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RESEARCH CORRESPONDENCE Thalidomide for treatment of gastrointestinal angiodysplasia in patients with left ventricular assist devices: Case series and treatment protocol Karen Draper, MD,a Parag Kale, MD,b Beth Martin, MD,a Kelly Cordero, RNP,a Richard Ha, MD,c and Dipanjan Banerjee, MD, MSa From the aDepartment of Medicine, Stanford University Hospital and Clinics, Stanford, California; bthe Department of Medicine, Kaiser Permanente, Santa Clara, California; and the cDepartment of Cardiothoracic Surgery, Stanford University Hospital and Clinics, Stanford, California
Gastrointestinal bleeding (GIB) is a common complication after left ventricular assist device (LVAD) implantation, occurring in 17% to 31% of patients.1,2 Bleeding from gastrointestinal angiodysplasia (GIAD) is the most common cause of GIB in these patients, accounting for 15% to 31% of the total.1,2 The high rate of GIB in the LVAD population leads to frequent and prolonged hospitalizations in these patients and adversely affects quality of life. Thalidomide, a potent anti-angiogenic compound, was used effectively for recurrent GIAD-related bleeding in 1 randomized controlled trial3 as well as in 1 small case series.4 We previously reported the successful use of thalidomide in a patient with recurrent LVAD-associated GIAD.5 Subsequently, at our institutions, we have used thalidomide to excellent effect for several refractory cases of GIAD in LVAD recipients. Thalidomide has been prescribed to 8 of 119 LVAD patients at our institution for this purpose (Table 1). The mean age was 59 (standard deviation [SD], 15) years, number of bleeding episodes was 3 (SD, 0.8), the mean time from implant to the first bleeding episode was 38 (SD, 24) days, and the mean time from implant to thalidomide use was 202 (SD, 234) days. We describe the protocol we have established at our institution for careful monitoring of patients receiving thalidomide to minimize the adverse effects of this promising therapy (Figure 1). Before thalidomide is prescribed, patients on LVAD support must be screened carefully for contraindications to its use. Strict exclusion criteria include thromboembolic disease without anti-coagulation, major wounds, symptomatic autonomic neuropathy, peripheral neuropathy, bradycardia,
and concurrent radiotherapy. Relative exclusions include small wounds, constipation, at risk of falls, a history of seizures. Upper and lower endoscopy is indicated to assess for treatable lesions, because GIAD may be treated endoscopically. Depending on the proficiency of the treating center, capsule endoscopy and push enteroscopy may also be used for diagnostic purposes. Women who are being considered as candidates for thalidomide use must be counseled to avoid pregnancy, and men must be counseled regarding the use of condoms as prophylactics rather than relying on oral contraceptives. In addition, the prescriber and the pharmacy must both be certified through the THALOMID Risk Evaluation and Mitigation Strategy (REMS) program to prescribe thalidomide. The usual starting dose of thalidomide in our LVAD cohort is 50 mg twice daily. If toxicity develops, the drug is discontinued until the toxicity resolves. Depending on the type of toxicity and severity, thalidomide may be reinitiated at a starting dose of 50 mg every other night and increased by 50 mg every 2 weeks as tolerated. Complete blood counts are monitored every month during dose titration. If there is continued evidence of bleeding, the dose may be increased monthly in increments of 50 mg until a total maximum daily dose of 200 mg is reached. We begin dose reductions when plasma hemoglobin levels have normalized. Generally, the dose may be reduced by 50% until the lowest effective dose is reached. In patients with relative contraindications, we favor starting thalidomide at 50 mg at bedtime every other day. Tolerance is assessed weekly by telephone or in person for the first month or at any dosage change. If tolerated, the dose is increased to 50 mg at bedtime daily for 2 weeks, then to 100 mg every night at bedtime or 50 mg twice daily. If bleeding persists after 1 month of 100 mg every night at bedtime, the dose may be increased to 150 mg every night at bedtime for 1 month. If bleeding still persists, the dose may be further increased to 200 mg every night. Thalidomide is discontinued if there is no response by 6 months or if intolerable toxicity develops. The use of thalidomide must be coupled with attention to iron repletion, because plasma hemoglobin concentrations will rebound more quickly if iron stores are adequately repleted, and the thalidomide dose can be decreased. In this series, we expand on our previous report of thalidomide use in a patient with LVAD-associated GI bleeding5 to demonstrate its utility in disparate clinical situations and the adverse effects associated with thalidomide use. All patients in our series exhibited cessation of GI bleeding with thalidomide use or a reduction in bleeding, reinforcing the utility of this therapy in patients with
1053-2498/$ - see front matter r 2015 International Society for Heart and Lung Transplantation. All rights reserved. http://dx.doi.org/10.1016/j.healun.2014.09.013
Research Correspondence
133
Table 1
Patients Supported With a Left Ventricular Assist Device Who Received Thalidomide
Patient
Age at time of LVAD (years)
Time from implant to GI bleed (days)
Bleeding episodes requiring transfusion (No.)
Time from implant to thalidomide use Documented (days) GIAD?
1 2
65 62
54 20
4 4
320 726
Yes Yes
3
63
88
2
86
Yes
4
67
11
3
31
No
5
29
44
3
43
No
6
61
30
3
45
Yes
7
35
29
2
52
Yes
8
65
31
4
312
Yes
Outcome No recurrence of bleeding No recurrence of bleeding, development of symptomatic neuropathy, thalidomide discontinued No recurrence of bleeding, development of symptomatic neuropathy, thalidomide discontinued No recurrence of bleeding, thalidomide dose reduced Reduced bleeding, successfully transplanted No recurrence of bleeding, successfully transplanted Reduction in bleeding, eventually died of sepsis Died of sepsis 1 week after thalidomide initiated
GI, gastrointestinal; GIAD, gastrointestinal angiodysplasia; LVAD, left ventricular assist device.
LVADs. A significant proportion of patients developed adverse effects requiring a reduction in the dosing of thalidomide or its cessation, serving as a reminder that these patients must be closely monitored. The protocol that we use for screening LVAD patients before thalidomide use and in directing thalidomide therapy is essential for reducing those complications.
The only randomized, controlled trial that assessed thalidomide use in patients with GIAD4 excluded patients with severe cardiac comorbidities and those taking antiplatelet or anti-coagulant agents. Our study demonstrates that this therapy can be safely administered to patients on LVAD support when they are monitored via a dedicated protocol.
Figure 1 Protocol for treatment of gastrointestinal angiodysplasia in patients supported with a left ventricular assist device. CBC, complete blood count; GIB, gastrointestinal bleeding; qhs, every night at bedtime.
134
The Journal of Heart and Lung Transplantation, Vol 34, No 1, January 2015
Limitations to our study include the lack of a control group or a different treatment arm. Owing to recurrent, lifethreatening, and refractory bleeding in these patients, we concluded that withholding a therapy that we had previously shown would benefit these patients would be unethical. We also did not assess the relative effect of thalidomide in reduction of LVAD-associated GIAD compared with other therapeutic agents. Other investigators have used agents, including octreotide, to reduce bleeding due to GIAD in LVAD patients, although octreotide is difficult to tolerate due to its mode of delivery (injection) and adverse effects, including nausea and bradycardia. Lenalidomide, a synthetic analog of thalidomide, has been shown to be as potent as the parent drug, with less of the non-hematologic adverse effects, and is another potential treatment option for these patients. In summary, thalidomide can be used safely in patients with LVAD-associated GIAD when prescribed as part of a treatment protocol. These findings must be replicated in multicenter, randomized studies to corroborate our results.
Disclosure statement
A modified implantation technique of the HeartWare ventricular assist device for pediatric patients
In addition, because the pump occupies a space in the left chest cavity, atelectasis of the left lower lobe can occur. Ideally, the inflow cannula should be parallel to the interventricular septum,3 and the pump housing should not interfere with proper lung expansion. We describe a surgical technique that ensures optimal positioning of the HVAD pump for pediatric patients. A median sternotomy is created. Preceding the administration of heparin, a pre-peritoneal pocket is fashioned by dividing the left diaphragm anteriorly. The pocket for the HVAD is considerably smaller than that necessary for the HeartMate II, making pocket-related complications less likely. Cardiopulmonary bypass is established. A left atrial vent is placed via the Waterston groove. The LV is incised and the myocardium is resected to achieve an adequate opening for the inflow cannula. The optimal site should lie slightly anterior to the left ventricular (LV) apex and at least 5 mm off from the left anterior descending coronary artery to avoid compromising the coronary circulation by the sewing ring. Meticulous attention is given, particularly in LV noncompaction, to remove any excess muscle that could potentially obstruct the inflow cannula once the device is implanted (Figure 1). A mural thrombus is not uncommon in hearts with LV non-compaction and should be promptly removed if present. The use of a left atrial vent will aid in maintaining a bloodless surgical field. Once satisfied with the LV apical core, 12 pairs of 2-0 TiCron (Covidien, New Haven, CT) mattress stitches are placed around the apical opening through a suitably trimmed circular-shaped felt strip. The sutures are passed through the sewing ring and tied down. While the sutures are being tied, particular care is given to make certain that the center of the sewing ring is properly aligned with respect to the LV apical opening. To prevent malalignment of the sewing ring, the
Iki Adachi, MD,a Francisco A. Guzmán-Pruneda, MD,a Aamir Jeewa, MD,b Charles D. Fraser Jr, MD,a and E. Dean McKenzie, MDa From the aCongenital Heart Surgery; and the b Pediatric Cardiology, Texas Children’s Hospital, Baylor College of Medicine, Houston, Texas
The last decade has witnessed significant maturation of durable ventricular assist device treatment. Among multiple contributing factors, the greatest effect would have certainly been derived from the emergence of implantable devices. Survival with an implantable, continuous-flow device has clearly been superior to that with an extracorporeal, pulsatile pump.1 In small children, however, a pulsatile device still remains the only viable option. This frustrating reality has compelled pediatric centers to explore the use of adult-sized implantable devices in adolescents. Although the HeartMate II (Thoratec Corporation Inc, Pleasanton, CA) represents an excellent option, its application is limited to larger children with a body surface area of approximately 1.3 m2 or greater.2 The HeartWare ventricular assist device (HVAD; HeartWare, Framingham, MA) has the potential to overcome this paradigm owing to its compact design. There exists, however, a concern for inflow cannula configuration with this particular device.3 If placed intrapericardially, as recommended by the manufacturer, the rotor housing may conform to the chest wall laterally, and the inflow cannula typically lies on a horizontal plane.
None of the authors has a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest to disclose.
References 1. Aggarwal A, Pant R, Kumar S, et al. Incidence and management of gastrointestinal bleeding with continuous flow assist devices. Ann Thorac Surg 2012;93:1534-40. 2. Demirozu ZT, Radovancevic R, Hochman LF, et al. Arteriovenous malformation and gastrointestinal bleeding in patients with the HeartMate II left ventricular assist device. J Heart Lung Transplant 2011;30:849-53. 3. Ge ZZ, Chen HM, Gao YJ, et al. Efficacy of thalidomide for refractory gastrointestinal bleeding from vascular malformation. Gastroenterology 2011:141:1629–37:(e1–4). 4. Kamalaporn P, Saravanan R, Cirocco M, et al. Thalidomide for the treatment of chronic gastrointestinal bleeding from angiodysplasias: a case series. Eur J Gastroenterol Hepatol 2009;21:1347-50. 5. Ray R, Kale PP, Ha R, Banerjee D. Treatment of left ventricular assist device associated arteriovenous malformations with thalidomide. ASAIO J 2014;60:482-3.
RESEARCH CORRESPONDENCE Thalidomide for treatment of gastrointestinal angiodysplasia in patients with left ventricular assist devices: Case series and treatment protocol Karen Draper, MD,a Parag Kale, MD,b Beth Martin, MD,a Kelly Cordero, RNP,a Richard Ha, MD,c and Dipanjan Banerjee, MD, MSa From the aDepartment of Medicine, Stanford University Hospital and Clinics, Stanford, California; bthe Department of Medicine, Kaiser Permanente, Santa Clara, California; and the cDepartment of Cardiothoracic Surgery, Stanford University Hospital and Clinics, Stanford, California
Gastrointestinal bleeding (GIB) is a common complication after left ventricular assist device (LVAD) implantation, occurring in 17% to 31% of patients.1,2 Bleeding from gastrointestinal angiodysplasia (GIAD) is the most common cause of GIB in these patients, accounting for 15% to 31% of the total.1,2 The high rate of GIB in the LVAD population leads to frequent and prolonged hospitalizations in these patients and adversely affects quality of life. Thalidomide, a potent anti-angiogenic compound, was used effectively for recurrent GIAD-related bleeding in 1 randomized controlled trial3 as well as in 1 small case series.4 We previously reported the successful use of thalidomide in a patient with recurrent LVAD-associated GIAD.5 Subsequently, at our institutions, we have used thalidomide to excellent effect for several refractory cases of GIAD in LVAD recipients. Thalidomide has been prescribed to 8 of 119 LVAD patients at our institution for this purpose (Table 1). The mean age was 59 (standard deviation [SD], 15) years, number of bleeding episodes was 3 (SD, 0.8), the mean time from implant to the first bleeding episode was 38 (SD, 24) days, and the mean time from implant to thalidomide use was 202 (SD, 234) days. We describe the protocol we have established at our institution for careful monitoring of patients receiving thalidomide to minimize the adverse effects of this promising therapy (Figure 1). Before thalidomide is prescribed, patients on LVAD support must be screened carefully for contraindications to its use. Strict exclusion criteria include thromboembolic disease without anti-coagulation, major wounds, symptomatic autonomic neuropathy, peripheral neuropathy, bradycardia,
and concurrent radiotherapy. Relative exclusions include small wounds, constipation, at risk of falls, a history of seizures. Upper and lower endoscopy is indicated to assess for treatable lesions, because GIAD may be treated endoscopically. Depending on the proficiency of the treating center, capsule endoscopy and push enteroscopy may also be used for diagnostic purposes. Women who are being considered as candidates for thalidomide use must be counseled to avoid pregnancy, and men must be counseled regarding the use of condoms as prophylactics rather than relying on oral contraceptives. In addition, the prescriber and the pharmacy must both be certified through the THALOMID Risk Evaluation and Mitigation Strategy (REMS) program to prescribe thalidomide. The usual starting dose of thalidomide in our LVAD cohort is 50 mg twice daily. If toxicity develops, the drug is discontinued until the toxicity resolves. Depending on the type of toxicity and severity, thalidomide may be reinitiated at a starting dose of 50 mg every other night and increased by 50 mg every 2 weeks as tolerated. Complete blood counts are monitored every month during dose titration. If there is continued evidence of bleeding, the dose may be increased monthly in increments of 50 mg until a total maximum daily dose of 200 mg is reached. We begin dose reductions when plasma hemoglobin levels have normalized. Generally, the dose may be reduced by 50% until the lowest effective dose is reached. In patients with relative contraindications, we favor starting thalidomide at 50 mg at bedtime every other day. Tolerance is assessed weekly by telephone or in person for the first month or at any dosage change. If tolerated, the dose is increased to 50 mg at bedtime daily for 2 weeks, then to 100 mg every night at bedtime or 50 mg twice daily. If bleeding persists after 1 month of 100 mg every night at bedtime, the dose may be increased to 150 mg every night at bedtime for 1 month. If bleeding still persists, the dose may be further increased to 200 mg every night. Thalidomide is discontinued if there is no response by 6 months or if intolerable toxicity develops. The use of thalidomide must be coupled with attention to iron repletion, because plasma hemoglobin concentrations will rebound more quickly if iron stores are adequately repleted, and the thalidomide dose can be decreased. In this series, we expand on our previous report of thalidomide use in a patient with LVAD-associated GI bleeding5 to demonstrate its utility in disparate clinical situations and the adverse effects associated with thalidomide use. All patients in our series exhibited cessation of GI bleeding with thalidomide use or a reduction in bleeding, reinforcing the utility of this therapy in patients with
1053-2498/$ - see front matter r 2015 International Society for Heart and Lung Transplantation. All rights reserved. http://dx.doi.org/10.1016/j.healun.2014.09.013
Research Correspondence
133
Table 1
Patients Supported With a Left Ventricular Assist Device Who Received Thalidomide
Patient
Age at time of LVAD (years)
Time from implant to GI bleed (days)
Bleeding episodes requiring transfusion (No.)
Time from implant to thalidomide use Documented (days) GIAD?
1 2
65 62
54 20
4 4
320 726
Yes Yes
3
63
88
2
86
Yes
4
67
11
3
31
No
5
29
44
3
43
No
6
61
30
3
45
Yes
7
35
29
2
52
Yes
8
65
31
4
312
Yes
Outcome No recurrence of bleeding No recurrence of bleeding, development of symptomatic neuropathy, thalidomide discontinued No recurrence of bleeding, development of symptomatic neuropathy, thalidomide discontinued No recurrence of bleeding, thalidomide dose reduced Reduced bleeding, successfully transplanted No recurrence of bleeding, successfully transplanted Reduction in bleeding, eventually died of sepsis Died of sepsis 1 week after thalidomide initiated
GI, gastrointestinal; GIAD, gastrointestinal angiodysplasia; LVAD, left ventricular assist device.
LVADs. A significant proportion of patients developed adverse effects requiring a reduction in the dosing of thalidomide or its cessation, serving as a reminder that these patients must be closely monitored. The protocol that we use for screening LVAD patients before thalidomide use and in directing thalidomide therapy is essential for reducing those complications.
The only randomized, controlled trial that assessed thalidomide use in patients with GIAD4 excluded patients with severe cardiac comorbidities and those taking antiplatelet or anti-coagulant agents. Our study demonstrates that this therapy can be safely administered to patients on LVAD support when they are monitored via a dedicated protocol.
Figure 1 Protocol for treatment of gastrointestinal angiodysplasia in patients supported with a left ventricular assist device. CBC, complete blood count; GIB, gastrointestinal bleeding; qhs, every night at bedtime.
134
The Journal of Heart and Lung Transplantation, Vol 34, No 1, January 2015
Limitations to our study include the lack of a control group or a different treatment arm. Owing to recurrent, lifethreatening, and refractory bleeding in these patients, we concluded that withholding a therapy that we had previously shown would benefit these patients would be unethical. We also did not assess the relative effect of thalidomide in reduction of LVAD-associated GIAD compared with other therapeutic agents. Other investigators have used agents, including octreotide, to reduce bleeding due to GIAD in LVAD patients, although octreotide is difficult to tolerate due to its mode of delivery (injection) and adverse effects, including nausea and bradycardia. Lenalidomide, a synthetic analog of thalidomide, has been shown to be as potent as the parent drug, with less of the non-hematologic adverse effects, and is another potential treatment option for these patients. In summary, thalidomide can be used safely in patients with LVAD-associated GIAD when prescribed as part of a treatment protocol. These findings must be replicated in multicenter, randomized studies to corroborate our results.
Disclosure statement
A modified implantation technique of the HeartWare ventricular assist device for pediatric patients
In addition, because the pump occupies a space in the left chest cavity, atelectasis of the left lower lobe can occur. Ideally, the inflow cannula should be parallel to the interventricular septum,3 and the pump housing should not interfere with proper lung expansion. We describe a surgical technique that ensures optimal positioning of the HVAD pump for pediatric patients. A median sternotomy is created. Preceding the administration of heparin, a pre-peritoneal pocket is fashioned by dividing the left diaphragm anteriorly. The pocket for the HVAD is considerably smaller than that necessary for the HeartMate II, making pocket-related complications less likely. Cardiopulmonary bypass is established. A left atrial vent is placed via the Waterston groove. The LV is incised and the myocardium is resected to achieve an adequate opening for the inflow cannula. The optimal site should lie slightly anterior to the left ventricular (LV) apex and at least 5 mm off from the left anterior descending coronary artery to avoid compromising the coronary circulation by the sewing ring. Meticulous attention is given, particularly in LV noncompaction, to remove any excess muscle that could potentially obstruct the inflow cannula once the device is implanted (Figure 1). A mural thrombus is not uncommon in hearts with LV non-compaction and should be promptly removed if present. The use of a left atrial vent will aid in maintaining a bloodless surgical field. Once satisfied with the LV apical core, 12 pairs of 2-0 TiCron (Covidien, New Haven, CT) mattress stitches are placed around the apical opening through a suitably trimmed circular-shaped felt strip. The sutures are passed through the sewing ring and tied down. While the sutures are being tied, particular care is given to make certain that the center of the sewing ring is properly aligned with respect to the LV apical opening. To prevent malalignment of the sewing ring, the
Iki Adachi, MD,a Francisco A. Guzmán-Pruneda, MD,a Aamir Jeewa, MD,b Charles D. Fraser Jr, MD,a and E. Dean McKenzie, MDa From the aCongenital Heart Surgery; and the b Pediatric Cardiology, Texas Children’s Hospital, Baylor College of Medicine, Houston, Texas
The last decade has witnessed significant maturation of durable ventricular assist device treatment. Among multiple contributing factors, the greatest effect would have certainly been derived from the emergence of implantable devices. Survival with an implantable, continuous-flow device has clearly been superior to that with an extracorporeal, pulsatile pump.1 In small children, however, a pulsatile device still remains the only viable option. This frustrating reality has compelled pediatric centers to explore the use of adult-sized implantable devices in adolescents. Although the HeartMate II (Thoratec Corporation Inc, Pleasanton, CA) represents an excellent option, its application is limited to larger children with a body surface area of approximately 1.3 m2 or greater.2 The HeartWare ventricular assist device (HVAD; HeartWare, Framingham, MA) has the potential to overcome this paradigm owing to its compact design. There exists, however, a concern for inflow cannula configuration with this particular device.3 If placed intrapericardially, as recommended by the manufacturer, the rotor housing may conform to the chest wall laterally, and the inflow cannula typically lies on a horizontal plane.
None of the authors has a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest to disclose.
References 1. Aggarwal A, Pant R, Kumar S, et al. Incidence and management of gastrointestinal bleeding with continuous flow assist devices. Ann Thorac Surg 2012;93:1534-40. 2. Demirozu ZT, Radovancevic R, Hochman LF, et al. Arteriovenous malformation and gastrointestinal bleeding in patients with the HeartMate II left ventricular assist device. J Heart Lung Transplant 2011;30:849-53. 3. Ge ZZ, Chen HM, Gao YJ, et al. Efficacy of thalidomide for refractory gastrointestinal bleeding from vascular malformation. Gastroenterology 2011:141:1629–37:(e1–4). 4. Kamalaporn P, Saravanan R, Cirocco M, et al. Thalidomide for the treatment of chronic gastrointestinal bleeding from angiodysplasias: a case series. Eur J Gastroenterol Hepatol 2009;21:1347-50. 5. Ray R, Kale PP, Ha R, Banerjee D. Treatment of left ventricular assist device associated arteriovenous malformations with thalidomide. ASAIO J 2014;60:482-3.
