared with other treatments.

Location and characteristics of the rash were not associated with likelihood of recurrence following treatment. Post-visit use of a topical soap was associated with recurrence of itching (P=.001) and erythema (P=.01). Recurrence of erythema was also more frequent in patients prescribed topical astringents (beta coefficient=0.28; P=.008), and recurrence of papules was more common in patients treated with low-potency topical corticosteroids (P<.0001). These results and several others that almost reached statistical significance are shown in TABLE 2.

In the multivariable models, the only variable associated with duration of pruritus was the combination of systemic and high-potency topical corticosteroids (8 vs 12 days.) Use of only parenteral or only high-potency topical corticosteroids did not predict shorter duration of pruritus. Use of topical soaps was associated with longer duration of papules (33 vs 9.6 days) and longer duration of any symptoms (33 vs 13.9 days). It was also associated with a higher likelihood of recurrence of pruritus (chi square test [χ²], 10.67) and recurrence of erythema (χ², 5.92) after initial resolution. Topical astringent use was predictive of recurrence of erythema (χ², 7.01) and use of low-potency corticosteroids was associated with recurrence of papules (χ², 20.96).

DISCUSSION

While network clinicians felt that studying poison ivy was of interest and importance, and we had preliminary survey information to suggest it was a common problem treated in primary care, our data suggest that clinical encounters for poison ivy are actually quite uncommon (less than 0.4% of all encounters) even during peak months. Our problems with recruitment were therefore unexpected, and we ended up with far fewer enrolled patients than we had projected, and needed, based on our power analysis. Also based on our preliminary survey, we anticipated considerably more variation in treatment approach than we found. Most clinicians recommended either an oral, parenteral, or high-potency topical corticosteroid, and some also recommended an oral antihistamine, usually diphenhydramine.

The literature and common sense suggest that most patients who seek medical treatment for poison ivy are primarily concerned about itching. Even with the smaller-than-anticipated number of participants in this study, we were able to show that the combination of a systemic (oral or parenteral) corticosteroid and a high-potency topical corticosteroid was associated with a statistically significant shorter duration of pruritus with no recurrence following treatment. We found no evidence that systemic corticosteroids alone, parenteral corticosteroids alone, or high-potency topical corticosteroids alone had any effect on duration of signs or symptoms, even at an alpha of .05. We also found no evidence that oral antihistamines were associated with a shorter duration of pruritus (P=.06); with a larger sample size, we might have found a difference.

Since only 2 patients used topical soaps following their initial clinician visit, the associations between use of these products and longer duration of signs and symptoms and with recurrence of signs and symptoms, although statistically significant, should be viewed with skepticism and with an eye toward possible confounders (eg, people who used these agents may have been more likely to notice and record minor symptoms). Furthermore, these agents have been effective only when used before or at the onset of the rash.

Study limitations. The study has a number of limitations. It had a high drop-out rate. Some patients might not have had poison ivy, but it is generally considered easy to diagnose with accuracy. We cannot be sure that all of the enrolled patients had Rhus dermatitis. Enrollment was based on the clinical impression of the patients’ primary care clinicians. The sample size reduced the power of the study to detect small differences in treatment effects and prevented more complex analyses (eg, combinations of medications, interactions).

The possibility of self-selection bias, weaknesses of the cohort design, and patient-reported outcome measures were additional limitations. The study was also carried out in a single southwestern state, which may not be representative of some other locations. However, it is one of only a few studies published on Rhus dermatitis and possibly the only one conducted in primary care settings.

CORRESPONDENCE
Cara Vaught, MPH, University of Oklahoma Health Sciences Center, Department of Family and Preventive Medicine, 900 NE 10th Street, Oklahoma City, OK 73104; [email protected].

ACKNOWLEDGEMENT
The authors thank the Oklahoma Physicians Resource/Research Network (OKPRN) and the OKPRN clinician members (as well as their staff and patients) for their contributions to this study. The authors also thank Bradley Long, Matthew Marr, and Kellie Hetherington for their involvement in the data collection for this study.

ABSTRACT

Purpose To determine the characteristics and clinical course of Rhus dermatitis in patients who seek assistance from primary care clinicians, as well as treatment approaches used by patients and recommended by clinicians, and treatment approaches associated with better outcomes.

Methods This was a prospective cohort study with standardized baseline data collection on patients and their rashes, followed by examination of patient-completed diaries of signs, symptoms, and treatments.

Results Thirty-six clinicians identified 186 interested patients, of which 89 completed and returned diaries and consent forms. Of those 89 patients, 92% reported pruritus; 91%, erythema; 87%, papules; and 49%, vesicles or bullae at baseline. Their rashes involved the head/face/neck, 61%; trunk, 56%; legs, 54%; and arms, 22%.

Patients seeking help for poison ivy can expect the rash to last an additional 2 weeks on average, regardless of the treatment prescribed.From the date of clinical consultation, the mean (standard deviation [SD]; range) duration of any symptom or sign was 14.4 days (8.0; 1-43). Patients most often had tried a topical antipruritic, astringent, or low-potency corticosteroid before seeking care. Clinicians prescribed oral or parenteral corticosteroids 81% of the time, sometimes in combination with a high-potency topical corticosteroid (25%) or oral antihistamine (31%). Only systemic corticosteroids plus high-potency topical corticosteroids were associated with a significantly shorter duration of itching (P=.005). No treatment was associated with reduced duration of erythema, papules, or vesicles.

Conclusions Patients who visit a primary care clinician for Rhus dermatitis can expect the rash to last another 2 weeks on average (total duration: one day to 6 weeks) regardless of what treatment is prescribed. Parenteral corticosteroids plus high-potency topical corticosteroids may reduce the duration of the itching.

Rhus dermatitis (poison ivy, oak, and sumac) is a common cause of contact dermatitis throughout the United States. The condition is usually mild and often not brought to the attention of primary care clinicians. Some patients, however, do see a health care provider for treatment, most often because of pruritus. This form of contact dermatitis results from a type IV hypersensitivity reaction to urushiol, a colorless oil in the leaves, stem, root, and fruit of poison ivy, poison oak, and poison sumac. The reaction, which occurs 24 to 72 hours following contact with the skin, can be prevented by washing the skin promptly with a detergent soap after exposure. By the age of 8, most people are sensitized to urushiol.¹

According to most standard texts and clinical reviews, untreated Rhus dermatitis usually resolves in one to 3 weeks. What is not known is whether particular patient or rash characteristics might affect prognosis and thereby influence treatment recommendations—eg, age, gender, race, location of the rash, prior episodes, chronic illnesses such as diabetes, or chronic use of medications such as nonsteroidal anti-inflammatory drugs and corticosteroids.

Impetus for our study. An informal survey of 10 clinician members of the Oklahoma Physicians Resource/Research Network (OKPRN), a statewide practice-based research network, suggested that primary care clinicians treat between one and 10 patients with poison ivy each week during the spring, summer, and fall (median 2.5). Their reported armamentarium included more than 15 different over-the-counter topical agents, several oral antihistamines, and a variety of topical, oral, and parenteral corticosteroids.

Systemic corticosteroids plus high-potency topical corticosteroids reduced the duration of itching.Surprisingly, there is very little published evidence on which to base treatment decisions. Using PubMed and the search terms, Rhus dermatitis, poison ivy, and poison oak, we found only 3 placebo-controlled clinical trials of Rhus dermatitis treatments in the English language literature after 1966. Based on these studies, Zanfel, a mixture of alcohol-soluble and anionic surfactant, may be somewhat effective, but pimecrolimus and jewelweed extract were no more effective than placebo.^2-4 There is some evidence that topical corticosteroids are effective only before vesicles appear.⁵ In one uncontrolled study, intramuscular injection of betamethasone and dexamethasone yielded about a 30% reduction in symptoms within 48 hours.⁶ Assuming that systemic corticosteroids do produce benefit, however, the most effective dose and duration of treatment have not been determined.^7,8

To address some of these gaps in our knowledge base, OKPRN members asked that we undertake a longitudinal cohort study of patients reporting to primary care practices.

 

 

METHODS

We conducted this study between May 2010 and October 2014. The project was approved by the University of Oklahoma Health Sciences Center Institutional Review Board. Clinician members of OKPRN were invited to participate in the study via listserv, fax, or letter. We instructed clinicians and office staff to ask patients with Rhus dermatitis if they might be interested in participating in a study, which would require that they keep a symptom diary and would earn them a $20 gift card. Interested patients were given a packet of information, and a member of the research team later called the patients with additional information, including an explanation of informed consent and instructions on completing and returning the diary and written consent form.

Clinicians recorded information about the patient and the rash on a customized template, releasing it to the team after written consent was obtained from the patient. Categories for characterizing the rash were head/face, arms/hands, trunk, and legs/feet. A subset of 5 participating clinicians, selected to include a variety of practice types and patient populations, were also asked to produce, from their billing software, the number of patients and encounters in which poison ivy was addressed in each month of 2013.

On the diary, patients were instructed to record the presence or absence of pruritus, erythema, raised lesions, and vesicles/bullae at the end of each day until the rash resolved, or for 6 weeks following onset of the rash, whichever came first. Patients were asked to mail their diaries to the principal investigator once they were free of symptoms for one week or after 6 weeks from the onset of symptoms, whichever came first.

We asked both patients and clinicians to report medications used before and after the primary care encounter. A member of the research team assigned these medications to one of 12 categories: topical antihistamines, topical soaps (eg, Zanfel or Tecnu), topical astringents, other topical antipruritics, topical aloe vera, topical bleach, low-potency topical corticosteroids, moderate-potency topical corticosteroids, high-potency topical corticosteroids, oral antihistamines, oral corticosteroids, and parenteral corticosteroids.

We used independent T-tests to evaluate associations between baseline variables, patient-initiated treatments, and clinician-initiated treatments and the time to complete resolution of individual signs and symptoms and complete resolution of all signs and symptoms following the clinical encounter. We created additional outcome variables for initial resolution followed by recurrence of itching, erythema, papules, and vesicles. The purpose of these variables was to determine if some treatments were initially effective but without lasting effect.

We used the chi square test to assess associations between clinician-initiated treatments and recurrence of signs or symptoms following initial resolution. To account for chance associations resulting from multiple analyses, we chose to set the level of statistical significance at P=.01. However, because of the lower-than-projected sample size, we chose to also report variables with P<.05 so that the reader could judge the likelihood that a larger sample might have disclosed other important associations.

We assumed that an average of 4 categories of treatment would be tried (eg, topical corticosteroids, systemic corticosteroids, topical antihistamines, and other topical agents), and that the mean number of days until resolution would be 21, with a standard deviation (SD) of 4 days. Setting power at 80% and alpha at .05, we calculated it would take 105 patients per group (N=420) to detect a difference of 2 days in time until resolution.

RESULTS

Over the 5-year study period, 36 clinicians identified 186 patients who expressed an interest in the study, and they transmitted the patient contact information to the research team. Patients were seen in a traditional primary care setting. All 186 patients were enrolled by phone. However, only 89 completed and returned their diaries and signed consent forms; of these, 60% were female, 92% were white, 4% were black, 4% were American Indians, 2% were Hispanic, and 7% had diabetes mellitus.

Five practices contributed data on numbers of poison ivy encounters per month and total encounters per month for the year 2013. They included an inner city academic practice in central Oklahoma and a rural community health center, a suburban private practice, and 2 private practices in a town of 30,000 in eastern Oklahoma. The largest average number of encounters occurred between April and August.

The distribution of enrolled-patient visits by month and season corresponded roughly to the proportions of all patient visits for poison ivy, with 1% occurring in the winter, 35% in the spring, 55% during the summer, and 9% in the fall. Virtually all study participants (92%) complained of pruritus and had erythema (91%) and papules (87%). Forty-nine percent had vesicles or bullae. The area of the body most often affected was the head/face/­­neck, 61%, followed by the trunk, 56%; legs, 54%; and arms, 22%.

From the date of initial clinical consultation, the mean/median (SD; range) duration of symptoms and signs were: pruritus, 10.9/9 days (7.1; 0-43); erythema, 13.7/13 days (7.7; 0-42); papules, 10.1/9.5 days (6.5; 0-37); and vesicles, 5.3/5 days (4.1; 0-15). The mean/median (SD; range) duration of any symptom or sign was 14.4/13.5 days (8; 1-43). Rashes with vesicles tended to last longer (16.1 vs 12.9 days), but this difference did not reach statistical significance.

Treatments used by patients before and after their primary care visit are shown in TABLE 1. Seventy-three percent of patients had tried something from one treatment category before consulting a clinician, and 31% had tried something from more than one category. They were most likely to have used a topical antipruritic, astringent, or low-potency corticosteroid, or a combination of these. Clinicians always recommended some treatment and, in 76% of cases, treatments from more than one category. They most often prescribed oral or parenteral corticosteroids (81% of the time), sometimes in combination with a high-potency topical corticosteroid (25% of the time) or oral antihistamine (31%). Oral corticosteroids were used for an average of 11 days; parenteral corticosteroids were given once. Oral antihistamines were recommended for 30% of patients, with an average course duration of 13 days. Clinicians did not prescribe systemic corticosteroids or any other treatment type more often based on location of the rash or presence of vesicles.

No statistically significant associations were found between the baseline non-treatment variables and duration of symptoms and signs. Patient-initiated treatments were also not associated with duration of symptoms and signs following the initial clinician visit.

Of the treatments prescribed by clinicians or independently chosen by patients following their initial office visit, only systemic corticosteroids plus high-potency topical corticosteroids were associated with a significantly shorter duration of itching (P=.005). No treatment was associated with reduced duration of erythema, papules, or vesicles. Use of topical soaps was associated with a longer duration of papules (P<.0001) and of total duration of signs or symptoms (P=.0004) compared with other treatments.

Location and characteristics of the rash were not associated with likelihood of recurrence following treatment. Post-visit use of a topical soap was associated with recurrence of itching (P=.001) and erythema (P=.01). Recurrence of erythema was also more frequent in patients prescribed topical astringents (beta coefficient=0.28; P=.008), and recurrence of papules was more common in patients treated with low-potency topical corticosteroids (P<.0001). These results and several others that almost reached statistical significance are shown in TABLE 2.

In the multivariable models, the only variable associated with duration of pruritus was the combination of systemic and high-potency topical corticosteroids (8 vs 12 days.) Use of only parenteral or only high-potency topical corticosteroids did not predict shorter duration of pruritus. Use of topical soaps was associated with longer duration of papules (33 vs 9.6 days) and longer duration of any symptoms (33 vs 13.9 days). It was also associated with a higher likelihood of recurrence of pruritus (chi square test [χ²], 10.67) and recurrence of erythema (χ², 5.92) after initial resolution. Topical astringent use was predictive of recurrence of erythema (χ², 7.01) and use of low-potency corticosteroids was associated with recurrence of papules (χ², 20.96).

DISCUSSION

While network clinicians felt that studying poison ivy was of interest and importance, and we had preliminary survey information to suggest it was a common problem treated in primary care, our data suggest that clinical encounters for poison ivy are actually quite uncommon (less than 0.4% of all encounters) even during peak months. Our problems with recruitment were therefore unexpected, and we ended up with far fewer enrolled patients than we had projected, and needed, based on our power analysis. Also based on our preliminary survey, we anticipated considerably more variation in treatment approach than we found. Most clinicians recommended either an oral, parenteral, or high-potency topical corticosteroid, and some also recommended an oral antihistamine, usually diphenhydramine.

The literature and common sense suggest that most patients who seek medical treatment for poison ivy are primarily concerned about itching. Even with the smaller-than-anticipated number of participants in this study, we were able to show that the combination of a systemic (oral or parenteral) corticosteroid and a high-potency topical corticosteroid was associated with a statistically significant shorter duration of pruritus with no recurrence following treatment. We found no evidence that systemic corticosteroids alone, parenteral corticosteroids alone, or high-potency topical corticosteroids alone had any effect on duration of signs or symptoms, even at an alpha of .05. We also found no evidence that oral antihistamines were associated with a shorter duration of pruritus (P=.06); with a larger sample size, we might have found a difference.

Since only 2 patients used topical soaps following their initial clinician visit, the associations between use of these products and longer duration of signs and symptoms and with recurrence of signs and symptoms, although statistically significant, should be viewed with skepticism and with an eye toward possible confounders (eg, people who used these agents may have been more likely to notice and record minor symptoms). Furthermore, these agents have been effective only when used before or at the onset of the rash.

Study limitations. The study has a number of limitations. It had a high drop-out rate. Some patients might not have had poison ivy, but it is generally considered easy to diagnose with accuracy. We cannot be sure that all of the enrolled patients had Rhus dermatitis. Enrollment was based on the clinical impression of the patients’ primary care clinicians. The sample size reduced the power of the study to detect small differences in treatment effects and prevented more complex analyses (eg, combinations of medications, interactions).

The possibility of self-selection bias, weaknesses of the cohort design, and patient-reported outcome measures were additional limitations. The study was also carried out in a single southwestern state, which may not be representative of some other locations. However, it is one of only a few studies published on Rhus dermatitis and possibly the only one conducted in primary care settings.

CORRESPONDENCE
Cara Vaught, MPH, University of Oklahoma Health Sciences Center, Department of Family and Preventive Medicine, 900 NE 10th Street, Oklahoma City, OK 73104; [email protected].

ACKNOWLEDGEMENT
The authors thank the Oklahoma Physicians Resource/Research Network (OKPRN) and the OKPRN clinician members (as well as their staff and patients) for their contributions to this study. The authors also thank Bradley Long, Matthew Marr, and Kellie Hetherington for their involvement in the data collection for this study.

ABSTRACT

Purpose To determine the characteristics and clinical course of Rhus dermatitis in patients who seek assistance from primary care clinicians, as well as treatment approaches used by patients and recommended by clinicians, and treatment approaches associated with better outcomes.

Methods This was a prospective cohort study with standardized baseline data collection on patients and their rashes, followed by examination of patient-completed diaries of signs, symptoms, and treatments.

Results Thirty-six clinicians identified 186 interested patients, of which 89 completed and returned diaries and consent forms. Of those 89 patients, 92% reported pruritus; 91%, erythema; 87%, papules; and 49%, vesicles or bullae at baseline. Their rashes involved the head/face/neck, 61%; trunk, 56%; legs, 54%; and arms, 22%.

Patients seeking help for poison ivy can expect the rash to last an additional 2 weeks on average, regardless of the treatment prescribed.From the date of clinical consultation, the mean (standard deviation [SD]; range) duration of any symptom or sign was 14.4 days (8.0; 1-43). Patients most often had tried a topical antipruritic, astringent, or low-potency corticosteroid before seeking care. Clinicians prescribed oral or parenteral corticosteroids 81% of the time, sometimes in combination with a high-potency topical corticosteroid (25%) or oral antihistamine (31%). Only systemic corticosteroids plus high-potency topical corticosteroids were associated with a significantly shorter duration of itching (P=.005). No treatment was associated with reduced duration of erythema, papules, or vesicles.

Conclusions Patients who visit a primary care clinician for Rhus dermatitis can expect the rash to last another 2 weeks on average (total duration: one day to 6 weeks) regardless of what treatment is prescribed. Parenteral corticosteroids plus high-potency topical corticosteroids may reduce the duration of the itching.

Rhus dermatitis (poison ivy, oak, and sumac) is a common cause of contact dermatitis throughout the United States. The condition is usually mild and often not brought to the attention of primary care clinicians. Some patients, however, do see a health care provider for treatment, most often because of pruritus. This form of contact dermatitis results from a type IV hypersensitivity reaction to urushiol, a colorless oil in the leaves, stem, root, and fruit of poison ivy, poison oak, and poison sumac. The reaction, which occurs 24 to 72 hours following contact with the skin, can be prevented by washing the skin promptly with a detergent soap after exposure. By the age of 8, most people are sensitized to urushiol.¹

According to most standard texts and clinical reviews, untreated Rhus dermatitis usually resolves in one to 3 weeks. What is not known is whether particular patient or rash characteristics might affect prognosis and thereby influence treatment recommendations—eg, age, gender, race, location of the rash, prior episodes, chronic illnesses such as diabetes, or chronic use of medications such as nonsteroidal anti-inflammatory drugs and corticosteroids.

Impetus for our study. An informal survey of 10 clinician members of the Oklahoma Physicians Resource/Research Network (OKPRN), a statewide practice-based research network, suggested that primary care clinicians treat between one and 10 patients with poison ivy each week during the spring, summer, and fall (median 2.5). Their reported armamentarium included more than 15 different over-the-counter topical agents, several oral antihistamines, and a variety of topical, oral, and parenteral corticosteroids.

Systemic corticosteroids plus high-potency topical corticosteroids reduced the duration of itching.Surprisingly, there is very little published evidence on which to base treatment decisions. Using PubMed and the search terms, Rhus dermatitis, poison ivy, and poison oak, we found only 3 placebo-controlled clinical trials of Rhus dermatitis treatments in the English language literature after 1966. Based on these studies, Zanfel, a mixture of alcohol-soluble and anionic surfactant, may be somewhat effective, but pimecrolimus and jewelweed extract were no more effective than placebo.^2-4 There is some evidence that topical corticosteroids are effective only before vesicles appear.⁵ In one uncontrolled study, intramuscular injection of betamethasone and dexamethasone yielded about a 30% reduction in symptoms within 48 hours.⁶ Assuming that systemic corticosteroids do produce benefit, however, the most effective dose and duration of treatment have not been determined.^7,8

To address some of these gaps in our knowledge base, OKPRN members asked that we undertake a longitudinal cohort study of patients reporting to primary care practices.

 

 

METHODS

We conducted this study between May 2010 and October 2014. The project was approved by the University of Oklahoma Health Sciences Center Institutional Review Board. Clinician members of OKPRN were invited to participate in the study via listserv, fax, or letter. We instructed clinicians and office staff to ask patients with Rhus dermatitis if they might be interested in participating in a study, which would require that they keep a symptom diary and would earn them a $20 gift card. Interested patients were given a packet of information, and a member of the research team later called the patients with additional information, including an explanation of informed consent and instructions on completing and returning the diary and written consent form.

Clinicians recorded information about the patient and the rash on a customized template, releasing it to the team after written consent was obtained from the patient. Categories for characterizing the rash were head/face, arms/hands, trunk, and legs/feet. A subset of 5 participating clinicians, selected to include a variety of practice types and patient populations, were also asked to produce, from their billing software, the number of patients and encounters in which poison ivy was addressed in each month of 2013.

On the diary, patients were instructed to record the presence or absence of pruritus, erythema, raised lesions, and vesicles/bullae at the end of each day until the rash resolved, or for 6 weeks following onset of the rash, whichever came first. Patients were asked to mail their diaries to the principal investigator once they were free of symptoms for one week or after 6 weeks from the onset of symptoms, whichever came first.

We asked both patients and clinicians to report medications used before and after the primary care encounter. A member of the research team assigned these medications to one of 12 categories: topical antihistamines, topical soaps (eg, Zanfel or Tecnu), topical astringents, other topical antipruritics, topical aloe vera, topical bleach, low-potency topical corticosteroids, moderate-potency topical corticosteroids, high-potency topical corticosteroids, oral antihistamines, oral corticosteroids, and parenteral corticosteroids.

We used independent T-tests to evaluate associations between baseline variables, patient-initiated treatments, and clinician-initiated treatments and the time to complete resolution of individual signs and symptoms and complete resolution of all signs and symptoms following the clinical encounter. We created additional outcome variables for initial resolution followed by recurrence of itching, erythema, papules, and vesicles. The purpose of these variables was to determine if some treatments were initially effective but without lasting effect.

We used the chi square test to assess associations between clinician-initiated treatments and recurrence of signs or symptoms following initial resolution. To account for chance associations resulting from multiple analyses, we chose to set the level of statistical significance at P=.01. However, because of the lower-than-projected sample size, we chose to also report variables with P<.05 so that the reader could judge the likelihood that a larger sample might have disclosed other important associations.

We assumed that an average of 4 categories of treatment would be tried (eg, topical corticosteroids, systemic corticosteroids, topical antihistamines, and other topical agents), and that the mean number of days until resolution would be 21, with a standard deviation (SD) of 4 days. Setting power at 80% and alpha at .05, we calculated it would take 105 patients per group (N=420) to detect a difference of 2 days in time until resolution.

RESULTS

Over the 5-year study period, 36 clinicians identified 186 patients who expressed an interest in the study, and they transmitted the patient contact information to the research team. Patients were seen in a traditional primary care setting. All 186 patients were enrolled by phone. However, only 89 completed and returned their diaries and signed consent forms; of these, 60% were female, 92% were white, 4% were black, 4% were American Indians, 2% were Hispanic, and 7% had diabetes mellitus.

Five practices contributed data on numbers of poison ivy encounters per month and total encounters per month for the year 2013. They included an inner city academic practice in central Oklahoma and a rural community health center, a suburban private practice, and 2 private practices in a town of 30,000 in eastern Oklahoma. The largest average number of encounters occurred between April and August.

The distribution of enrolled-patient visits by month and season corresponded roughly to the proportions of all patient visits for poison ivy, with 1% occurring in the winter, 35% in the spring, 55% during the summer, and 9% in the fall. Virtually all study participants (92%) complained of pruritus and had erythema (91%) and papules (87%). Forty-nine percent had vesicles or bullae. The area of the body most often affected was the head/face/­­neck, 61%, followed by the trunk, 56%; legs, 54%; and arms, 22%.

From the date of initial clinical consultation, the mean/median (SD; range) duration of symptoms and signs were: pruritus, 10.9/9 days (7.1; 0-43); erythema, 13.7/13 days (7.7; 0-42); papules, 10.1/9.5 days (6.5; 0-37); and vesicles, 5.3/5 days (4.1; 0-15). The mean/median (SD; range) duration of any symptom or sign was 14.4/13.5 days (8; 1-43). Rashes with vesicles tended to last longer (16.1 vs 12.9 days), but this difference did not reach statistical significance.

Treatments used by patients before and after their primary care visit are shown in TABLE 1. Seventy-three percent of patients had tried something from one treatment category before consulting a clinician, and 31% had tried something from more than one category. They were most likely to have used a topical antipruritic, astringent, or low-potency corticosteroid, or a combination of these. Clinicians always recommended some treatment and, in 76% of cases, treatments from more than one category. They most often prescribed oral or parenteral corticosteroids (81% of the time), sometimes in combination with a high-potency topical corticosteroid (25% of the time) or oral antihistamine (31%). Oral corticosteroids were used for an average of 11 days; parenteral corticosteroids were given once. Oral antihistamines were recommended for 30% of patients, with an average course duration of 13 days. Clinicians did not prescribe systemic corticosteroids or any other treatment type more often based on location of the rash or presence of vesicles.

No statistically significant associations were found between the baseline non-treatment variables and duration of symptoms and signs. Patient-initiated treatments were also not associated with duration of symptoms and signs following the initial clinician visit.

Of the treatments prescribed by clinicians or independently chosen by patients following their initial office visit, only systemic corticosteroids plus high-potency topical corticosteroids were associated with a significantly shorter duration of itching (P=.005). No treatment was associated with reduced duration of erythema, papules, or vesicles. Use of topical soaps was associated with a longer duration of papules (P<.0001) and of total duration of signs or symptoms (P=.0004) compared with other treatments.

Location and characteristics of the rash were not associated with likelihood of recurrence following treatment. Post-visit use of a topical soap was associated with recurrence of itching (P=.001) and erythema (P=.01). Recurrence of erythema was also more frequent in patients prescribed topical astringents (beta coefficient=0.28; P=.008), and recurrence of papules was more common in patients treated with low-potency topical corticosteroids (P<.0001). These results and several others that almost reached statistical significance are shown in TABLE 2.

In the multivariable models, the only variable associated with duration of pruritus was the combination of systemic and high-potency topical corticosteroids (8 vs 12 days.) Use of only parenteral or only high-potency topical corticosteroids did not predict shorter duration of pruritus. Use of topical soaps was associated with longer duration of papules (33 vs 9.6 days) and longer duration of any symptoms (33 vs 13.9 days). It was also associated with a higher likelihood of recurrence of pruritus (chi square test [χ²], 10.67) and recurrence of erythema (χ², 5.92) after initial resolution. Topical astringent use was predictive of recurrence of erythema (χ², 7.01) and use of low-potency corticosteroids was associated with recurrence of papules (χ², 20.96).

DISCUSSION

While network clinicians felt that studying poison ivy was of interest and importance, and we had preliminary survey information to suggest it was a common problem treated in primary care, our data suggest that clinical encounters for poison ivy are actually quite uncommon (less than 0.4% of all encounters) even during peak months. Our problems with recruitment were therefore unexpected, and we ended up with far fewer enrolled patients than we had projected, and needed, based on our power analysis. Also based on our preliminary survey, we anticipated considerably more variation in treatment approach than we found. Most clinicians recommended either an oral, parenteral, or high-potency topical corticosteroid, and some also recommended an oral antihistamine, usually diphenhydramine.

The literature and common sense suggest that most patients who seek medical treatment for poison ivy are primarily concerned about itching. Even with the smaller-than-anticipated number of participants in this study, we were able to show that the combination of a systemic (oral or parenteral) corticosteroid and a high-potency topical corticosteroid was associated with a statistically significant shorter duration of pruritus with no recurrence following treatment. We found no evidence that systemic corticosteroids alone, parenteral corticosteroids alone, or high-potency topical corticosteroids alone had any effect on duration of signs or symptoms, even at an alpha of .05. We also found no evidence that oral antihistamines were associated with a shorter duration of pruritus (P=.06); with a larger sample size, we might have found a difference.

Since only 2 patients used topical soaps following their initial clinician visit, the associations between use of these products and longer duration of signs and symptoms and with recurrence of signs and symptoms, although statistically significant, should be viewed with skepticism and with an eye toward possible confounders (eg, people who used these agents may have been more likely to notice and record minor symptoms). Furthermore, these agents have been effective only when used before or at the onset of the rash.

Study limitations. The study has a number of limitations. It had a high drop-out rate. Some patients might not have had poison ivy, but it is generally considered easy to diagnose with accuracy. We cannot be sure that all of the enrolled patients had Rhus dermatitis. Enrollment was based on the clinical impression of the patients’ primary care clinicians. The sample size reduced the power of the study to detect small differences in treatment effects and prevented more complex analyses (eg, combinations of medications, interactions).

The possibility of self-selection bias, weaknesses of the cohort design, and patient-reported outcome measures were additional limitations. The study was also carried out in a single southwestern state, which may not be representative of some other locations. However, it is one of only a few studies published on Rhus dermatitis and possibly the only one conducted in primary care settings.

CORRESPONDENCE
Cara Vaught, MPH, University of Oklahoma Health Sciences Center, Department of Family and Preventive Medicine, 900 NE 10th Street, Oklahoma City, OK 73104; [email protected].

ACKNOWLEDGEMENT
The authors thank the Oklahoma Physicians Resource/Research Network (OKPRN) and the OKPRN clinician members (as well as their staff and patients) for their contributions to this study. The authors also thank Bradley Long, Matthew Marr, and Kellie Hetherington for their involvement in the data collection for this study.

CASE › James G, age 43, recently had blood work performed for a life insurance policy, and his human immunodeficiency virus (HIV) test came back positive. At a follow-up office visit, Mr. G reports having anonymous male sexual partners when traveling to New York on business and rarely using condoms. His last HIV test was “about 4 years ago.” He is otherwise in good health, takes no regular medications, and is not married.

Having recently completed a primary care CME program on HIV disease, you order a CD4/T-cell count, an HIV RNA (viral load) test, and an HIV genotype drug resistance test on Mr. G, along with other baseline lab work, including a complete blood count, chemistry panel, and hepatitis panel. You schedule a follow-up visit with Mr. G in 2 weeks when all of the lab results will be available so that you can discuss his plan of care.

A diagnosis of HIV has moved from being a fatal disease to that of a chronic condition that can be effectively managed with combination antiretroviral therapy (ART) regimens over an almost normal lifespan. As a result, the role of the primary care practitioner in the ongoing care of patients with HIV has grown and will continue to do so, making knowledge of these drug combinations vital.

20 years have changed everything

Combination ART has existed since 1996 when the first protease inhibitors (PIs) were approved by the US Food and Drug Administration (FDA). Prior to this, treatment was limited to mono or dual therapy with nucleoside reverse transcriptase inhibitors (NRTIs). These agents provided some short-term clinical benefit, but didn’t significantly improve patient survival and ultimately failed due to viral resistance.¹

Since the approval of zidovudine (AZT) in 1987, the FDA has approved more than 25 drugs in 6 different classes for the treatment of HIV disease.² These include the NRTIs, non-nucleoside reverse transcriptase inhibitors (NNRTIs), PIs, a fusion inhibitor (FI), a CCR5 antagonist, and, more recently, integrase strand transfer inhibitors (INSTIs). In addition, 2 drugs, cobicistat and ritonavir, are used solely to improve or “boost” the pharmacokinetic profiles of several antiretroviral drugs.²

Most of these newer agents are more potent, have a higher genetic barrier to resistance, and a longer half-life than their predecessors. Moreover, many are less toxic and thus more tolerable than older drugs. With the progressive development and approval of single-tablet regimens (STRs) that contain 3 or 4 drugs, the majority of patients with HIV in the United States now take just one pill per day to treat their infection, facilitating far greater medication adherence.

 

 

Initiation of antiretroviral therapy

The US Department of Health and Human Services (DHHS) guidelines now recommend that all people infected with HIV, regardless of CD4 cell count, begin ART.² The evidence for this recommendation comes largely from the START³ and TEMPRANO⁴ trials, which found that early initiation of ART significantly reduces morbidity and mortality associated with HIV. In addition, the HPTN 052 study concluded that early ART is associated with a 93% lower risk of viral transmission in serodiscordant heterosexual couples.⁵ The DHHS guidelines do note that when initiating ART, it is important to appropriately educate patients on the benefits of treatment and address strategies to optimize adherence.² (For more on factors to consider when selecting an initial HIV regimen, see TABLE 1.²) On a case-by-case basis, ART may be deferred because of clinical and/or psychosocial factors, but it should never be withheld unless the risks clearly outweigh the benefits. Ideally, ART should be initiated as soon as possible after the initial diagnosis of HIV.

The DHHS guidelines divide treatment options into 3 categories:²

• Recommended regimens are backed by randomized controlled trials that show optimal and durable virologic efficacy, they have favorable tolerability and toxicity profiles, and they are easy to use.
• Alternative regimens have less or lower quality supporting data than recommended regimens. Although they are effective and may be optimal for certain individual patients, they have potential disadvantages and/or limitations in certain populations.
• Other regimens have limited supporting data, reduced virologic activity, a higher pill burden, more drug interactions, and greater toxicity.

Currently recommended first-line therapies

An antiretroviral regimen for a treatment-naive patient should consist of 2 NRTIs in combination with a third active antiretroviral drug from one of 3 drug classes. These include: an INSTI, a boosted PI, or, in some situations, an NNRTI. The DHHS guidelines panel currently recommends 6 different ART combinations as first-line treatment in treatment-naive patients (TABLE 2).²

 

 

INSTI-based regimens

Dolutegravir/abacavir/lamivudine (Triumeq). Approved by the FDA as a single-tablet regimen in 2014, the combination of dolutegravir/abacavir/lamivudine has proven to be highly effective and well-tolerated in many clinical trials.^6-9 However, before this regimen is started, patients must be screened for the HLA-B*5701 allele, which predicts hypersensitivity to abacavir.¹⁰ Assessing patients’ risk for cardiovascular disease is also advised because some data suggest that abacavir may increase the risk of cardiovascular events, although this remains controversial.²

Most of the newer agents are more potent, less toxic, have a higher genetic barrier to resistance, and a longer half-life than their predecessors.Dolutegravir is generally well-tolerated with minimal adverse effects (≥2% incidence of headache and insomnia) and toxicity.¹¹ Dolutegravir/abacavir/lamivudine should be taken 2 hours before or 6 hours after taking antacids or laxatives, sucralfate, and oral supplements with iron or calcium. However, it may be taken with calcium or iron supplements if it is also taken with food.¹¹ Dolutegravir increases levels of metformin about 2-fold, so patients should not take more than 1000 mg/d of this oral hypoglycemic agent.¹¹

Dolutegravir plus tenofovir disoproxil fumarate/emtricitabine (Tivicay plus Truvada). The combination of dolutegravir plus fixed-dose tenofovir disoproxil fumarate and emtricitabine is administered as 2 pills per day. Because tenofovir disoproxil fumarate can cause proximal renal tubular dysfunction, phosphate wasting, and decreased bone mineral density (BMD), avoid prescribing it for patients with underlying renal dysfunction (creatinine clearance [CrCl] <50 mL/min) and prescribe it cautiously for patients with hypertension or diabetes who are at increased risk of renal disease. Emtricitabine is generally safe and well tolerated, but the dose should be reduced in patients with renal insufficiency, which would preclude the use of this fixed-dose combination.¹²

Elvitegravir/cobicistat/tenofovir alafenamide/emtricitabine (Genvoya). The newer 4-drug combination of elvite­gravir/­­cobicistat/tenofovir alafenamide/emtricitabine­­ that was approved by the FDA in November 2015,¹³ contains the more recently approved form of tenofovir, which can be used in patients who have a CrCl as low as 30 mL/min. Compared to formulations containing tenofovir disoproxil fumarate, the newer tenofovir alafenamide formulation achieves higher intracellular levels in CD4 lymphocytes (but not in renal tubular cells). This allows for a lower dose of the drug and a smaller tablet size with co-formulation. It does not appear to cause kidney problems or loss of BMD as can be seen with tenofovir disoproxil fumarate.¹⁴ This newer single-tablet regimen may be best suited for older patients with HIV or those with comorbidities such as hypertension or diabetes.

Elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine (Stribild). The FDA approved the combination of elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine as a single-tablet regimen in 2012. The integrase inhibitor, elvitegravir, requires boosting with the CYP3A inhibitor, cobicistat, and should be taken with food.¹⁵ Two clinical trials demonstrated the superior efficacy of elvitegravir compared to a boosted PI and NNRTI-based regimen.^16,17 Elvitegravir is generally well tolerated, but sometimes causes dyspepsia, nausea, or diarrhea.¹⁵ Similar to dolutegravir, it should not be taken concurrently with certain supplements—in this case, those containing aluminum, calcium, iron, magnesium, or zinc.¹⁵ Because it contains tenofovir disoproxil fumarate as an active agent, it should not be used in patients with a CrCl of <70 mL/min.¹⁵

Cobicistat inhibits tubular secretion of creatinine, so it may produce an elevation in serum creatinine without actually affecting glomerular function. Cobicistat may also cause drug-drug interactions with certain antiarrhythmics, sedative-hypnotics, and erectile dysfunction agents, and is contraindicated with some statins, anticonvulsants, and ergot derivatives.¹⁸

Raltegravir plus tenofovir disoproxil fumarate/emtricitabine (Isentress plus Truvada). The combination of the integrase inhibitor raltegravir plus fixed-dose tenofovir disoproxil fumarate and emtricitabine has been recommended by the DHHS as first-line therapy for approximately 5 years. The recommendation is based mainly on data from the STARTMRK trial, a phase III non-inferiority trial that followed more than 500 patients for 5 years and concluded that raltegravir/tenofovir/emtricitabine has superior efficacy with fewer drug-related adverse effects than efavirenz/tenofovir/emtricitabine.¹⁹ The overall pill burden with this regimen is 3 tablets per day. Although highly effective, the main drawbacks of raltegravir are that it must be dosed twice daily (which may be less preferable if adherence is a concern) and the genetic barrier to resistance is lower than that of the other 2 approved integrase inhibitors. There is a once-daily formulation of raltegravir that's expected to be available late in 2017.²⁰

Before starting a regimen with abacavir, screen patients for the HLA-B*5701 allele, which predicts hypersensitivity to the drug.Adverse effects and toxicities (except the renal and bone effects due to tenofovir disoproxil fumarate mentioned earlier) and drug interactions with this regimen are infrequent. Raltegravir can be taken with or without food. Concurrent use of antacids that contain aluminum or magnesium may reduce absorption of raltegravir and so should be avoided.²¹

PI-based regimen

Darunavir (Prezista) and ritonavir (Norvir) plus tenofovir disoproxil fumarate/emtricitabine (Truvada). PIs were once the key component of all ART regimens; however, boosted darunavir is now the only PI-based regimen currently recommended as first-line therapy. It is taken as 3 tablets once daily. If the co-formulation with cobicistat is used, just 2 tablets daily are required. One advantage with darunavir with either of the boosting agents is that it does not appear to cause insulin resistance or dyslipidemia as occurs with older PIs, such as indinavir and lopinavir.² The boosting agents do, however, increase the likelihood of drug-drug interactions. As with all PIs, darunavir has a very high genetic barrier to resistance, which is important in patients for whom adherence is a concern.

Adverse effects of the PIs may include nausea, vomiting, and diarrhea, all of which are typically mild and self-limiting.²² Co-formulation of darunavir with cobicistat, tenofovir alafenamide, and emtricitabine is in phase III studies. Projected to be available in late 2017, it will provide yet another daily STR option.²³

The addition of fixed-dose tenofovir alafenamide/emtricitabine

In July 2016, the DHHS panel made some additions to their guidelines to reflect the FDA approval of 3 fixed-dose combination products that contain tenofovir alafenamide. Specifically, the combination of tenofovir alafenamide and emtricitabine is recommended for use with the integrase inhibitors—dolutegravir or raltegravir. It is also recommended in combination with ritonavir-boosted darunavir.

 

 

DHHS “alternative” and“other” regimens

The DHHS guidelines also include “alternative” (TABLE 3²) and “other” regimens (available at: http://aidsinfo.nih.gov/guidelines) that may be used when first-line regimens may not. These second-line options are very effective, but have some possible clinical disadvantages or limitations. They are also less well supported by data from clinical trials. However, in certain situations, depending on an individual patient’s comorbidities, inability to tolerate one of the preferred regimens, or personal preferences, an alternative regimen may be the optimal choice.

Under the category of alternative regimens, the panel has included tenofovir alafenamide and emtricitabine in combination with the NNRTI efavirenz or with ritonavir- or cobicistat-boosted atazanavir or darunavir.

Consider the new 4-drug, single-tablet formulation for older patients with HIV or those with comorbidities such as hypertension or diabetes.The third group or “other” regimens have reduced virologic activity, increased toxicity, and even more limited data from clinical trials. Generally, medications from the DHHS “alternative” and “other” categories should be prescribed in consultation with an HIV specialist.

The future of ART

The currently available drugs are highly effective in fully suppressing HIV and allowing for immune recovery and clinical stability for most patients. Life expectancy for patients living with HIV is estimated to be approaching that of uninfected adults—provided they remain on ART.²⁴ As a way to further simplify ART, current clinical trials are looking at 2-drug regimens including an integrase inhibitor with an NRTI, an INSTI, or an NNRTI, or a PI with one NRTI.^25,26 This approach could further reduce pill burden and toxicity and substantially decrease the cost of long-term treatment.²⁷ Also on the horizon are long-acting injectable antiretroviral drugs that will likely be available for clinical use in the next 2 to 3 years.^28,29

CASE › At the 2-week follow-up visit, you discuss with Mr. G that his CD4+ count is 390 cells/mm³, his HIV RNA level is 32,450 copies/mL, and his HIV genotype test showed no antiviral drug resistance. Explaining that all patients with HIV should be treated with antiviral therapy regardless of CD4+ count, you recommend that Mr. G begin taking fixed-dose tenofovir disoproxil fumarate/emtricitabine/elvitegravir/cobicistat (Stribild), noting that it is one of the regimens recommended by the DHHS national treatment guidelines. You provide a patient handout that discusses dosing and adverse effects, including nausea and headache. The patient’s pharmacy was contacted and it was determined that Mr. G’s co-pay for the drug would be $50, which he found acceptable.

In addition, you discuss the importance of good adherence to this medication, and instruct Mr. G to contact the office via phone or patient portal for any concerns or questions that arise after starting the medication. Lastly, you advise him to return in 4 weeks for follow-up blood testing, including viral load monitoring, and additional care, if needed, and strongly recommend that he begin using condoms regularly.

CORRESPONDENCE
Jeffrey T. Kirchner, DO, FAAFP, AAHIVS, Medical Director, LGHP Comprehensive Care, 554 North Duke St., 3rd Floor, Lancaster, PA 1760; [email protected].

CASE › James G, age 43, recently had blood work performed for a life insurance policy, and his human immunodeficiency virus (HIV) test came back positive. At a follow-up office visit, Mr. G reports having anonymous male sexual partners when traveling to New York on business and rarely using condoms. His last HIV test was “about 4 years ago.” He is otherwise in good health, takes no regular medications, and is not married.

Having recently completed a primary care CME program on HIV disease, you order a CD4/T-cell count, an HIV RNA (viral load) test, and an HIV genotype drug resistance test on Mr. G, along with other baseline lab work, including a complete blood count, chemistry panel, and hepatitis panel. You schedule a follow-up visit with Mr. G in 2 weeks when all of the lab results will be available so that you can discuss his plan of care.

A diagnosis of HIV has moved from being a fatal disease to that of a chronic condition that can be effectively managed with combination antiretroviral therapy (ART) regimens over an almost normal lifespan. As a result, the role of the primary care practitioner in the ongoing care of patients with HIV has grown and will continue to do so, making knowledge of these drug combinations vital.

20 years have changed everything

Combination ART has existed since 1996 when the first protease inhibitors (PIs) were approved by the US Food and Drug Administration (FDA). Prior to this, treatment was limited to mono or dual therapy with nucleoside reverse transcriptase inhibitors (NRTIs). These agents provided some short-term clinical benefit, but didn’t significantly improve patient survival and ultimately failed due to viral resistance.¹

Since the approval of zidovudine (AZT) in 1987, the FDA has approved more than 25 drugs in 6 different classes for the treatment of HIV disease.² These include the NRTIs, non-nucleoside reverse transcriptase inhibitors (NNRTIs), PIs, a fusion inhibitor (FI), a CCR5 antagonist, and, more recently, integrase strand transfer inhibitors (INSTIs). In addition, 2 drugs, cobicistat and ritonavir, are used solely to improve or “boost” the pharmacokinetic profiles of several antiretroviral drugs.²

Most of these newer agents are more potent, have a higher genetic barrier to resistance, and a longer half-life than their predecessors. Moreover, many are less toxic and thus more tolerable than older drugs. With the progressive development and approval of single-tablet regimens (STRs) that contain 3 or 4 drugs, the majority of patients with HIV in the United States now take just one pill per day to treat their infection, facilitating far greater medication adherence.

 

 

Initiation of antiretroviral therapy

The US Department of Health and Human Services (DHHS) guidelines now recommend that all people infected with HIV, regardless of CD4 cell count, begin ART.² The evidence for this recommendation comes largely from the START³ and TEMPRANO⁴ trials, which found that early initiation of ART significantly reduces morbidity and mortality associated with HIV. In addition, the HPTN 052 study concluded that early ART is associated with a 93% lower risk of viral transmission in serodiscordant heterosexual couples.⁵ The DHHS guidelines do note that when initiating ART, it is important to appropriately educate patients on the benefits of treatment and address strategies to optimize adherence.² (For more on factors to consider when selecting an initial HIV regimen, see TABLE 1.²) On a case-by-case basis, ART may be deferred because of clinical and/or psychosocial factors, but it should never be withheld unless the risks clearly outweigh the benefits. Ideally, ART should be initiated as soon as possible after the initial diagnosis of HIV.

The DHHS guidelines divide treatment options into 3 categories:²

• Recommended regimens are backed by randomized controlled trials that show optimal and durable virologic efficacy, they have favorable tolerability and toxicity profiles, and they are easy to use.
• Alternative regimens have less or lower quality supporting data than recommended regimens. Although they are effective and may be optimal for certain individual patients, they have potential disadvantages and/or limitations in certain populations.
• Other regimens have limited supporting data, reduced virologic activity, a higher pill burden, more drug interactions, and greater toxicity.

Currently recommended first-line therapies

An antiretroviral regimen for a treatment-naive patient should consist of 2 NRTIs in combination with a third active antiretroviral drug from one of 3 drug classes. These include: an INSTI, a boosted PI, or, in some situations, an NNRTI. The DHHS guidelines panel currently recommends 6 different ART combinations as first-line treatment in treatment-naive patients (TABLE 2).²

 

 

INSTI-based regimens

Dolutegravir/abacavir/lamivudine (Triumeq). Approved by the FDA as a single-tablet regimen in 2014, the combination of dolutegravir/abacavir/lamivudine has proven to be highly effective and well-tolerated in many clinical trials.^6-9 However, before this regimen is started, patients must be screened for the HLA-B*5701 allele, which predicts hypersensitivity to abacavir.¹⁰ Assessing patients’ risk for cardiovascular disease is also advised because some data suggest that abacavir may increase the risk of cardiovascular events, although this remains controversial.²

Most of the newer agents are more potent, less toxic, have a higher genetic barrier to resistance, and a longer half-life than their predecessors.Dolutegravir is generally well-tolerated with minimal adverse effects (≥2% incidence of headache and insomnia) and toxicity.¹¹ Dolutegravir/abacavir/lamivudine should be taken 2 hours before or 6 hours after taking antacids or laxatives, sucralfate, and oral supplements with iron or calcium. However, it may be taken with calcium or iron supplements if it is also taken with food.¹¹ Dolutegravir increases levels of metformin about 2-fold, so patients should not take more than 1000 mg/d of this oral hypoglycemic agent.¹¹

Dolutegravir plus tenofovir disoproxil fumarate/emtricitabine (Tivicay plus Truvada). The combination of dolutegravir plus fixed-dose tenofovir disoproxil fumarate and emtricitabine is administered as 2 pills per day. Because tenofovir disoproxil fumarate can cause proximal renal tubular dysfunction, phosphate wasting, and decreased bone mineral density (BMD), avoid prescribing it for patients with underlying renal dysfunction (creatinine clearance [CrCl] <50 mL/min) and prescribe it cautiously for patients with hypertension or diabetes who are at increased risk of renal disease. Emtricitabine is generally safe and well tolerated, but the dose should be reduced in patients with renal insufficiency, which would preclude the use of this fixed-dose combination.¹²

Elvitegravir/cobicistat/tenofovir alafenamide/emtricitabine (Genvoya). The newer 4-drug combination of elvite­gravir/­­cobicistat/tenofovir alafenamide/emtricitabine­­ that was approved by the FDA in November 2015,¹³ contains the more recently approved form of tenofovir, which can be used in patients who have a CrCl as low as 30 mL/min. Compared to formulations containing tenofovir disoproxil fumarate, the newer tenofovir alafenamide formulation achieves higher intracellular levels in CD4 lymphocytes (but not in renal tubular cells). This allows for a lower dose of the drug and a smaller tablet size with co-formulation. It does not appear to cause kidney problems or loss of BMD as can be seen with tenofovir disoproxil fumarate.¹⁴ This newer single-tablet regimen may be best suited for older patients with HIV or those with comorbidities such as hypertension or diabetes.

Elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine (Stribild). The FDA approved the combination of elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine as a single-tablet regimen in 2012. The integrase inhibitor, elvitegravir, requires boosting with the CYP3A inhibitor, cobicistat, and should be taken with food.¹⁵ Two clinical trials demonstrated the superior efficacy of elvitegravir compared to a boosted PI and NNRTI-based regimen.^16,17 Elvitegravir is generally well tolerated, but sometimes causes dyspepsia, nausea, or diarrhea.¹⁵ Similar to dolutegravir, it should not be taken concurrently with certain supplements—in this case, those containing aluminum, calcium, iron, magnesium, or zinc.¹⁵ Because it contains tenofovir disoproxil fumarate as an active agent, it should not be used in patients with a CrCl of <70 mL/min.¹⁵

Cobicistat inhibits tubular secretion of creatinine, so it may produce an elevation in serum creatinine without actually affecting glomerular function. Cobicistat may also cause drug-drug interactions with certain antiarrhythmics, sedative-hypnotics, and erectile dysfunction agents, and is contraindicated with some statins, anticonvulsants, and ergot derivatives.¹⁸

Raltegravir plus tenofovir disoproxil fumarate/emtricitabine (Isentress plus Truvada). The combination of the integrase inhibitor raltegravir plus fixed-dose tenofovir disoproxil fumarate and emtricitabine has been recommended by the DHHS as first-line therapy for approximately 5 years. The recommendation is based mainly on data from the STARTMRK trial, a phase III non-inferiority trial that followed more than 500 patients for 5 years and concluded that raltegravir/tenofovir/emtricitabine has superior efficacy with fewer drug-related adverse effects than efavirenz/tenofovir/emtricitabine.¹⁹ The overall pill burden with this regimen is 3 tablets per day. Although highly effective, the main drawbacks of raltegravir are that it must be dosed twice daily (which may be less preferable if adherence is a concern) and the genetic barrier to resistance is lower than that of the other 2 approved integrase inhibitors. There is a once-daily formulation of raltegravir that's expected to be available late in 2017.²⁰

Before starting a regimen with abacavir, screen patients for the HLA-B*5701 allele, which predicts hypersensitivity to the drug.Adverse effects and toxicities (except the renal and bone effects due to tenofovir disoproxil fumarate mentioned earlier) and drug interactions with this regimen are infrequent. Raltegravir can be taken with or without food. Concurrent use of antacids that contain aluminum or magnesium may reduce absorption of raltegravir and so should be avoided.²¹

PI-based regimen

Darunavir (Prezista) and ritonavir (Norvir) plus tenofovir disoproxil fumarate/emtricitabine (Truvada). PIs were once the key component of all ART regimens; however, boosted darunavir is now the only PI-based regimen currently recommended as first-line therapy. It is taken as 3 tablets once daily. If the co-formulation with cobicistat is used, just 2 tablets daily are required. One advantage with darunavir with either of the boosting agents is that it does not appear to cause insulin resistance or dyslipidemia as occurs with older PIs, such as indinavir and lopinavir.² The boosting agents do, however, increase the likelihood of drug-drug interactions. As with all PIs, darunavir has a very high genetic barrier to resistance, which is important in patients for whom adherence is a concern.

Adverse effects of the PIs may include nausea, vomiting, and diarrhea, all of which are typically mild and self-limiting.²² Co-formulation of darunavir with cobicistat, tenofovir alafenamide, and emtricitabine is in phase III studies. Projected to be available in late 2017, it will provide yet another daily STR option.²³

The addition of fixed-dose tenofovir alafenamide/emtricitabine

In July 2016, the DHHS panel made some additions to their guidelines to reflect the FDA approval of 3 fixed-dose combination products that contain tenofovir alafenamide. Specifically, the combination of tenofovir alafenamide and emtricitabine is recommended for use with the integrase inhibitors—dolutegravir or raltegravir. It is also recommended in combination with ritonavir-boosted darunavir.

 

 

DHHS “alternative” and“other” regimens

The DHHS guidelines also include “alternative” (TABLE 3²) and “other” regimens (available at: http://aidsinfo.nih.gov/guidelines) that may be used when first-line regimens may not. These second-line options are very effective, but have some possible clinical disadvantages or limitations. They are also less well supported by data from clinical trials. However, in certain situations, depending on an individual patient’s comorbidities, inability to tolerate one of the preferred regimens, or personal preferences, an alternative regimen may be the optimal choice.

Under the category of alternative regimens, the panel has included tenofovir alafenamide and emtricitabine in combination with the NNRTI efavirenz or with ritonavir- or cobicistat-boosted atazanavir or darunavir.

Consider the new 4-drug, single-tablet formulation for older patients with HIV or those with comorbidities such as hypertension or diabetes.The third group or “other” regimens have reduced virologic activity, increased toxicity, and even more limited data from clinical trials. Generally, medications from the DHHS “alternative” and “other” categories should be prescribed in consultation with an HIV specialist.

The future of ART

The currently available drugs are highly effective in fully suppressing HIV and allowing for immune recovery and clinical stability for most patients. Life expectancy for patients living with HIV is estimated to be approaching that of uninfected adults—provided they remain on ART.²⁴ As a way to further simplify ART, current clinical trials are looking at 2-drug regimens including an integrase inhibitor with an NRTI, an INSTI, or an NNRTI, or a PI with one NRTI.^25,26 This approach could further reduce pill burden and toxicity and substantially decrease the cost of long-term treatment.²⁷ Also on the horizon are long-acting injectable antiretroviral drugs that will likely be available for clinical use in the next 2 to 3 years.^28,29

CASE › At the 2-week follow-up visit, you discuss with Mr. G that his CD4+ count is 390 cells/mm³, his HIV RNA level is 32,450 copies/mL, and his HIV genotype test showed no antiviral drug resistance. Explaining that all patients with HIV should be treated with antiviral therapy regardless of CD4+ count, you recommend that Mr. G begin taking fixed-dose tenofovir disoproxil fumarate/emtricitabine/elvitegravir/cobicistat (Stribild), noting that it is one of the regimens recommended by the DHHS national treatment guidelines. You provide a patient handout that discusses dosing and adverse effects, including nausea and headache. The patient’s pharmacy was contacted and it was determined that Mr. G’s co-pay for the drug would be $50, which he found acceptable.

In addition, you discuss the importance of good adherence to this medication, and instruct Mr. G to contact the office via phone or patient portal for any concerns or questions that arise after starting the medication. Lastly, you advise him to return in 4 weeks for follow-up blood testing, including viral load monitoring, and additional care, if needed, and strongly recommend that he begin using condoms regularly.

CORRESPONDENCE
Jeffrey T. Kirchner, DO, FAAFP, AAHIVS, Medical Director, LGHP Comprehensive Care, 554 North Duke St., 3rd Floor, Lancaster, PA 1760; [email protected].

CASE › James G, age 43, recently had blood work performed for a life insurance policy, and his human immunodeficiency virus (HIV) test came back positive. At a follow-up office visit, Mr. G reports having anonymous male sexual partners when traveling to New York on business and rarely using condoms. His last HIV test was “about 4 years ago.” He is otherwise in good health, takes no regular medications, and is not married.

Having recently completed a primary care CME program on HIV disease, you order a CD4/T-cell count, an HIV RNA (viral load) test, and an HIV genotype drug resistance test on Mr. G, along with other baseline lab work, including a complete blood count, chemistry panel, and hepatitis panel. You schedule a follow-up visit with Mr. G in 2 weeks when all of the lab results will be available so that you can discuss his plan of care.

A diagnosis of HIV has moved from being a fatal disease to that of a chronic condition that can be effectively managed with combination antiretroviral therapy (ART) regimens over an almost normal lifespan. As a result, the role of the primary care practitioner in the ongoing care of patients with HIV has grown and will continue to do so, making knowledge of these drug combinations vital.

20 years have changed everything

Combination ART has existed since 1996 when the first protease inhibitors (PIs) were approved by the US Food and Drug Administration (FDA). Prior to this, treatment was limited to mono or dual therapy with nucleoside reverse transcriptase inhibitors (NRTIs). These agents provided some short-term clinical benefit, but didn’t significantly improve patient survival and ultimately failed due to viral resistance.¹

Since the approval of zidovudine (AZT) in 1987, the FDA has approved more than 25 drugs in 6 different classes for the treatment of HIV disease.² These include the NRTIs, non-nucleoside reverse transcriptase inhibitors (NNRTIs), PIs, a fusion inhibitor (FI), a CCR5 antagonist, and, more recently, integrase strand transfer inhibitors (INSTIs). In addition, 2 drugs, cobicistat and ritonavir, are used solely to improve or “boost” the pharmacokinetic profiles of several antiretroviral drugs.²

Most of these newer agents are more potent, have a higher genetic barrier to resistance, and a longer half-life than their predecessors. Moreover, many are less toxic and thus more tolerable than older drugs. With the progressive development and approval of single-tablet regimens (STRs) that contain 3 or 4 drugs, the majority of patients with HIV in the United States now take just one pill per day to treat their infection, facilitating far greater medication adherence.

 

 

Initiation of antiretroviral therapy

The US Department of Health and Human Services (DHHS) guidelines now recommend that all people infected with HIV, regardless of CD4 cell count, begin ART.² The evidence for this recommendation comes largely from the START³ and TEMPRANO⁴ trials, which found that early initiation of ART significantly reduces morbidity and mortality associated with HIV. In addition, the HPTN 052 study concluded that early ART is associated with a 93% lower risk of viral transmission in serodiscordant heterosexual couples.⁵ The DHHS guidelines do note that when initiating ART, it is important to appropriately educate patients on the benefits of treatment and address strategies to optimize adherence.² (For more on factors to consider when selecting an initial HIV regimen, see TABLE 1.²) On a case-by-case basis, ART may be deferred because of clinical and/or psychosocial factors, but it should never be withheld unless the risks clearly outweigh the benefits. Ideally, ART should be initiated as soon as possible after the initial diagnosis of HIV.

The DHHS guidelines divide treatment options into 3 categories:²

• Recommended regimens are backed by randomized controlled trials that show optimal and durable virologic efficacy, they have favorable tolerability and toxicity profiles, and they are easy to use.
• Alternative regimens have less or lower quality supporting data than recommended regimens. Although they are effective and may be optimal for certain individual patients, they have potential disadvantages and/or limitations in certain populations.
• Other regimens have limited supporting data, reduced virologic activity, a higher pill burden, more drug interactions, and greater toxicity.

Currently recommended first-line therapies

An antiretroviral regimen for a treatment-naive patient should consist of 2 NRTIs in combination with a third active antiretroviral drug from one of 3 drug classes. These include: an INSTI, a boosted PI, or, in some situations, an NNRTI. The DHHS guidelines panel currently recommends 6 different ART combinations as first-line treatment in treatment-naive patients (TABLE 2).²

 

 

INSTI-based regimens

Dolutegravir/abacavir/lamivudine (Triumeq). Approved by the FDA as a single-tablet regimen in 2014, the combination of dolutegravir/abacavir/lamivudine has proven to be highly effective and well-tolerated in many clinical trials.^6-9 However, before this regimen is started, patients must be screened for the HLA-B*5701 allele, which predicts hypersensitivity to abacavir.¹⁰ Assessing patients’ risk for cardiovascular disease is also advised because some data suggest that abacavir may increase the risk of cardiovascular events, although this remains controversial.²

Most of the newer agents are more potent, less toxic, have a higher genetic barrier to resistance, and a longer half-life than their predecessors.Dolutegravir is generally well-tolerated with minimal adverse effects (≥2% incidence of headache and insomnia) and toxicity.¹¹ Dolutegravir/abacavir/lamivudine should be taken 2 hours before or 6 hours after taking antacids or laxatives, sucralfate, and oral supplements with iron or calcium. However, it may be taken with calcium or iron supplements if it is also taken with food.¹¹ Dolutegravir increases levels of metformin about 2-fold, so patients should not take more than 1000 mg/d of this oral hypoglycemic agent.¹¹

Dolutegravir plus tenofovir disoproxil fumarate/emtricitabine (Tivicay plus Truvada). The combination of dolutegravir plus fixed-dose tenofovir disoproxil fumarate and emtricitabine is administered as 2 pills per day. Because tenofovir disoproxil fumarate can cause proximal renal tubular dysfunction, phosphate wasting, and decreased bone mineral density (BMD), avoid prescribing it for patients with underlying renal dysfunction (creatinine clearance [CrCl] <50 mL/min) and prescribe it cautiously for patients with hypertension or diabetes who are at increased risk of renal disease. Emtricitabine is generally safe and well tolerated, but the dose should be reduced in patients with renal insufficiency, which would preclude the use of this fixed-dose combination.¹²

Elvitegravir/cobicistat/tenofovir alafenamide/emtricitabine (Genvoya). The newer 4-drug combination of elvite­gravir/­­cobicistat/tenofovir alafenamide/emtricitabine­­ that was approved by the FDA in November 2015,¹³ contains the more recently approved form of tenofovir, which can be used in patients who have a CrCl as low as 30 mL/min. Compared to formulations containing tenofovir disoproxil fumarate, the newer tenofovir alafenamide formulation achieves higher intracellular levels in CD4 lymphocytes (but not in renal tubular cells). This allows for a lower dose of the drug and a smaller tablet size with co-formulation. It does not appear to cause kidney problems or loss of BMD as can be seen with tenofovir disoproxil fumarate.¹⁴ This newer single-tablet regimen may be best suited for older patients with HIV or those with comorbidities such as hypertension or diabetes.

Elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine (Stribild). The FDA approved the combination of elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine as a single-tablet regimen in 2012. The integrase inhibitor, elvitegravir, requires boosting with the CYP3A inhibitor, cobicistat, and should be taken with food.¹⁵ Two clinical trials demonstrated the superior efficacy of elvitegravir compared to a boosted PI and NNRTI-based regimen.^16,17 Elvitegravir is generally well tolerated, but sometimes causes dyspepsia, nausea, or diarrhea.¹⁵ Similar to dolutegravir, it should not be taken concurrently with certain supplements—in this case, those containing aluminum, calcium, iron, magnesium, or zinc.¹⁵ Because it contains tenofovir disoproxil fumarate as an active agent, it should not be used in patients with a CrCl of <70 mL/min.¹⁵

Cobicistat inhibits tubular secretion of creatinine, so it may produce an elevation in serum creatinine without actually affecting glomerular function. Cobicistat may also cause drug-drug interactions with certain antiarrhythmics, sedative-hypnotics, and erectile dysfunction agents, and is contraindicated with some statins, anticonvulsants, and ergot derivatives.¹⁸

Raltegravir plus tenofovir disoproxil fumarate/emtricitabine (Isentress plus Truvada). The combination of the integrase inhibitor raltegravir plus fixed-dose tenofovir disoproxil fumarate and emtricitabine has been recommended by the DHHS as first-line therapy for approximately 5 years. The recommendation is based mainly on data from the STARTMRK trial, a phase III non-inferiority trial that followed more than 500 patients for 5 years and concluded that raltegravir/tenofovir/emtricitabine has superior efficacy with fewer drug-related adverse effects than efavirenz/tenofovir/emtricitabine.¹⁹ The overall pill burden with this regimen is 3 tablets per day. Although highly effective, the main drawbacks of raltegravir are that it must be dosed twice daily (which may be less preferable if adherence is a concern) and the genetic barrier to resistance is lower than that of the other 2 approved integrase inhibitors. There is a once-daily formulation of raltegravir that's expected to be available late in 2017.²⁰

Before starting a regimen with abacavir, screen patients for the HLA-B*5701 allele, which predicts hypersensitivity to the drug.Adverse effects and toxicities (except the renal and bone effects due to tenofovir disoproxil fumarate mentioned earlier) and drug interactions with this regimen are infrequent. Raltegravir can be taken with or without food. Concurrent use of antacids that contain aluminum or magnesium may reduce absorption of raltegravir and so should be avoided.²¹

PI-based regimen

Darunavir (Prezista) and ritonavir (Norvir) plus tenofovir disoproxil fumarate/emtricitabine (Truvada). PIs were once the key component of all ART regimens; however, boosted darunavir is now the only PI-based regimen currently recommended as first-line therapy. It is taken as 3 tablets once daily. If the co-formulation with cobicistat is used, just 2 tablets daily are required. One advantage with darunavir with either of the boosting agents is that it does not appear to cause insulin resistance or dyslipidemia as occurs with older PIs, such as indinavir and lopinavir.² The boosting agents do, however, increase the likelihood of drug-drug interactions. As with all PIs, darunavir has a very high genetic barrier to resistance, which is important in patients for whom adherence is a concern.

Adverse effects of the PIs may include nausea, vomiting, and diarrhea, all of which are typically mild and self-limiting.²² Co-formulation of darunavir with cobicistat, tenofovir alafenamide, and emtricitabine is in phase III studies. Projected to be available in late 2017, it will provide yet another daily STR option.²³

The addition of fixed-dose tenofovir alafenamide/emtricitabine

In July 2016, the DHHS panel made some additions to their guidelines to reflect the FDA approval of 3 fixed-dose combination products that contain tenofovir alafenamide. Specifically, the combination of tenofovir alafenamide and emtricitabine is recommended for use with the integrase inhibitors—dolutegravir or raltegravir. It is also recommended in combination with ritonavir-boosted darunavir.

 

 

DHHS “alternative” and“other” regimens

The DHHS guidelines also include “alternative” (TABLE 3²) and “other” regimens (available at: http://aidsinfo.nih.gov/guidelines) that may be used when first-line regimens may not. These second-line options are very effective, but have some possible clinical disadvantages or limitations. They are also less well supported by data from clinical trials. However, in certain situations, depending on an individual patient’s comorbidities, inability to tolerate one of the preferred regimens, or personal preferences, an alternative regimen may be the optimal choice.

Under the category of alternative regimens, the panel has included tenofovir alafenamide and emtricitabine in combination with the NNRTI efavirenz or with ritonavir- or cobicistat-boosted atazanavir or darunavir.

Consider the new 4-drug, single-tablet formulation for older patients with HIV or those with comorbidities such as hypertension or diabetes.The third group or “other” regimens have reduced virologic activity, increased toxicity, and even more limited data from clinical trials. Generally, medications from the DHHS “alternative” and “other” categories should be prescribed in consultation with an HIV specialist.

The future of ART

The currently available drugs are highly effective in fully suppressing HIV and allowing for immune recovery and clinical stability for most patients. Life expectancy for patients living with HIV is estimated to be approaching that of uninfected adults—provided they remain on ART.²⁴ As a way to further simplify ART, current clinical trials are looking at 2-drug regimens including an integrase inhibitor with an NRTI, an INSTI, or an NNRTI, or a PI with one NRTI.^25,26 This approach could further reduce pill burden and toxicity and substantially decrease the cost of long-term treatment.²⁷ Also on the horizon are long-acting injectable antiretroviral drugs that will likely be available for clinical use in the next 2 to 3 years.^28,29

CASE › At the 2-week follow-up visit, you discuss with Mr. G that his CD4+ count is 390 cells/mm³, his HIV RNA level is 32,450 copies/mL, and his HIV genotype test showed no antiviral drug resistance. Explaining that all patients with HIV should be treated with antiviral therapy regardless of CD4+ count, you recommend that Mr. G begin taking fixed-dose tenofovir disoproxil fumarate/emtricitabine/elvitegravir/cobicistat (Stribild), noting that it is one of the regimens recommended by the DHHS national treatment guidelines. You provide a patient handout that discusses dosing and adverse effects, including nausea and headache. The patient’s pharmacy was contacted and it was determined that Mr. G’s co-pay for the drug would be $50, which he found acceptable.

In addition, you discuss the importance of good adherence to this medication, and instruct Mr. G to contact the office via phone or patient portal for any concerns or questions that arise after starting the medication. Lastly, you advise him to return in 4 weeks for follow-up blood testing, including viral load monitoring, and additional care, if needed, and strongly recommend that he begin using condoms regularly.

CORRESPONDENCE
Jeffrey T. Kirchner, DO, FAAFP, AAHIVS, Medical Director, LGHP Comprehensive Care, 554 North Duke St., 3rd Floor, Lancaster, PA 1760; [email protected].

One of my brothers has adult onset bipolar disorder. As luck would have it, he also has type 2 diabetes mellitus. He struggles constantly with blood sugar control since he needs to take 2 psychotropic medications, both of which cause weight gain.

I mistakenly told a patient that her beta-blocker wasn't interfering with her weight loss.His situation has prompted me to think about the responsibility we have as we care, and advocate, for our patients with major mental illness who require these effective medications. At a minimum, we must be knowledgeable about the adverse metabolic effects of these drugs, avoid prescribing them when possible, and advocate for dose reductions when feasible. Knowing, for example, that these drugs fall on a spectrum, with haloperidol causing the least weight gain and olanzapine causing the most, is important.¹

An eye-opener. The article by Saunders in this issue provides advice on avoiding medications that commonly cause weight gain when prescribing for overweight or obese patients with diabetes, hypertension, and/or depression. I was unaware that some of the drugs on the list contribute to the problem. For example, I saw a new patient last week who has hypertension and is obese; she has been taking the beta-blocker metoprolol for the past 8 years. She has tried unsuccessfully to lose weight. She asked me if the metoprolol could be interfering with weight loss, and I mistakenly told her “No.” Thankfully, we decided to discontinue it anyway. I will admit to her my knowledge gap when I see her next month for follow-up. Errors are great teachers, especially when no harm is done.

The scope of the Saunders article is not meant to be comprehensive, since it focuses on medications for diabetes, hypertension, and depression. I think all of us are aware of the weight gain associated with other commonly prescribed drugs, such as systemic corticosteroids and long-acting progesterone for contraception. Thankfully, combination oral contraceptives do not appear to be associated with weight gain²—answering one of the more common questions I receive from patients about weight and medications.

The bottom line. Avoid prescribing medications that can cause weight gain in overweight and obese patients when possible, use the lowest effective dose when such agents are necessary, and warn patients of this adverse effect so that they can take precautions, such as walking an extra mile a day or giving up that high-calorie latte in the morning.

1. Leucht S, Cipriani A, Spineli L, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet. 2013;382:951-962.

2. Gallo MF, Lopez LM, Grimes DA, et al. Combination contraceptives: effects on weight. Cochrane Database Syst Rev. 2011;CD003987.

One of my brothers has adult onset bipolar disorder. As luck would have it, he also has type 2 diabetes mellitus. He struggles constantly with blood sugar control since he needs to take 2 psychotropic medications, both of which cause weight gain.

I mistakenly told a patient that her beta-blocker wasn't interfering with her weight loss.His situation has prompted me to think about the responsibility we have as we care, and advocate, for our patients with major mental illness who require these effective medications. At a minimum, we must be knowledgeable about the adverse metabolic effects of these drugs, avoid prescribing them when possible, and advocate for dose reductions when feasible. Knowing, for example, that these drugs fall on a spectrum, with haloperidol causing the least weight gain and olanzapine causing the most, is important.¹

An eye-opener. The article by Saunders in this issue provides advice on avoiding medications that commonly cause weight gain when prescribing for overweight or obese patients with diabetes, hypertension, and/or depression. I was unaware that some of the drugs on the list contribute to the problem. For example, I saw a new patient last week who has hypertension and is obese; she has been taking the beta-blocker metoprolol for the past 8 years. She has tried unsuccessfully to lose weight. She asked me if the metoprolol could be interfering with weight loss, and I mistakenly told her “No.” Thankfully, we decided to discontinue it anyway. I will admit to her my knowledge gap when I see her next month for follow-up. Errors are great teachers, especially when no harm is done.

The scope of the Saunders article is not meant to be comprehensive, since it focuses on medications for diabetes, hypertension, and depression. I think all of us are aware of the weight gain associated with other commonly prescribed drugs, such as systemic corticosteroids and long-acting progesterone for contraception. Thankfully, combination oral contraceptives do not appear to be associated with weight gain²—answering one of the more common questions I receive from patients about weight and medications.

The bottom line. Avoid prescribing medications that can cause weight gain in overweight and obese patients when possible, use the lowest effective dose when such agents are necessary, and warn patients of this adverse effect so that they can take precautions, such as walking an extra mile a day or giving up that high-calorie latte in the morning.

1. Leucht S, Cipriani A, Spineli L, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet. 2013;382:951-962.

2. Gallo MF, Lopez LM, Grimes DA, et al. Combination contraceptives: effects on weight. Cochrane Database Syst Rev. 2011;CD003987.

One of my brothers has adult onset bipolar disorder. As luck would have it, he also has type 2 diabetes mellitus. He struggles constantly with blood sugar control since he needs to take 2 psychotropic medications, both of which cause weight gain.

I mistakenly told a patient that her beta-blocker wasn't interfering with her weight loss.His situation has prompted me to think about the responsibility we have as we care, and advocate, for our patients with major mental illness who require these effective medications. At a minimum, we must be knowledgeable about the adverse metabolic effects of these drugs, avoid prescribing them when possible, and advocate for dose reductions when feasible. Knowing, for example, that these drugs fall on a spectrum, with haloperidol causing the least weight gain and olanzapine causing the most, is important.¹

An eye-opener. The article by Saunders in this issue provides advice on avoiding medications that commonly cause weight gain when prescribing for overweight or obese patients with diabetes, hypertension, and/or depression. I was unaware that some of the drugs on the list contribute to the problem. For example, I saw a new patient last week who has hypertension and is obese; she has been taking the beta-blocker metoprolol for the past 8 years. She has tried unsuccessfully to lose weight. She asked me if the metoprolol could be interfering with weight loss, and I mistakenly told her “No.” Thankfully, we decided to discontinue it anyway. I will admit to her my knowledge gap when I see her next month for follow-up. Errors are great teachers, especially when no harm is done.

The scope of the Saunders article is not meant to be comprehensive, since it focuses on medications for diabetes, hypertension, and depression. I think all of us are aware of the weight gain associated with other commonly prescribed drugs, such as systemic corticosteroids and long-acting progesterone for contraception. Thankfully, combination oral contraceptives do not appear to be associated with weight gain²—answering one of the more common questions I receive from patients about weight and medications.

The bottom line. Avoid prescribing medications that can cause weight gain in overweight and obese patients when possible, use the lowest effective dose when such agents are necessary, and warn patients of this adverse effect so that they can take precautions, such as walking an extra mile a day or giving up that high-calorie latte in the morning.

1. Leucht S, Cipriani A, Spineli L, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet. 2013;382:951-962.

2. Gallo MF, Lopez LM, Grimes DA, et al. Combination contraceptives: effects on weight. Cochrane Database Syst Rev. 2011;CD003987.

Separate sampling of the duodenal bulb increased detection of celiac disease by only 0.1% when endoscopy patients had a low pretest probability of celiac disease, according to research published in the November issue of Clinical Gastroenterology and Hepatology.

Duodenal bulb histology did reveal other abnormal findings, such as chronic peptic duodenitis, gastric heterotopia, and Brunner gland hyperplasia, wrote Samantha Stoven, MD, of Mayo Clinic, Rochester, Minn., and her associates. These findings did not seem to impede the identification of celiac disease, but their clinical implications were unclear, the researchers noted.

©Monthian/Thinkstock

Most studies of the diagnostic yield of duodenal bulb specimens have been performed in patients with known celiac disease or positive serology. In past studies of these high-probability cohorts, duodenal bulb sampling increased the diagnostic yield of celiac disease anywhere from 1.8% to 18%, but whether and how that finding translates to low-probability cohorts is unclear, the researchers said. Therefore, they retrospectively analyzed data from 679 endoscopy patients who had both duodenal bulb and small bowel biopsies collected at three Mayo Clinic sites in 2011. These sites are “open access,” meaning that patients can be referred for endoscopy without the approval of a gastroenterologist.

The average age of the patients was 50 years, and 63% were female. They were most commonly referred for duodenal biopsy because of chronic dyspepsia (46% of patients), diarrhea (35%), or nausea (17%). Patients with either known celiac disease or positive serology were excluded from the study (Clin Gastroenterol Hepatol. 2016 Mar 7. doi: 10.1016/j.cgh.2016.02.026). A total of 265 patients (39%) had abnormal duodenal histology, which was most often diagnosed as chronic peptic duodenitis, the researchers said. Histologic abnormalities usually involved the duodenal bulb (36% of cases), not the distal duodenum (15%; P less than .0001). However, among the 16 patients (2%) found to have celiac disease, just one patient had disease only in the duodenal bulb. Thus, duodenal bulb sampling increased the diagnostic yield of celiac disease by only 0.1% when considering the overall cohort. The patient with celiac disease limited to the bulb was a 46-year-old female presenting with diarrhea and anemia who had normal serologies but a permissive human leukocyte antigen test. Her duodenal bulb had villous atrophy and more than 25 intraepithelial lymphocytes per 100 epithelial cells, while her distal duodenum was normal.

Among the 85% of patients who had normal distal duodenums, 28% had abnormal bulb histology, most often chronic peptic duodenitis, active chronic peptic duodenitis, or gastric heterotopia, the researchers said. Among the 59% of patients whose celiac serology before endoscopy was truly unknown, only two (0.5%) had histologic changes consistent with celiac disease, which in both cases were located in the distal duodenum.

SOURCE: American Gastroenterological Association

“Individual sampling of the duodenal bulb in patients with either negative or unknown celiac serologic status can be considered in practices where expert gastrointestinal pathologists are present and there is agreement that both samples can be submitted in the same bottle, or there is not a separate charge for the additional container. Further studies may be needed to assess the diagnostic yield of separate bulb biopsies for celiac detection in all comers.”

An American College of Gastroenterology Junior Faculty Development Award helped support the work. Senior author Joseph A. Murray, MD, disclosed ties to Alba Therapeutics, Alvine Pharmaceuticals, AMAG Pharmaceuticals, and several other corporate entities. The remaining authors had no disclosures.

Separate sampling of the duodenal bulb increased detection of celiac disease by only 0.1% when endoscopy patients had a low pretest probability of celiac disease, according to research published in the November issue of Clinical Gastroenterology and Hepatology.

Duodenal bulb histology did reveal other abnormal findings, such as chronic peptic duodenitis, gastric heterotopia, and Brunner gland hyperplasia, wrote Samantha Stoven, MD, of Mayo Clinic, Rochester, Minn., and her associates. These findings did not seem to impede the identification of celiac disease, but their clinical implications were unclear, the researchers noted.

©Monthian/Thinkstock

Most studies of the diagnostic yield of duodenal bulb specimens have been performed in patients with known celiac disease or positive serology. In past studies of these high-probability cohorts, duodenal bulb sampling increased the diagnostic yield of celiac disease anywhere from 1.8% to 18%, but whether and how that finding translates to low-probability cohorts is unclear, the researchers said. Therefore, they retrospectively analyzed data from 679 endoscopy patients who had both duodenal bulb and small bowel biopsies collected at three Mayo Clinic sites in 2011. These sites are “open access,” meaning that patients can be referred for endoscopy without the approval of a gastroenterologist.

The average age of the patients was 50 years, and 63% were female. They were most commonly referred for duodenal biopsy because of chronic dyspepsia (46% of patients), diarrhea (35%), or nausea (17%). Patients with either known celiac disease or positive serology were excluded from the study (Clin Gastroenterol Hepatol. 2016 Mar 7. doi: 10.1016/j.cgh.2016.02.026). A total of 265 patients (39%) had abnormal duodenal histology, which was most often diagnosed as chronic peptic duodenitis, the researchers said. Histologic abnormalities usually involved the duodenal bulb (36% of cases), not the distal duodenum (15%; P less than .0001). However, among the 16 patients (2%) found to have celiac disease, just one patient had disease only in the duodenal bulb. Thus, duodenal bulb sampling increased the diagnostic yield of celiac disease by only 0.1% when considering the overall cohort. The patient with celiac disease limited to the bulb was a 46-year-old female presenting with diarrhea and anemia who had normal serologies but a permissive human leukocyte antigen test. Her duodenal bulb had villous atrophy and more than 25 intraepithelial lymphocytes per 100 epithelial cells, while her distal duodenum was normal.

Among the 85% of patients who had normal distal duodenums, 28% had abnormal bulb histology, most often chronic peptic duodenitis, active chronic peptic duodenitis, or gastric heterotopia, the researchers said. Among the 59% of patients whose celiac serology before endoscopy was truly unknown, only two (0.5%) had histologic changes consistent with celiac disease, which in both cases were located in the distal duodenum.

SOURCE: American Gastroenterological Association

“Individual sampling of the duodenal bulb in patients with either negative or unknown celiac serologic status can be considered in practices where expert gastrointestinal pathologists are present and there is agreement that both samples can be submitted in the same bottle, or there is not a separate charge for the additional container. Further studies may be needed to assess the diagnostic yield of separate bulb biopsies for celiac detection in all comers.”

An American College of Gastroenterology Junior Faculty Development Award helped support the work. Senior author Joseph A. Murray, MD, disclosed ties to Alba Therapeutics, Alvine Pharmaceuticals, AMAG Pharmaceuticals, and several other corporate entities. The remaining authors had no disclosures.

Separate sampling of the duodenal bulb increased detection of celiac disease by only 0.1% when endoscopy patients had a low pretest probability of celiac disease, according to research published in the November issue of Clinical Gastroenterology and Hepatology.

Duodenal bulb histology did reveal other abnormal findings, such as chronic peptic duodenitis, gastric heterotopia, and Brunner gland hyperplasia, wrote Samantha Stoven, MD, of Mayo Clinic, Rochester, Minn., and her associates. These findings did not seem to impede the identification of celiac disease, but their clinical implications were unclear, the researchers noted.

©Monthian/Thinkstock

Most studies of the diagnostic yield of duodenal bulb specimens have been performed in patients with known celiac disease or positive serology. In past studies of these high-probability cohorts, duodenal bulb sampling increased the diagnostic yield of celiac disease anywhere from 1.8% to 18%, but whether and how that finding translates to low-probability cohorts is unclear, the researchers said. Therefore, they retrospectively analyzed data from 679 endoscopy patients who had both duodenal bulb and small bowel biopsies collected at three Mayo Clinic sites in 2011. These sites are “open access,” meaning that patients can be referred for endoscopy without the approval of a gastroenterologist.

The average age of the patients was 50 years, and 63% were female. They were most commonly referred for duodenal biopsy because of chronic dyspepsia (46% of patients), diarrhea (35%), or nausea (17%). Patients with either known celiac disease or positive serology were excluded from the study (Clin Gastroenterol Hepatol. 2016 Mar 7. doi: 10.1016/j.cgh.2016.02.026). A total of 265 patients (39%) had abnormal duodenal histology, which was most often diagnosed as chronic peptic duodenitis, the researchers said. Histologic abnormalities usually involved the duodenal bulb (36% of cases), not the distal duodenum (15%; P less than .0001). However, among the 16 patients (2%) found to have celiac disease, just one patient had disease only in the duodenal bulb. Thus, duodenal bulb sampling increased the diagnostic yield of celiac disease by only 0.1% when considering the overall cohort. The patient with celiac disease limited to the bulb was a 46-year-old female presenting with diarrhea and anemia who had normal serologies but a permissive human leukocyte antigen test. Her duodenal bulb had villous atrophy and more than 25 intraepithelial lymphocytes per 100 epithelial cells, while her distal duodenum was normal.

Among the 85% of patients who had normal distal duodenums, 28% had abnormal bulb histology, most often chronic peptic duodenitis, active chronic peptic duodenitis, or gastric heterotopia, the researchers said. Among the 59% of patients whose celiac serology before endoscopy was truly unknown, only two (0.5%) had histologic changes consistent with celiac disease, which in both cases were located in the distal duodenum.

SOURCE: American Gastroenterological Association

“Individual sampling of the duodenal bulb in patients with either negative or unknown celiac serologic status can be considered in practices where expert gastrointestinal pathologists are present and there is agreement that both samples can be submitted in the same bottle, or there is not a separate charge for the additional container. Further studies may be needed to assess the diagnostic yield of separate bulb biopsies for celiac detection in all comers.”

An American College of Gastroenterology Junior Faculty Development Award helped support the work. Senior author Joseph A. Murray, MD, disclosed ties to Alba Therapeutics, Alvine Pharmaceuticals, AMAG Pharmaceuticals, and several other corporate entities. The remaining authors had no disclosures.

A 62-year-old man with hypertension, type 2 diabetes mellitus, and hypercholesterolemia presented to the emergency department with substernal chest pain that started about 15 hours earlier while he was at rest watching television.

On examination, his pulse was 92 beats per minute and regular, his blood pressure was 160/88 mm Hg, and he had no evidence of jugular venous distention or pedal edema. Lung examination was positive for bibasilar crackles.

Electrocardiography revealed Q waves with ST elevation in leads I, aVL, V₄, V₅, and V₆ with reciprocal ST depression in leads II, III, and aVF.

His troponin T level on presentation was markedly elevated.

Image

He underwent heart catheterization and was found to have 100% occlusion of the proximal left anterior descending artery. He underwent successful percutaneous coronary intervention with placement of a drug-eluting stent, and afterward had grade 3 flow on the Thrombolysis in Myocardial Infarction (TIMI) scale.

Echocardiography the next day revealed a mobile echo-dense mass in the left ventricular apex (Figure 1) and a left ventricular ejection fraction of 35%.

THE INCIDENCE OF LEFT VENTRICULAR THROMBOSIS IN ACUTE MI

1. What is the incidence of left ventricular thrombosis after acute myocardial infarction (MI), now that primary percutaneous coronary intervention is common?

• 0.1%
• 2%
• 20%
• 40%

Left ventricular thrombosis is a serious complication of acute MI that can cause systemic thromboembolism, including stroke.¹ Before thrombolytic therapy was available, this complication occurred in 20% to 60% of patients with acute MI.^2,3 But early reperfusion strategies, anticoagulation for the first 48 hours, and dual antiplatelet therapy have reduced the incidence of this complication significantly.

In the thrombolytic era, the incidence of left ventricular thrombosis was 5.1% in the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI) 3 study, which had 8,326 patients. A subset of patients who had an anterior MI had almost double the incidence (11.5%).³

Image

The incidence has further declined with the advent of primary percutaneous coronary intervention, likely thanks to enhanced myocardial salvage, and now ranges from 2.5% to 15% (Table 1).^4–11 The largest observational study, with 2,911 patients undergoing percutaneous coronary intervention, reported an incidence of 2.5% within 3 to 5 days of the MI.⁷ At our center, the incidence was found to be even lower, 1.8% in 1,700 patients presenting with ST-elevation MI undergoing primary percutaneous coronary intervention. Hence, of the answers to the question above, 2% would be closest.

Large infarct size with a low left ventricular ejection fraction (< 40%), anterior wall MI, hypertension, and delay in time from symptom onset to intervention were independent predictors of left ventricular thrombus formation in most studies.^7,12 The risk is highest during the first 2 weeks after MI, and thrombosis almost never occurs more than 3 months after the index event.^5,13–16

WHAT IS THE PATHOGENESIS OF LEFT VENTRICULAR THROMBOSIS?

A large transmural infarct results in loss of contractile function, which causes stagnation and pooling of blood adjacent to the infarcted ventricular segment. In addition, endocardial injury exposes tissue factor, which then initiates the coagulation cascade. To make matters worse, MI results in a hypercoagulable state through unclear mechanisms, which completes the Virchow triad for thrombus formation. Elevations of D-dimer, fibrinogen, anticardiolipin antibodies (IgM and IgG), and tissue factor have also been reported after acute MI.¹⁷

Thrombus formation begins with platelet aggregation at the site of endocardial damage, forming a platelet plug, followed by activation of clotting factors. These thrombi are referred to as “mural,” as they adhere to the chamber wall (endocardium). They are composed of fibrin and entrapped red and white blood cells (Figure 2).

The natural course of thrombus evolution is established but variable. A left ventricular thrombus may dislodge and embolize, resulting in stroke or other thromboembolic complications. Alternately, it can dissolve over time, aided by intrinsic fibrinolytic mechanisms. On other occasions, the thrombus may organize, a process characterized by ingrowth of smooth muscle cells, fibroblasts, and endothelium.

HOW IS LEFT VENTRICULAR THROMBOSIS DIAGNOSED?

2. What is the best imaging test for detecting a thrombus?

• Transesophageal echocardiography
• Transthoracic echocardiography
• Cardiac magnetic resonance imaging (MRI) without gadolinium contrast
• Cardiac MRI with gadolinium contrast

Evaluation of left ventricular function after acute MI carries a class I indication (ie, it should be performed).¹⁸ 

Echocardiography is commonly used, and it has a 60% sensitivity to detect a thrombus.¹⁹ In patients with poorer transthoracic echocardiographic windows, contrast can be used to better delineate the left ventricular cavity and show the thrombus. Transesophageal echocardiography is seldom useful, as the left ventricular apex is foreshortened and in the far field.

A left ventricular thrombus is confirmed if an echo-dense mass with well-demarcated margins distinct from the endocardium is seen throughout the cardiac cycle. It should be evident in at least two different views (apical and short-axis) and should be adjacent to a hypokinetic or akinetic left ventricular wall. False-positive findings can occur due to misidentified false tendons, papillary muscles, and trabeculae.

Cardiac MRI with late gadolinium enhancement is now the gold standard for diagnostic imaging, as it accurately characterizes the shape, size, and location of the thrombus (Figure 3). Gadolinium contrast increases the enhancement of the ventricular cavity, thus allowing easy detection of thrombus, which appears dark. Cardiac MRI with delayed enhancement has 88% to 91% sensitivity and 99% specificity to detect left ventricular thrombosis.^20,21 However, compared with echocardiography, routine cardiac MRI is time-intensive, costly, and not routinely available. As a result, it should be performed only in patients with poor acoustic windows and a high clinical suspicion of left ventricular thrombosis.

Delayed-contrast cardiac computed tomography can be used to identify left ventricular thrombosis, using absence of contrast uptake. The need to use contrast is a disadvantage, but computed tomography can be an alternative in patients with contraindications to cardiac MRI.

WHAT COMPLICATIONS ARISE FROM LEFT VENTRICULAR THROMBOSIS?

The most feared complication of left ventricular thrombosis is thromboembolism. Cardioembolic stroke is generally severe, prone to early and long-term recurrence, and associated with a higher death rate than noncardioembolic ischemic stroke.^22,23 Thrombi associated with thromboembolism are often acute and mobile rather than organized and immobile.²⁴ They may embolize to the brain,  spleen, kidneys, and bowel.²⁵ In a meta-analysis of 11 studies, the pooled odds ratio for risk of embolization was 5.45 (95% confidence interval [CI] 3.02–9.83) with left ventricular thrombi vs without.²⁶ Before systemic thrombolysis and antiplatelet therapy became available, stroke rates ranged from 1.5% to 10%.^27–29

In a meta-analysis of 22 studies from 1978 to 2004, the incidence of ischemic stroke after MI during hospitalization was around 11.1 per 1,000 MIs.³⁰ This study found that anterior MI was associated with a higher risk of stroke, but reported no difference in the incidence of stroke with percutaneous coronary intervention, systemic thrombolysis, or no reperfusion.

In a large prospective cohort study of 2,160 patients,³¹ 259 (12%) had a stroke after MI. In multivariable analysis, age, diabetes, and previous stroke were predictors of stroke after MI. This study reported significantly fewer strokes in patients who underwent percutaneous coronary intervention than with other or no reperfusion therapies.³¹

ANTICOAGULATION TREATMENT

3. How would you treat a patient who has a drug-eluting stent in the left anterior descending artery and a new diagnosis of left ventricular thrombosis?

• Warfarin
• Aspirin and clopidogrel
• Aspirin, clopidogrel, and warfarin
• Aspirin and warfarin

The management of left ventricular thrombosis has been summarized in guidelines from the American College of Chest Physicians (ACCP) in 2012,³² and from the American College of Cardiology/American Heart Association in 2013,¹⁸ which recommend anticoagulation for at least 3 months, or indefinitely if bleeding risk is low, for all patients developing a left ventricular thrombus.

For patients with acute MI and left ventricular thrombosis, the ACCP guidelines recommend warfarin with a target international normalized ratio of 2.0 to 3.0 plus dual antiplatelet therapy (eg, aspirin plus clopidogrel)  for 3 months, after which warfarin is discontinued but dual antiplatelet therapy is continued for up to 12 months.³²

The European Society of Cardiology guidelines³³ recommend 6 months of anticoagulation. However, if the patient is receiving dual antiplatelet therapy, they recommend repeated imaging of the left ventricle after 3 months of anticoagulation, which may allow for earlier discontinuation of anticoagulation if the thrombus has resolved and apical wall motion has recovered. Therefore, most experts recommend 3 months of anticoagulation when used in combination with dual antiplatelet therapy and repeating echocardiography at 3 months to safely discontinue anticoagulation. The best answer to the question posed here is aspirin, clopidogrel, and warfarin.

Decisions about antithrombotic therapy may also depend on stent type and the patient’s bleeding risk. With bare-metal stents, dual antiplatelet therapy along with anticoagulation should be used for 1 month, after which anticoagulation should be used with a single antiplatelet agent for another 2 months; after this, the anticoagulant can be discontinued and dual antiplatelet therapy can be resumed for a total of 12 months. Newer anticoagulants such as rivaroxaban, dabigatran, edoxaban, and apixaban may also have a role, but they have not yet been studied for this indication.

Surgical thrombectomy is rarely considered now, given the known efficacy of anticoagulants in dissolving the thrombus. It was done in the past for large, mobile, or protruding left ventricular thrombi, which have a higher potential for embolization.³⁴ Currently, it can be done under very special circumstances, such as before placement of a left ventricular assist device or if the thrombus is large, to prevent embolism.^35,36

BLEEDING COMPLICATIONS WITH TRIPLE ANTITHROMBOTIC THERAPY

After stent placement, almost all patients need to be on dual antiplatelet therapy for a specified duration depending on the type and generation of stent used. Such patients end up on “triple” antithrombotic therapy (two antiplatelet drugs plus an anticoagulant), which poses a high risk of bleeding.³⁷ Consideration needs to be given to the risks of stroke, stent thrombosis, and major bleeding when selecting the antithrombotic regimen.³⁸ Triple antithrombotic therapy has been associated with a risk of fatal and nonfatal bleeding of 4% to 16% when used for indications such as atrial fibrillation.^39–41

Risks of triple antithrombotic therapy (aspirin 80–100 mg, clopidogrel 75 mg, and warfarin) were compared with those of clopidogrel plus warfarin in the What Is the Optimal Antiplatelet and Anticoagulant therapy in Patients With Oral Anticoagulation and Coronary Stenting Trial,³⁷ which reported a significantly lower risk of  major and minor bleeding with clopidogrel-plus-warfarin therapy than with triple antithrombotic therapy, 14.3% vs 31.7% (hazard ratio 0.40, 95% CI 0.28–0.58, P < .0001).

Additionally, the increased risk of major and minor bleeding associated with triple antithrombotic therapy has been confirmed in many observational studies; other studies found a trend toward lower risk with triple therapy, but this was not statistically significant (Table 2).^{38,40,42–55} A large multicenter European trial is being conducted to compare dual antiplatelet therapy vs triple antithrombotic therapy in patients with left ventricular thrombosis.

CASE FOLLOW-UP

Our patient was started on warfarin, clopidogrel 75 mg, and aspirin 75 mg at the time of discharge. He was continued on warfarin for 3 months, at which time a follow-up echocardiogram showed no thrombus in the left ventricle. Warfarin was discontinued, and he had no thromboembolic complications.

TAKE-HOME POINTS

Left ventricular thrombosis after an acute MI is very important to detect, as it can lead to serious complications through arterial embolism.

The incidence of left ventricular thrombosis has declined significantly with the use of percutaneous coronary intervention. However, it may still occur in a small number of patients with larger infarcts owing to delay in revascularization or proximal (left main or left anterior descending) occlusions with larger infarct size.

Echocardiography, which is routinely performed after acute MI to assess myocardial function, uncovers most left ventricular thrombi. In high-risk cases, MRI with late gadolinium enhancement can increase the diagnostic yield.

Anticoagulation with warfarin is recommended for at least 3 months. Post-MI patients undergoing stent implantation may need triple antithrombotic therapy, which, however, increases the bleeding risk significantly. Large randomized trials are needed to guide physicians in risk stratification of such patients.

A 62-year-old man with hypertension, type 2 diabetes mellitus, and hypercholesterolemia presented to the emergency department with substernal chest pain that started about 15 hours earlier while he was at rest watching television.

On examination, his pulse was 92 beats per minute and regular, his blood pressure was 160/88 mm Hg, and he had no evidence of jugular venous distention or pedal edema. Lung examination was positive for bibasilar crackles.

Electrocardiography revealed Q waves with ST elevation in leads I, aVL, V₄, V₅, and V₆ with reciprocal ST depression in leads II, III, and aVF.

His troponin T level on presentation was markedly elevated.

Image

He underwent heart catheterization and was found to have 100% occlusion of the proximal left anterior descending artery. He underwent successful percutaneous coronary intervention with placement of a drug-eluting stent, and afterward had grade 3 flow on the Thrombolysis in Myocardial Infarction (TIMI) scale.

Echocardiography the next day revealed a mobile echo-dense mass in the left ventricular apex (Figure 1) and a left ventricular ejection fraction of 35%.

THE INCIDENCE OF LEFT VENTRICULAR THROMBOSIS IN ACUTE MI

1. What is the incidence of left ventricular thrombosis after acute myocardial infarction (MI), now that primary percutaneous coronary intervention is common?

• 0.1%
• 2%
• 20%
• 40%

Left ventricular thrombosis is a serious complication of acute MI that can cause systemic thromboembolism, including stroke.¹ Before thrombolytic therapy was available, this complication occurred in 20% to 60% of patients with acute MI.^2,3 But early reperfusion strategies, anticoagulation for the first 48 hours, and dual antiplatelet therapy have reduced the incidence of this complication significantly.

In the thrombolytic era, the incidence of left ventricular thrombosis was 5.1% in the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI) 3 study, which had 8,326 patients. A subset of patients who had an anterior MI had almost double the incidence (11.5%).³

Image

The incidence has further declined with the advent of primary percutaneous coronary intervention, likely thanks to enhanced myocardial salvage, and now ranges from 2.5% to 15% (Table 1).^4–11 The largest observational study, with 2,911 patients undergoing percutaneous coronary intervention, reported an incidence of 2.5% within 3 to 5 days of the MI.⁷ At our center, the incidence was found to be even lower, 1.8% in 1,700 patients presenting with ST-elevation MI undergoing primary percutaneous coronary intervention. Hence, of the answers to the question above, 2% would be closest.

Large infarct size with a low left ventricular ejection fraction (< 40%), anterior wall MI, hypertension, and delay in time from symptom onset to intervention were independent predictors of left ventricular thrombus formation in most studies.^7,12 The risk is highest during the first 2 weeks after MI, and thrombosis almost never occurs more than 3 months after the index event.^5,13–16

WHAT IS THE PATHOGENESIS OF LEFT VENTRICULAR THROMBOSIS?

A large transmural infarct results in loss of contractile function, which causes stagnation and pooling of blood adjacent to the infarcted ventricular segment. In addition, endocardial injury exposes tissue factor, which then initiates the coagulation cascade. To make matters worse, MI results in a hypercoagulable state through unclear mechanisms, which completes the Virchow triad for thrombus formation. Elevations of D-dimer, fibrinogen, anticardiolipin antibodies (IgM and IgG), and tissue factor have also been reported after acute MI.¹⁷

Thrombus formation begins with platelet aggregation at the site of endocardial damage, forming a platelet plug, followed by activation of clotting factors. These thrombi are referred to as “mural,” as they adhere to the chamber wall (endocardium). They are composed of fibrin and entrapped red and white blood cells (Figure 2).

The natural course of thrombus evolution is established but variable. A left ventricular thrombus may dislodge and embolize, resulting in stroke or other thromboembolic complications. Alternately, it can dissolve over time, aided by intrinsic fibrinolytic mechanisms. On other occasions, the thrombus may organize, a process characterized by ingrowth of smooth muscle cells, fibroblasts, and endothelium.

HOW IS LEFT VENTRICULAR THROMBOSIS DIAGNOSED?

2. What is the best imaging test for detecting a thrombus?

• Transesophageal echocardiography
• Transthoracic echocardiography
• Cardiac magnetic resonance imaging (MRI) without gadolinium contrast
• Cardiac MRI with gadolinium contrast

Evaluation of left ventricular function after acute MI carries a class I indication (ie, it should be performed).¹⁸ 

Echocardiography is commonly used, and it has a 60% sensitivity to detect a thrombus.¹⁹ In patients with poorer transthoracic echocardiographic windows, contrast can be used to better delineate the left ventricular cavity and show the thrombus. Transesophageal echocardiography is seldom useful, as the left ventricular apex is foreshortened and in the far field.

A left ventricular thrombus is confirmed if an echo-dense mass with well-demarcated margins distinct from the endocardium is seen throughout the cardiac cycle. It should be evident in at least two different views (apical and short-axis) and should be adjacent to a hypokinetic or akinetic left ventricular wall. False-positive findings can occur due to misidentified false tendons, papillary muscles, and trabeculae.

Cardiac MRI with late gadolinium enhancement is now the gold standard for diagnostic imaging, as it accurately characterizes the shape, size, and location of the thrombus (Figure 3). Gadolinium contrast increases the enhancement of the ventricular cavity, thus allowing easy detection of thrombus, which appears dark. Cardiac MRI with delayed enhancement has 88% to 91% sensitivity and 99% specificity to detect left ventricular thrombosis.^20,21 However, compared with echocardiography, routine cardiac MRI is time-intensive, costly, and not routinely available. As a result, it should be performed only in patients with poor acoustic windows and a high clinical suspicion of left ventricular thrombosis.

Delayed-contrast cardiac computed tomography can be used to identify left ventricular thrombosis, using absence of contrast uptake. The need to use contrast is a disadvantage, but computed tomography can be an alternative in patients with contraindications to cardiac MRI.

WHAT COMPLICATIONS ARISE FROM LEFT VENTRICULAR THROMBOSIS?

The most feared complication of left ventricular thrombosis is thromboembolism. Cardioembolic stroke is generally severe, prone to early and long-term recurrence, and associated with a higher death rate than noncardioembolic ischemic stroke.^22,23 Thrombi associated with thromboembolism are often acute and mobile rather than organized and immobile.²⁴ They may embolize to the brain,  spleen, kidneys, and bowel.²⁵ In a meta-analysis of 11 studies, the pooled odds ratio for risk of embolization was 5.45 (95% confidence interval [CI] 3.02–9.83) with left ventricular thrombi vs without.²⁶ Before systemic thrombolysis and antiplatelet therapy became available, stroke rates ranged from 1.5% to 10%.^27–29

In a meta-analysis of 22 studies from 1978 to 2004, the incidence of ischemic stroke after MI during hospitalization was around 11.1 per 1,000 MIs.³⁰ This study found that anterior MI was associated with a higher risk of stroke, but reported no difference in the incidence of stroke with percutaneous coronary intervention, systemic thrombolysis, or no reperfusion.

In a large prospective cohort study of 2,160 patients,³¹ 259 (12%) had a stroke after MI. In multivariable analysis, age, diabetes, and previous stroke were predictors of stroke after MI. This study reported significantly fewer strokes in patients who underwent percutaneous coronary intervention than with other or no reperfusion therapies.³¹

ANTICOAGULATION TREATMENT

3. How would you treat a patient who has a drug-eluting stent in the left anterior descending artery and a new diagnosis of left ventricular thrombosis?

• Warfarin
• Aspirin and clopidogrel
• Aspirin, clopidogrel, and warfarin
• Aspirin and warfarin

The management of left ventricular thrombosis has been summarized in guidelines from the American College of Chest Physicians (ACCP) in 2012,³² and from the American College of Cardiology/American Heart Association in 2013,¹⁸ which recommend anticoagulation for at least 3 months, or indefinitely if bleeding risk is low, for all patients developing a left ventricular thrombus.

For patients with acute MI and left ventricular thrombosis, the ACCP guidelines recommend warfarin with a target international normalized ratio of 2.0 to 3.0 plus dual antiplatelet therapy (eg, aspirin plus clopidogrel)  for 3 months, after which warfarin is discontinued but dual antiplatelet therapy is continued for up to 12 months.³²

The European Society of Cardiology guidelines³³ recommend 6 months of anticoagulation. However, if the patient is receiving dual antiplatelet therapy, they recommend repeated imaging of the left ventricle after 3 months of anticoagulation, which may allow for earlier discontinuation of anticoagulation if the thrombus has resolved and apical wall motion has recovered. Therefore, most experts recommend 3 months of anticoagulation when used in combination with dual antiplatelet therapy and repeating echocardiography at 3 months to safely discontinue anticoagulation. The best answer to the question posed here is aspirin, clopidogrel, and warfarin.

Decisions about antithrombotic therapy may also depend on stent type and the patient’s bleeding risk. With bare-metal stents, dual antiplatelet therapy along with anticoagulation should be used for 1 month, after which anticoagulation should be used with a single antiplatelet agent for another 2 months; after this, the anticoagulant can be discontinued and dual antiplatelet therapy can be resumed for a total of 12 months. Newer anticoagulants such as rivaroxaban, dabigatran, edoxaban, and apixaban may also have a role, but they have not yet been studied for this indication.

Surgical thrombectomy is rarely considered now, given the known efficacy of anticoagulants in dissolving the thrombus. It was done in the past for large, mobile, or protruding left ventricular thrombi, which have a higher potential for embolization.³⁴ Currently, it can be done under very special circumstances, such as before placement of a left ventricular assist device or if the thrombus is large, to prevent embolism.^35,36

BLEEDING COMPLICATIONS WITH TRIPLE ANTITHROMBOTIC THERAPY

After stent placement, almost all patients need to be on dual antiplatelet therapy for a specified duration depending on the type and generation of stent used. Such patients end up on “triple” antithrombotic therapy (two antiplatelet drugs plus an anticoagulant), which poses a high risk of bleeding.³⁷ Consideration needs to be given to the risks of stroke, stent thrombosis, and major bleeding when selecting the antithrombotic regimen.³⁸ Triple antithrombotic therapy has been associated with a risk of fatal and nonfatal bleeding of 4% to 16% when used for indications such as atrial fibrillation.^39–41

Risks of triple antithrombotic therapy (aspirin 80–100 mg, clopidogrel 75 mg, and warfarin) were compared with those of clopidogrel plus warfarin in the What Is the Optimal Antiplatelet and Anticoagulant therapy in Patients With Oral Anticoagulation and Coronary Stenting Trial,³⁷ which reported a significantly lower risk of  major and minor bleeding with clopidogrel-plus-warfarin therapy than with triple antithrombotic therapy, 14.3% vs 31.7% (hazard ratio 0.40, 95% CI 0.28–0.58, P < .0001).

Additionally, the increased risk of major and minor bleeding associated with triple antithrombotic therapy has been confirmed in many observational studies; other studies found a trend toward lower risk with triple therapy, but this was not statistically significant (Table 2).^{38,40,42–55} A large multicenter European trial is being conducted to compare dual antiplatelet therapy vs triple antithrombotic therapy in patients with left ventricular thrombosis.

CASE FOLLOW-UP

Our patient was started on warfarin, clopidogrel 75 mg, and aspirin 75 mg at the time of discharge. He was continued on warfarin for 3 months, at which time a follow-up echocardiogram showed no thrombus in the left ventricle. Warfarin was discontinued, and he had no thromboembolic complications.

TAKE-HOME POINTS

Left ventricular thrombosis after an acute MI is very important to detect, as it can lead to serious complications through arterial embolism.

The incidence of left ventricular thrombosis has declined significantly with the use of percutaneous coronary intervention. However, it may still occur in a small number of patients with larger infarcts owing to delay in revascularization or proximal (left main or left anterior descending) occlusions with larger infarct size.

Echocardiography, which is routinely performed after acute MI to assess myocardial function, uncovers most left ventricular thrombi. In high-risk cases, MRI with late gadolinium enhancement can increase the diagnostic yield.

Anticoagulation with warfarin is recommended for at least 3 months. Post-MI patients undergoing stent implantation may need triple antithrombotic therapy, which, however, increases the bleeding risk significantly. Large randomized trials are needed to guide physicians in risk stratification of such patients.

A 62-year-old man with hypertension, type 2 diabetes mellitus, and hypercholesterolemia presented to the emergency department with substernal chest pain that started about 15 hours earlier while he was at rest watching television.

On examination, his pulse was 92 beats per minute and regular, his blood pressure was 160/88 mm Hg, and he had no evidence of jugular venous distention or pedal edema. Lung examination was positive for bibasilar crackles.

Electrocardiography revealed Q waves with ST elevation in leads I, aVL, V₄, V₅, and V₆ with reciprocal ST depression in leads II, III, and aVF.

His troponin T level on presentation was markedly elevated.

Image

He underwent heart catheterization and was found to have 100% occlusion of the proximal left anterior descending artery. He underwent successful percutaneous coronary intervention with placement of a drug-eluting stent, and afterward had grade 3 flow on the Thrombolysis in Myocardial Infarction (TIMI) scale.

Echocardiography the next day revealed a mobile echo-dense mass in the left ventricular apex (Figure 1) and a left ventricular ejection fraction of 35%.

THE INCIDENCE OF LEFT VENTRICULAR THROMBOSIS IN ACUTE MI

1. What is the incidence of left ventricular thrombosis after acute myocardial infarction (MI), now that primary percutaneous coronary intervention is common?

• 0.1%
• 2%
• 20%
• 40%

Left ventricular thrombosis is a serious complication of acute MI that can cause systemic thromboembolism, including stroke.¹ Before thrombolytic therapy was available, this complication occurred in 20% to 60% of patients with acute MI.^2,3 But early reperfusion strategies, anticoagulation for the first 48 hours, and dual antiplatelet therapy have reduced the incidence of this complication significantly.

In the thrombolytic era, the incidence of left ventricular thrombosis was 5.1% in the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI) 3 study, which had 8,326 patients. A subset of patients who had an anterior MI had almost double the incidence (11.5%).³

Image

The incidence has further declined with the advent of primary percutaneous coronary intervention, likely thanks to enhanced myocardial salvage, and now ranges from 2.5% to 15% (Table 1).^4–11 The largest observational study, with 2,911 patients undergoing percutaneous coronary intervention, reported an incidence of 2.5% within 3 to 5 days of the MI.⁷ At our center, the incidence was found to be even lower, 1.8% in 1,700 patients presenting with ST-elevation MI undergoing primary percutaneous coronary intervention. Hence, of the answers to the question above, 2% would be closest.

Large infarct size with a low left ventricular ejection fraction (< 40%), anterior wall MI, hypertension, and delay in time from symptom onset to intervention were independent predictors of left ventricular thrombus formation in most studies.^7,12 The risk is highest during the first 2 weeks after MI, and thrombosis almost never occurs more than 3 months after the index event.^5,13–16

WHAT IS THE PATHOGENESIS OF LEFT VENTRICULAR THROMBOSIS?

A large transmural infarct results in loss of contractile function, which causes stagnation and pooling of blood adjacent to the infarcted ventricular segment. In addition, endocardial injury exposes tissue factor, which then initiates the coagulation cascade. To make matters worse, MI results in a hypercoagulable state through unclear mechanisms, which completes the Virchow triad for thrombus formation. Elevations of D-dimer, fibrinogen, anticardiolipin antibodies (IgM and IgG), and tissue factor have also been reported after acute MI.¹⁷

Thrombus formation begins with platelet aggregation at the site of endocardial damage, forming a platelet plug, followed by activation of clotting factors. These thrombi are referred to as “mural,” as they adhere to the chamber wall (endocardium). They are composed of fibrin and entrapped red and white blood cells (Figure 2).

The natural course of thrombus evolution is established but variable. A left ventricular thrombus may dislodge and embolize, resulting in stroke or other thromboembolic complications. Alternately, it can dissolve over time, aided by intrinsic fibrinolytic mechanisms. On other occasions, the thrombus may organize, a process characterized by ingrowth of smooth muscle cells, fibroblasts, and endothelium.

HOW IS LEFT VENTRICULAR THROMBOSIS DIAGNOSED?

2. What is the best imaging test for detecting a thrombus?

• Transesophageal echocardiography
• Transthoracic echocardiography
• Cardiac magnetic resonance imaging (MRI) without gadolinium contrast
• Cardiac MRI with gadolinium contrast

Evaluation of left ventricular function after acute MI carries a class I indication (ie, it should be performed).¹⁸ 

Echocardiography is commonly used, and it has a 60% sensitivity to detect a thrombus.¹⁹ In patients with poorer transthoracic echocardiographic windows, contrast can be used to better delineate the left ventricular cavity and show the thrombus. Transesophageal echocardiography is seldom useful, as the left ventricular apex is foreshortened and in the far field.

A left ventricular thrombus is confirmed if an echo-dense mass with well-demarcated margins distinct from the endocardium is seen throughout the cardiac cycle. It should be evident in at least two different views (apical and short-axis) and should be adjacent to a hypokinetic or akinetic left ventricular wall. False-positive findings can occur due to misidentified false tendons, papillary muscles, and trabeculae.

Cardiac MRI with late gadolinium enhancement is now the gold standard for diagnostic imaging, as it accurately characterizes the shape, size, and location of the thrombus (Figure 3). Gadolinium contrast increases the enhancement of the ventricular cavity, thus allowing easy detection of thrombus, which appears dark. Cardiac MRI with delayed enhancement has 88% to 91% sensitivity and 99% specificity to detect left ventricular thrombosis.^20,21 However, compared with echocardiography, routine cardiac MRI is time-intensive, costly, and not routinely available. As a result, it should be performed only in patients with poor acoustic windows and a high clinical suspicion of left ventricular thrombosis.

Delayed-contrast cardiac computed tomography can be used to identify left ventricular thrombosis, using absence of contrast uptake. The need to use contrast is a disadvantage, but computed tomography can be an alternative in patients with contraindications to cardiac MRI.

WHAT COMPLICATIONS ARISE FROM LEFT VENTRICULAR THROMBOSIS?

The most feared complication of left ventricular thrombosis is thromboembolism. Cardioembolic stroke is generally severe, prone to early and long-term recurrence, and associated with a higher death rate than noncardioembolic ischemic stroke.^22,23 Thrombi associated with thromboembolism are often acute and mobile rather than organized and immobile.²⁴ They may embolize to the brain,  spleen, kidneys, and bowel.²⁵ In a meta-analysis of 11 studies, the pooled odds ratio for risk of embolization was 5.45 (95% confidence interval [CI] 3.02–9.83) with left ventricular thrombi vs without.²⁶ Before systemic thrombolysis and antiplatelet therapy became available, stroke rates ranged from 1.5% to 10%.^27–29

In a meta-analysis of 22 studies from 1978 to 2004, the incidence of ischemic stroke after MI during hospitalization was around 11.1 per 1,000 MIs.³⁰ This study found that anterior MI was associated with a higher risk of stroke, but reported no difference in the incidence of stroke with percutaneous coronary intervention, systemic thrombolysis, or no reperfusion.

In a large prospective cohort study of 2,160 patients,³¹ 259 (12%) had a stroke after MI. In multivariable analysis, age, diabetes, and previous stroke were predictors of stroke after MI. This study reported significantly fewer strokes in patients who underwent percutaneous coronary intervention than with other or no reperfusion therapies.³¹

ANTICOAGULATION TREATMENT

3. How would you treat a patient who has a drug-eluting stent in the left anterior descending artery and a new diagnosis of left ventricular thrombosis?

• Warfarin
• Aspirin and clopidogrel
• Aspirin, clopidogrel, and warfarin
• Aspirin and warfarin

The management of left ventricular thrombosis has been summarized in guidelines from the American College of Chest Physicians (ACCP) in 2012,³² and from the American College of Cardiology/American Heart Association in 2013,¹⁸ which recommend anticoagulation for at least 3 months, or indefinitely if bleeding risk is low, for all patients developing a left ventricular thrombus.

For patients with acute MI and left ventricular thrombosis, the ACCP guidelines recommend warfarin with a target international normalized ratio of 2.0 to 3.0 plus dual antiplatelet therapy (eg, aspirin plus clopidogrel)  for 3 months, after which warfarin is discontinued but dual antiplatelet therapy is continued for up to 12 months.³²

The European Society of Cardiology guidelines³³ recommend 6 months of anticoagulation. However, if the patient is receiving dual antiplatelet therapy, they recommend repeated imaging of the left ventricle after 3 months of anticoagulation, which may allow for earlier discontinuation of anticoagulation if the thrombus has resolved and apical wall motion has recovered. Therefore, most experts recommend 3 months of anticoagulation when used in combination with dual antiplatelet therapy and repeating echocardiography at 3 months to safely discontinue anticoagulation. The best answer to the question posed here is aspirin, clopidogrel, and warfarin.

Decisions about antithrombotic therapy may also depend on stent type and the patient’s bleeding risk. With bare-metal stents, dual antiplatelet therapy along with anticoagulation should be used for 1 month, after which anticoagulation should be used with a single antiplatelet agent for another 2 months; after this, the anticoagulant can be discontinued and dual antiplatelet therapy can be resumed for a total of 12 months. Newer anticoagulants such as rivaroxaban, dabigatran, edoxaban, and apixaban may also have a role, but they have not yet been studied for this indication.

Surgical thrombectomy is rarely considered now, given the known efficacy of anticoagulants in dissolving the thrombus. It was done in the past for large, mobile, or protruding left ventricular thrombi, which have a higher potential for embolization.³⁴ Currently, it can be done under very special circumstances, such as before placement of a left ventricular assist device or if the thrombus is large, to prevent embolism.^35,36

BLEEDING COMPLICATIONS WITH TRIPLE ANTITHROMBOTIC THERAPY

After stent placement, almost all patients need to be on dual antiplatelet therapy for a specified duration depending on the type and generation of stent used. Such patients end up on “triple” antithrombotic therapy (two antiplatelet drugs plus an anticoagulant), which poses a high risk of bleeding.³⁷ Consideration needs to be given to the risks of stroke, stent thrombosis, and major bleeding when selecting the antithrombotic regimen.³⁸ Triple antithrombotic therapy has been associated with a risk of fatal and nonfatal bleeding of 4% to 16% when used for indications such as atrial fibrillation.^39–41

Risks of triple antithrombotic therapy (aspirin 80–100 mg, clopidogrel 75 mg, and warfarin) were compared with those of clopidogrel plus warfarin in the What Is the Optimal Antiplatelet and Anticoagulant therapy in Patients With Oral Anticoagulation and Coronary Stenting Trial,³⁷ which reported a significantly lower risk of  major and minor bleeding with clopidogrel-plus-warfarin therapy than with triple antithrombotic therapy, 14.3% vs 31.7% (hazard ratio 0.40, 95% CI 0.28–0.58, P < .0001).

Additionally, the increased risk of major and minor bleeding associated with triple antithrombotic therapy has been confirmed in many observational studies; other studies found a trend toward lower risk with triple therapy, but this was not statistically significant (Table 2).^{38,40,42–55} A large multicenter European trial is being conducted to compare dual antiplatelet therapy vs triple antithrombotic therapy in patients with left ventricular thrombosis.

CASE FOLLOW-UP

Our patient was started on warfarin, clopidogrel 75 mg, and aspirin 75 mg at the time of discharge. He was continued on warfarin for 3 months, at which time a follow-up echocardiogram showed no thrombus in the left ventricle. Warfarin was discontinued, and he had no thromboembolic complications.

TAKE-HOME POINTS

Left ventricular thrombosis after an acute MI is very important to detect, as it can lead to serious complications through arterial embolism.

The incidence of left ventricular thrombosis has declined significantly with the use of percutaneous coronary intervention. However, it may still occur in a small number of patients with larger infarcts owing to delay in revascularization or proximal (left main or left anterior descending) occlusions with larger infarct size.

Echocardiography, which is routinely performed after acute MI to assess myocardial function, uncovers most left ventricular thrombi. In high-risk cases, MRI with late gadolinium enhancement can increase the diagnostic yield.

Anticoagulation with warfarin is recommended for at least 3 months. Post-MI patients undergoing stent implantation may need triple antithrombotic therapy, which, however, increases the bleeding risk significantly. Large randomized trials are needed to guide physicians in risk stratification of such patients.

Low-grade esophageal dysplasia must be confirmed by a GI pathologist with a special interest in Barrett’s esophagus, one who deals with the problem on a daily basis and whom peers recognize as an expert in the field, according to a new expert review from the American Gastroenterological Association (Gastroenterology. doi: http://dx.doi.org/10.1053/j.gastro.2016.09.040).

In the absence of reliable biomarkers, it’s the best guarantee that low-grade dysplasia (LGD) is truly present. Overdiagnosis of early dysplasia is common, and it leads to mistreatment and uncertainty about study results, the AGA said.

[email protected]

Low-grade esophageal dysplasia must be confirmed by a GI pathologist with a special interest in Barrett’s esophagus, one who deals with the problem on a daily basis and whom peers recognize as an expert in the field, according to a new expert review from the American Gastroenterological Association (Gastroenterology. doi: http://dx.doi.org/10.1053/j.gastro.2016.09.040).

In the absence of reliable biomarkers, it’s the best guarantee that low-grade dysplasia (LGD) is truly present. Overdiagnosis of early dysplasia is common, and it leads to mistreatment and uncertainty about study results, the AGA said.

[email protected]

Low-grade esophageal dysplasia must be confirmed by a GI pathologist with a special interest in Barrett’s esophagus, one who deals with the problem on a daily basis and whom peers recognize as an expert in the field, according to a new expert review from the American Gastroenterological Association (Gastroenterology. doi: http://dx.doi.org/10.1053/j.gastro.2016.09.040).

In the absence of reliable biomarkers, it’s the best guarantee that low-grade dysplasia (LGD) is truly present. Overdiagnosis of early dysplasia is common, and it leads to mistreatment and uncertainty about study results, the AGA said.

[email protected]

New gout treatment guidelines support the use of urate-lowering therapy, but find no place for treating patients to achieve any specific serum urate target – a dichotomy that has some rheumatologists scratching their heads.

Created by the American College of Physicians, the gout diagnosis and treatment guideline doesn’t recommend monitoring physiologic response to urate-lowering therapy or treating to specific serum urate target (Ann Int Med. 2016 Nov 1. doi: 10.7326/M16-0570). Instead, it says patients should be treated according to their symptomatic response – a recommendation that flies in the face of accepted clinical practice.

• Corticosteroids, NSAIDs, and colchicine are effective treatments to reduce pain in patients with acute gout.

• Lower doses of colchicine (1.2 mg, followed by 0.6 mg 1 hour later) are as effective as higher doses (1.2 mg, followed by 0.6 mg/hour for 6 hours) at reducing pain and are associated with fewer gastrointestinal adverse effects.

• Do not initiate long-term uric acid–lowering therapy in most patients after a first gout attack or in patients with infrequent attacks.

• Although evidence supports the benefits of using uric acid–lowering therapy for shorter durations to reduce gout flares, the benefits of long-term use in patients with a single or infrequent gout attacks have not been studied.

• Clinicians should discuss benefits, harms, costs, and individual preferences with patients before initiating uric acid–lowering therapy, including concomitant prophylaxis, in patients with recurrent gout attacks. (Grade: strong recommendation, moderate-quality evidence).

• Febuxostat (40 mg/day) and allopurinol (300 mg/day) are equally effective at decreasing serum urate levels, and prophylactic therapy with low-dose colchicine or low-dose NSAIDs reduces the risk for acute gout attacks in patients initiating urate-lowering therapy.

Allopurinol dosage, however, is one key point upon which the ACP and ACR guidelines are sharply divided. The ACR guideline calls for starting at low doses – 100 mg/day, and even lower in patients with kidney disease – with very slow upward titration, only if necessary, to 300 mg/day or more. Allopurinol is not without risk and should be used with caution, Dr. Neogi wrote in her commentary.

“Continuing a management strategy of starting allopurinol at an inappropriately high dose will perpetuate the problem of unnecessarily increasing flare risk, because this risk in the early treatment phase is directly proportional to the potency of the urate-lowering therapy used.”

However, allopurinol doses of 300 mg/day or less leave more than half of all patients undertreated, she said. This dilemma points up the difficulty with symptomatic treatment. Without checking urate levels, clinicians may be shooting blind when trying to dose appropriately.

She refuted any suggestion that the ACR guidelines were based on a lesser degree of evidence than the ACP document.

“The ACR uses a rigorous evidence-based method to develop treatment guidelines. It is inaccurate to say that ACR relies on lower-class evidence or expert opinion ‘to a large extent.’ In the absence of randomized controlled data, other peer-reviewed, available published data are used to formulate guidance, supported by the known biology.”

Current practices outlined in the ACR document are based on a thorough understanding of the biology of gout and how it progresses. Hard data on uric acid targets would greatly impact current therapeutic thinking. But in the meantime, there are patients to be treated, Dr. Neogi said.

“Of course, it would be ideal if we had randomized trial data to definitively provide insights, but we don’t have that right now. So does that mean that patients should suffer unnecessarily because we can’t use the remaining existing body of scientific knowledge to guide rational treatment decisions? What if funding agencies never fund such a study – should gout patients remain poorly managed? Should we abandon all scientific knowledge that isn’t randomized trial data and just not treat at all while waiting to see if a randomized trial will ever be funded and conducted?”

Dr. McLean sees the flip side of that coin.

“I think the effect of our guideline will be to help push the need for more explicit evidence in treat to target being the right way to go. But right now there is not enough evidence now to endorse that approach.”

Dr. McLean reports personal fees from Takeda Pharmaceuticals speakers’ bureau before 2015. Dr. Neogi had no financial disclosures.

[email protected]

New gout treatment guidelines support the use of urate-lowering therapy, but find no place for treating patients to achieve any specific serum urate target – a dichotomy that has some rheumatologists scratching their heads.

Created by the American College of Physicians, the gout diagnosis and treatment guideline doesn’t recommend monitoring physiologic response to urate-lowering therapy or treating to specific serum urate target (Ann Int Med. 2016 Nov 1. doi: 10.7326/M16-0570). Instead, it says patients should be treated according to their symptomatic response – a recommendation that flies in the face of accepted clinical practice.

• Corticosteroids, NSAIDs, and colchicine are effective treatments to reduce pain in patients with acute gout.

• Lower doses of colchicine (1.2 mg, followed by 0.6 mg 1 hour later) are as effective as higher doses (1.2 mg, followed by 0.6 mg/hour for 6 hours) at reducing pain and are associated with fewer gastrointestinal adverse effects.

• Do not initiate long-term uric acid–lowering therapy in most patients after a first gout attack or in patients with infrequent attacks.

• Although evidence supports the benefits of using uric acid–lowering therapy for shorter durations to reduce gout flares, the benefits of long-term use in patients with a single or infrequent gout attacks have not been studied.

• Clinicians should discuss benefits, harms, costs, and individual preferences with patients before initiating uric acid–lowering therapy, including concomitant prophylaxis, in patients with recurrent gout attacks. (Grade: strong recommendation, moderate-quality evidence).

• Febuxostat (40 mg/day) and allopurinol (300 mg/day) are equally effective at decreasing serum urate levels, and prophylactic therapy with low-dose colchicine or low-dose NSAIDs reduces the risk for acute gout attacks in patients initiating urate-lowering therapy.

Allopurinol dosage, however, is one key point upon which the ACP and ACR guidelines are sharply divided. The ACR guideline calls for starting at low doses – 100 mg/day, and even lower in patients with kidney disease – with very slow upward titration, only if necessary, to 300 mg/day or more. Allopurinol is not without risk and should be used with caution, Dr. Neogi wrote in her commentary.

“Continuing a management strategy of starting allopurinol at an inappropriately high dose will perpetuate the problem of unnecessarily increasing flare risk, because this risk in the early treatment phase is directly proportional to the potency of the urate-lowering therapy used.”

However, allopurinol doses of 300 mg/day or less leave more than half of all patients undertreated, she said. This dilemma points up the difficulty with symptomatic treatment. Without checking urate levels, clinicians may be shooting blind when trying to dose appropriately.

She refuted any suggestion that the ACR guidelines were based on a lesser degree of evidence than the ACP document.

“The ACR uses a rigorous evidence-based method to develop treatment guidelines. It is inaccurate to say that ACR relies on lower-class evidence or expert opinion ‘to a large extent.’ In the absence of randomized controlled data, other peer-reviewed, available published data are used to formulate guidance, supported by the known biology.”

Current practices outlined in the ACR document are based on a thorough understanding of the biology of gout and how it progresses. Hard data on uric acid targets would greatly impact current therapeutic thinking. But in the meantime, there are patients to be treated, Dr. Neogi said.

“Of course, it would be ideal if we had randomized trial data to definitively provide insights, but we don’t have that right now. So does that mean that patients should suffer unnecessarily because we can’t use the remaining existing body of scientific knowledge to guide rational treatment decisions? What if funding agencies never fund such a study – should gout patients remain poorly managed? Should we abandon all scientific knowledge that isn’t randomized trial data and just not treat at all while waiting to see if a randomized trial will ever be funded and conducted?”

Dr. McLean sees the flip side of that coin.

“I think the effect of our guideline will be to help push the need for more explicit evidence in treat to target being the right way to go. But right now there is not enough evidence now to endorse that approach.”

Dr. McLean reports personal fees from Takeda Pharmaceuticals speakers’ bureau before 2015. Dr. Neogi had no financial disclosures.

[email protected]

New gout treatment guidelines support the use of urate-lowering therapy, but find no place for treating patients to achieve any specific serum urate target – a dichotomy that has some rheumatologists scratching their heads.

Created by the American College of Physicians, the gout diagnosis and treatment guideline doesn’t recommend monitoring physiologic response to urate-lowering therapy or treating to specific serum urate target (Ann Int Med. 2016 Nov 1. doi: 10.7326/M16-0570). Instead, it says patients should be treated according to their symptomatic response – a recommendation that flies in the face of accepted clinical practice.

• Corticosteroids, NSAIDs, and colchicine are effective treatments to reduce pain in patients with acute gout.

• Lower doses of colchicine (1.2 mg, followed by 0.6 mg 1 hour later) are as effective as higher doses (1.2 mg, followed by 0.6 mg/hour for 6 hours) at reducing pain and are associated with fewer gastrointestinal adverse effects.

• Do not initiate long-term uric acid–lowering therapy in most patients after a first gout attack or in patients with infrequent attacks.

• Although evidence supports the benefits of using uric acid–lowering therapy for shorter durations to reduce gout flares, the benefits of long-term use in patients with a single or infrequent gout attacks have not been studied.

• Clinicians should discuss benefits, harms, costs, and individual preferences with patients before initiating uric acid–lowering therapy, including concomitant prophylaxis, in patients with recurrent gout attacks. (Grade: strong recommendation, moderate-quality evidence).

• Febuxostat (40 mg/day) and allopurinol (300 mg/day) are equally effective at decreasing serum urate levels, and prophylactic therapy with low-dose colchicine or low-dose NSAIDs reduces the risk for acute gout attacks in patients initiating urate-lowering therapy.

Allopurinol dosage, however, is one key point upon which the ACP and ACR guidelines are sharply divided. The ACR guideline calls for starting at low doses – 100 mg/day, and even lower in patients with kidney disease – with very slow upward titration, only if necessary, to 300 mg/day or more. Allopurinol is not without risk and should be used with caution, Dr. Neogi wrote in her commentary.

“Continuing a management strategy of starting allopurinol at an inappropriately high dose will perpetuate the problem of unnecessarily increasing flare risk, because this risk in the early treatment phase is directly proportional to the potency of the urate-lowering therapy used.”

However, allopurinol doses of 300 mg/day or less leave more than half of all patients undertreated, she said. This dilemma points up the difficulty with symptomatic treatment. Without checking urate levels, clinicians may be shooting blind when trying to dose appropriately.

She refuted any suggestion that the ACR guidelines were based on a lesser degree of evidence than the ACP document.

“The ACR uses a rigorous evidence-based method to develop treatment guidelines. It is inaccurate to say that ACR relies on lower-class evidence or expert opinion ‘to a large extent.’ In the absence of randomized controlled data, other peer-reviewed, available published data are used to formulate guidance, supported by the known biology.”

Current practices outlined in the ACR document are based on a thorough understanding of the biology of gout and how it progresses. Hard data on uric acid targets would greatly impact current therapeutic thinking. But in the meantime, there are patients to be treated, Dr. Neogi said.

“Of course, it would be ideal if we had randomized trial data to definitively provide insights, but we don’t have that right now. So does that mean that patients should suffer unnecessarily because we can’t use the remaining existing body of scientific knowledge to guide rational treatment decisions? What if funding agencies never fund such a study – should gout patients remain poorly managed? Should we abandon all scientific knowledge that isn’t randomized trial data and just not treat at all while waiting to see if a randomized trial will ever be funded and conducted?”

Dr. McLean sees the flip side of that coin.

“I think the effect of our guideline will be to help push the need for more explicit evidence in treat to target being the right way to go. But right now there is not enough evidence now to endorse that approach.”

Dr. McLean reports personal fees from Takeda Pharmaceuticals speakers’ bureau before 2015. Dr. Neogi had no financial disclosures.

[email protected]

MONTREAL  – Three-fifths of pediatric liver-transplant recipients who were doing well enough to attempt weaning from their immunosuppression regimen succeeded in getting off immunosuppression and staying off for more than a year. In the process, they also significantly improved their health-related quality of life.

“Health-related quality of life domains associated with social interactions, worry, and medications improved” in pediatric liver recipients who had undergone immunosuppression withdrawal, Saeed Mohammad, MD, said at the World Congress of Pediatric Gastroenterology, Hepatology and Nutrition.

Patients who succeeded in staying off immunosuppressant drugs for at least 2 years after they first began ratcheting down their regimen showed better quality of life scores compared with their scores at baseline, and also compared with the scores of other pediatric liver transplant patients who unsuccessfully tried coming off immunosuppression.

Not every pediatric liver transplant patient should attempt withdrawing immunosuppression, cautioned Dr. Mohammad, a pediatric gastroenterologist at Northwestern University in Chicago. “To be successful withdrawal of immunosuppression needs to be in selected patients; not every patient is a good candidate.”

The Immunosuppression Withdrawal for Stable Pediatric Liver Transplant Recipients (iWITH) study ran at 11 U.S. center and one center in Toronto during October 2012 through June 2014. Pediatric liver transplant recipients were eligible to start a 9-10 month graduated withdrawal from their immunosuppression regimen if they met several criteria of stability including no rejection episode over at least the prior 12 months, normal laboratory-test results, no autoimmune disease and no problems detected in a liver biopsy. The prospective study enrolled 88 patients who averaged 10 years old. Patients underwent comprehensive examinations and laboratory testing at baseline and again  several times during the subsequent 2 years including assessment of several quality of life measures.

During follow-up, 35 of the 88 patients (40%) developed symptoms of rejection and had to go back on immunosuppression. Most of these patients developed their rejection symptoms early during immunosuppression weaning, but a few patients failed later including one patient who failed 22 months after starting immunosuppression withdrawal, Dr. Mohammad said. Researchers from the iWITH study first reported these results at the American Transplant Congress in June 2016.

The quality of life findings reported by Dr. Mohammad came from assessments at baseline, after 12 months, and after 24 months, and included 30 of the patients who resumed immunosuppression and 48 patients who remained off immunosuppression for 2 years. All of these 78 patients had relatively robust quality of life profiles at baseline. Their scores for both physical and social subscales as well as for total score were significantly superior to the average scores for a large number of primarily U.S. pediatric liver transplant patients in the SPLIT database. Dr. Mohammad called the patients who attempted immunosuppression discontinuation as the “creme de la creme” of pediatric liver transplant patients in terms of their clinical status.

Analysis of scores after 2 years compared with baseline showed statistically significant improvements among patients who stayed off immunosuppression for the domains of social function, treatment attitudes and compliance, communication, and worry. A comparison of changes in quality of life scores from baseline to 2 years showed that patients who stayed off immunosuppression had improvements in several of their scores while patients who went back onto immunosuppression had on average a small deterioration of their scores.
Dr. Mohammad had no disclosures.

[email protected]
On Twitter @mitchelzoler

MONTREAL  – Three-fifths of pediatric liver-transplant recipients who were doing well enough to attempt weaning from their immunosuppression regimen succeeded in getting off immunosuppression and staying off for more than a year. In the process, they also significantly improved their health-related quality of life.

“Health-related quality of life domains associated with social interactions, worry, and medications improved” in pediatric liver recipients who had undergone immunosuppression withdrawal, Saeed Mohammad, MD, said at the World Congress of Pediatric Gastroenterology, Hepatology and Nutrition.

Patients who succeeded in staying off immunosuppressant drugs for at least 2 years after they first began ratcheting down their regimen showed better quality of life scores compared with their scores at baseline, and also compared with the scores of other pediatric liver transplant patients who unsuccessfully tried coming off immunosuppression.

Not every pediatric liver transplant patient should attempt withdrawing immunosuppression, cautioned Dr. Mohammad, a pediatric gastroenterologist at Northwestern University in Chicago. “To be successful withdrawal of immunosuppression needs to be in selected patients; not every patient is a good candidate.”

The Immunosuppression Withdrawal for Stable Pediatric Liver Transplant Recipients (iWITH) study ran at 11 U.S. center and one center in Toronto during October 2012 through June 2014. Pediatric liver transplant recipients were eligible to start a 9-10 month graduated withdrawal from their immunosuppression regimen if they met several criteria of stability including no rejection episode over at least the prior 12 months, normal laboratory-test results, no autoimmune disease and no problems detected in a liver biopsy. The prospective study enrolled 88 patients who averaged 10 years old. Patients underwent comprehensive examinations and laboratory testing at baseline and again  several times during the subsequent 2 years including assessment of several quality of life measures.

During follow-up, 35 of the 88 patients (40%) developed symptoms of rejection and had to go back on immunosuppression. Most of these patients developed their rejection symptoms early during immunosuppression weaning, but a few patients failed later including one patient who failed 22 months after starting immunosuppression withdrawal, Dr. Mohammad said. Researchers from the iWITH study first reported these results at the American Transplant Congress in June 2016.

The quality of life findings reported by Dr. Mohammad came from assessments at baseline, after 12 months, and after 24 months, and included 30 of the patients who resumed immunosuppression and 48 patients who remained off immunosuppression for 2 years. All of these 78 patients had relatively robust quality of life profiles at baseline. Their scores for both physical and social subscales as well as for total score were significantly superior to the average scores for a large number of primarily U.S. pediatric liver transplant patients in the SPLIT database. Dr. Mohammad called the patients who attempted immunosuppression discontinuation as the “creme de la creme” of pediatric liver transplant patients in terms of their clinical status.

Analysis of scores after 2 years compared with baseline showed statistically significant improvements among patients who stayed off immunosuppression for the domains of social function, treatment attitudes and compliance, communication, and worry. A comparison of changes in quality of life scores from baseline to 2 years showed that patients who stayed off immunosuppression had improvements in several of their scores while patients who went back onto immunosuppression had on average a small deterioration of their scores.
Dr. Mohammad had no disclosures.

[email protected]
On Twitter @mitchelzoler

MONTREAL  – Three-fifths of pediatric liver-transplant recipients who were doing well enough to attempt weaning from their immunosuppression regimen succeeded in getting off immunosuppression and staying off for more than a year. In the process, they also significantly improved their health-related quality of life.

“Health-related quality of life domains associated with social interactions, worry, and medications improved” in pediatric liver recipients who had undergone immunosuppression withdrawal, Saeed Mohammad, MD, said at the World Congress of Pediatric Gastroenterology, Hepatology and Nutrition.

Patients who succeeded in staying off immunosuppressant drugs for at least 2 years after they first began ratcheting down their regimen showed better quality of life scores compared with their scores at baseline, and also compared with the scores of other pediatric liver transplant patients who unsuccessfully tried coming off immunosuppression.

Not every pediatric liver transplant patient should attempt withdrawing immunosuppression, cautioned Dr. Mohammad, a pediatric gastroenterologist at Northwestern University in Chicago. “To be successful withdrawal of immunosuppression needs to be in selected patients; not every patient is a good candidate.”

The Immunosuppression Withdrawal for Stable Pediatric Liver Transplant Recipients (iWITH) study ran at 11 U.S. center and one center in Toronto during October 2012 through June 2014. Pediatric liver transplant recipients were eligible to start a 9-10 month graduated withdrawal from their immunosuppression regimen if they met several criteria of stability including no rejection episode over at least the prior 12 months, normal laboratory-test results, no autoimmune disease and no problems detected in a liver biopsy. The prospective study enrolled 88 patients who averaged 10 years old. Patients underwent comprehensive examinations and laboratory testing at baseline and again  several times during the subsequent 2 years including assessment of several quality of life measures.

During follow-up, 35 of the 88 patients (40%) developed symptoms of rejection and had to go back on immunosuppression. Most of these patients developed their rejection symptoms early during immunosuppression weaning, but a few patients failed later including one patient who failed 22 months after starting immunosuppression withdrawal, Dr. Mohammad said. Researchers from the iWITH study first reported these results at the American Transplant Congress in June 2016.

The quality of life findings reported by Dr. Mohammad came from assessments at baseline, after 12 months, and after 24 months, and included 30 of the patients who resumed immunosuppression and 48 patients who remained off immunosuppression for 2 years. All of these 78 patients had relatively robust quality of life profiles at baseline. Their scores for both physical and social subscales as well as for total score were significantly superior to the average scores for a large number of primarily U.S. pediatric liver transplant patients in the SPLIT database. Dr. Mohammad called the patients who attempted immunosuppression discontinuation as the “creme de la creme” of pediatric liver transplant patients in terms of their clinical status.

Analysis of scores after 2 years compared with baseline showed statistically significant improvements among patients who stayed off immunosuppression for the domains of social function, treatment attitudes and compliance, communication, and worry. A comparison of changes in quality of life scores from baseline to 2 years showed that patients who stayed off immunosuppression had improvements in several of their scores while patients who went back onto immunosuppression had on average a small deterioration of their scores.
Dr. Mohammad had no disclosures.

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