The Public Presentation does not include any confidential information or findings from this Team Masters Project with BioMarin Pharmaceutical.
BioMarin and KGI titled our project as:
"Recurrent bleeding in patients with mechanical flow devices: an environmental study."
Rivaroxaban for thromboprophylaxis after Hospitalization for Medical IllnessShadab Ahmad
Anticoagulant prophylaxis reduces the risk of in-hospital venous thromboembolism by 50 to 60% but is rarely continued after discharge in accordance with current guidelines
When not to simplify haemostasis management. Case presentations.scanFOAM
A talk by Anna Ågren at the 2017 meeting of the Scandinavian Society of Anaestesiology and Intensive Care Medicine.
All available content from SSAI2017: https://scanfoam.org/ssai2017/
Delivered in collaboration between scanFOAM, SSAI & SFAI.
A talk by Christian Fenger-Eriksen at the 2017 meeting of the Scandinavian Society of Anaestesiology and Intensive Care Medicine.
All available content from SSAI2017: https://scanfoam.org/ssai2017/
Delivered in collaboration between scanFOAM, SSAI & SFAI.
Rivaroxaban for thromboprophylaxis after Hospitalization for Medical IllnessShadab Ahmad
Anticoagulant prophylaxis reduces the risk of in-hospital venous thromboembolism by 50 to 60% but is rarely continued after discharge in accordance with current guidelines
When not to simplify haemostasis management. Case presentations.scanFOAM
A talk by Anna Ågren at the 2017 meeting of the Scandinavian Society of Anaestesiology and Intensive Care Medicine.
All available content from SSAI2017: https://scanfoam.org/ssai2017/
Delivered in collaboration between scanFOAM, SSAI & SFAI.
A talk by Christian Fenger-Eriksen at the 2017 meeting of the Scandinavian Society of Anaestesiology and Intensive Care Medicine.
All available content from SSAI2017: https://scanfoam.org/ssai2017/
Delivered in collaboration between scanFOAM, SSAI & SFAI.
A talk by Jakob Stensballe at the 2017 meeting of the Scandinavian Society of Anaestesiology and Intensive Care Medicine.
All available content from SSAI2017: https://scanfoam.org/ssai2017/
Delivered in collaboration between scanFOAM, SSAI & SFAI.
Patients admitted to the intensive care unit (ICU) are at increased risk for cardiac arrhythmias. They may be the reason for admission or resulting from the underlying condition. Treating exacerbating and contributing factors is the first step in management, however in certain cases may not be sufficient. Further the diagnosis of the arrhythmia may difficult from the ECG. An invasive cardiac electrophysiology study (EPS) can be helpful in establishing the diagnosis and can be combined with catheter ablation to eliminate the substrate. The field of cardiac electrophysiology is rapidly developing with technological advances providing insights into the mechanism of certain arrhythmias and expanding the therapeutic potential. This presentation will provide an overview of recent developments and insights into the management of common arrhythmias on the ICU.
kawasaki disease is disease of pediatric age group leading to involvement of coronaries in 25% of case. some of presented as fetal complication. early diagnosis and treatment useful measure to prevent complications.
postgraduate education for cardiothoracic anaesthesia and intensive care doctors in cardiac operations on patients with unstable ischemic heart disease
Effect of restrictive versus liberal transfusion strategies on outcomes in pa...Mohd Saif Khan
Restrictive red cell transfusion policies are recommended as safe for most hospital patients with anaemia. Uncertainty exists for patients with cardiovascular disease, whose hearts may be more susceptible to limited coronary oxygen supply.
Alcohol septal ablation is emerging as an alternative to surgical myectomy in the management of symptomatic cases of Hypertrophic obstructive cardiomyopathy (HOCM). This involves injection of absolute alcohol into 1st septal perforator thereby producing myocardial necrosis with resultant septal remodelling within 3-6 months. This results in reduction of septal thickness and LV outflow gradients with improvement in symptoms.
A talk by Jakob Stensballe at the 2017 meeting of the Scandinavian Society of Anaestesiology and Intensive Care Medicine.
All available content from SSAI2017: https://scanfoam.org/ssai2017/
Delivered in collaboration between scanFOAM, SSAI & SFAI.
Patients admitted to the intensive care unit (ICU) are at increased risk for cardiac arrhythmias. They may be the reason for admission or resulting from the underlying condition. Treating exacerbating and contributing factors is the first step in management, however in certain cases may not be sufficient. Further the diagnosis of the arrhythmia may difficult from the ECG. An invasive cardiac electrophysiology study (EPS) can be helpful in establishing the diagnosis and can be combined with catheter ablation to eliminate the substrate. The field of cardiac electrophysiology is rapidly developing with technological advances providing insights into the mechanism of certain arrhythmias and expanding the therapeutic potential. This presentation will provide an overview of recent developments and insights into the management of common arrhythmias on the ICU.
kawasaki disease is disease of pediatric age group leading to involvement of coronaries in 25% of case. some of presented as fetal complication. early diagnosis and treatment useful measure to prevent complications.
postgraduate education for cardiothoracic anaesthesia and intensive care doctors in cardiac operations on patients with unstable ischemic heart disease
Effect of restrictive versus liberal transfusion strategies on outcomes in pa...Mohd Saif Khan
Restrictive red cell transfusion policies are recommended as safe for most hospital patients with anaemia. Uncertainty exists for patients with cardiovascular disease, whose hearts may be more susceptible to limited coronary oxygen supply.
Alcohol septal ablation is emerging as an alternative to surgical myectomy in the management of symptomatic cases of Hypertrophic obstructive cardiomyopathy (HOCM). This involves injection of absolute alcohol into 1st septal perforator thereby producing myocardial necrosis with resultant septal remodelling within 3-6 months. This results in reduction of septal thickness and LV outflow gradients with improvement in symptoms.
Buenas Tardes
Esta es un diccionario Pictórico referente a las lecturas: Pensamiento vísible, Rutinas del pensamiento y Habilidades del siglo XX elaborado por la estudiante: Viviana Chaves Jiménez. Materia: Aplicaciones Informáticas en Contextos Educativos
Social media strategy for Locker Room UpdatePeterman W
Here, I've assembled the network objectives for Locker Room Update, my website, in a social media plan for both myself and my staff of sports journalists.
Deep vein thrombosis (DVT) usually affects the deep vein of the legs, though it may also occur in the veins of the arms, mesenteric and cerebral
veins. Venous thromboembolism can cause sudden pulmonary embolism with instantaneous death. In patients who have developed deep vein
thrombosis there is likelihood of recurrent thrombosis and post thrombotic syndrome. Deep venous thrombosis is preventable in majority of the
cases. Understanding the etiopathogenesis, clinical presentation, evaluation and management is essential for both prevention and management
thereby reducing the morbidity and mortality associated with the disease.
Anticoagulation in Valvular Heart Disease.pptxzeinabnm
Brief definition with pathology, types, risk factors, clinical manifestation and staging in Valvular heart disease.
with detailed discussion of clinical management and approaches in different situation.
necessary information about each anti-coagulation used.
Acquired hemophilia is a rare disorder and if missed can cost lives. This presentation has been prepared keeping in view the non hematologist health care workers to broaden their index of suspicion and increase their awareness. The target people are medical residents those who work in ER and ICUs.
Factor v deficiency is rare
first described in a Norwegian patient in 1943, Identified by Dr. Paul Owren .
Fewer than 200 cases of congenital factor V deficiency have been reported worldwide since 1943.
inheritance of factor V deficiency is autosomal recessive.
usually only needed for severe bleeds or before surgery.
there is no concentrate containing only factor V.
fresh plasma or (FFP) infusions are used to correct the deficiency temporarily and should be given daily during a bleeding episode.
1. RECURRENT BLEEDING IN PATIENTS WITH
MECHANICAL FLOW DEVICES:
AN ENVIRONMENTAL STUDY
TMP Faculty Presentation, Spring 2016
Courtney Lamb, Cyrus Nguyen, Jill Nicholas,
Hitesh Pathak, Suchitra Ramachandran
1
2. Executive Summary
Project Objectives
• Current therapeutic
approach
• Business opportunity
• Clinical trial concepts
Methods
• Secondary literature
research
• Primary research
• KOL interviews
• Physician Survey
Outcomes
• Target product profile
• Business
assessment
• Clinical trial concepts
Current State
Recurrent gastrointestinal bleeding is recognized as a significant medical problem in
patients following implantation of Left Ventricular Assist Devices (LVADs). Shear stress
applied by LVADs induces Acquired von Willebrand Syndrome. There is no current
therapy indicated to specifically address this type of bleeding.
2
4. Left VentricularAssist Devices and GI Bleeding
LVADs
• Assist the heart in pumping blood in
advanced heart failure patients
Uses
• Bridge to Transplant (BTT)
• Destination Therapy (DT)
• Bridge to Candidacy (BTC)
• Bridge to Recovery (BR)
Risks and Complications
• Development of clots, pump
thrombosis, damage to heart
valves, discomfort or pain
• Bleeding: Gastrointestinal bleeding
GI Bleeding
• ~22 percent of LVAD patients
develop GI bleeding
• ~60 percent of these patients
developed a recurrent bleed
Possible Causative Factors
• Treatment related
• Chronic anticoagulation
• Device related
• Platelet dysfunction
• Induced shear stress
Bleeding complications can arise after implantation of LVADs due to increased shear
force associated with the pump
https://www.nhlbi.nih.gov/health/health-topics/topics/vad
Loor, G. & Gonzalez Stawinski, G. Best Pract. Res. Clin. Anaesthesiol. 26 (2012), 105–115
Aggarwal, A. Annual Throacic Surgery. (2010)
4
4
5. Changes in vWF structure after LVAD implantation
• Von Willebrand Factor (vWF) in its multimeric structure is essential for
hemostasis
• Increased shear forces due to LVADs induce conformational change, unravel
VWF and increase its protease susceptibility
• Change in vWF structure and the associated decrease in vWF multimers
increases bleeding risk
While LVADs serve to treat one disease, they also cause another. Therefore, a novel
solution is needed to address this significant issue
Franchi, F., et al. Thromb. Res. 2014, 134 (6), 1316–1322. Geisen, U., et al. Eur. J. Cardiothorac. Surg. 2008, 33 (4), 679–684.
5
5
6. Von Willebrand Disease (VWD)
• A group of bleeding disorders characterized by any
deficiency in or defective functioning of the von
Willebrand factor (vWF)
• vWF: glycoprotein that carries factor VIII and stimulates
platelet aggregation
• Congenital VWD: three major types
1. Type 1: characterized by vWF deficiency
2. Type 2: characterized by functional vWF defects
• Further categorized into 4 subgroups
• Type 2A: most common
3. Type 3: characterized by complete vWF absence
• Acquired von Willebrand Syndrome (AVWS) – vWD
developed secondary to other diseases
6
7. Acquired von Willebrand Syndrome (AVWS)
• Genetic and acquired VWD are
characterized by:
• Lack of high molecular weight vWF
multimers due to proteolysis
• A causal link to increased bleeding
risk
Franchi, F., et al. Thromb. Res. 2014, 134 (6), 1316–1322.
Geisen, U., et al. Eur. J. Cardiothorac. Surg. 2008, 33 (4), 679–684.
7
7
8. Diagnosis of AVWS
Doctors treat LVAD patients with a GI bleed under the assumption that they
HAVE AVWS because of the high shear stress
Initial evaluation
(history and physical
examination)
No further evaluation
Initial VWD assays
• VW: Ag
• VWP: Rco
• Factor VIII
Referral for other
appropriate
evaluationReferral for selected specified VWD
studies
• Repeat initial VWD assays if
necessary
• Ration of VWF: RCo to
VWF:Wg
• Multimer distribution
• Collagen binding
• Factor VIII binding
• Platelet VWF studies
• DNA sequencing for VWF gene
Possible referral for other
appropriate evaluation
Positive Negative
Isolated prolonged PTT that
corrects on 1:1 mixing study or no
abnormalities
No test abnormal1 or more tests
abnormal
Other cause identified low
platelets, isolated abnormal
PT, low fibrinogen,
abnormal TT
Laboratory evaluation Initial
hemostasis tests
• CBC and platelet count
• PTT
• PT
• Fibrinogen or TT
(optional)
If bleeding history is strong,
perform initial VWD assays
U.S. Department of Health Services. NIH: National Heart, Lung and Blood Institute. 2015.
Dr. Slaughter, Interview, 2015; Dr. Tiede, Interview, 2015.
8
9. • Lymphoproliferative disorders
• Immunological disorders
Autoantibody degradation of vWF
• Myeloproliferative disorders
Adsorption of vWF to surfaces of transformed platelets
and cells
• LVAD implantation
• Aortic stenosis
• Dysfunctional valve prosthesis
• Endocarditis
Proteolytic cleavage due shear stress induced
unfolding
The multiple mechanisms ofAVWS induced by
comorbidities
Understanding of the various diseases and mechanisms associated with AVWS
is important in understanding the optimal therapy for AVWS patients
Tiede, A. et al. Blood 2011, 117 (25), 6777–6785.
Velik-Salchner, C. et al. J. Cardiothorac. Vasc. Anesth. 2008, 22 (5), 719–724.
9
10. There are three goals in the treatment for GI
bleeding in LVAD patients:
Current therapeutic strategy
Control acute bleeding
Prevent bleeding in high risk situations
Obtain long term remission
1
2
3
10
11. For LVAD patients, long-term treatment options are
limited and primarily based on case studies
Variability in the underlying disorders and mechanisms of AVWS
precludes one standardized course of treatment
Whitlow, C. B. Clin. Colon Rectal Surg. 2010, 23 (1), 31–36.
Cerulli, M. A. Medscape 2015.
Tiede, A., et al. Blood 2011, 117 (25), 6777–6785.
Geisen, U., et al. Eur. J. Cardiothorac. Surg. 2008, 33 (4), 679–684.
Acute Treatments for GI
bleeding
• Hemostatic therapies
administered
endoscopically
• Submucosal injection of
epinephrine
• Bipolar electrocoagulation
via cauterization
• Hemostatic Clips
Treatments for Prevention
and Control of AVWS
• Desmopressin
• VWF-containing Factor VIII
concentrates
• Recombinant Factor VIIa
• Antifibrinolytics
11
12. Physician survey suggests inadequacy of current
treatment options
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
Not satisfied Neutral Very
satisfied
Satisfaction with Current Treatment Options (n=12)
Hematology Gastroenterology
12
13. The balancing act between anticoagulation and
thrombosis in patients with LVADS
GI Bleeding Event
• Hold anticoagulation/antiplatelet therapy
• GI consult to identify bleeding source
• Endoscopic treatment of bleeding source
Resolution of Bleeding?
Resume anticoagulation
Recurrent Bleed
• Hold anticoagulation until resolution. When
bleeding stops, resume anticoagulation
OR
• Hold anticoagulation indefinitely
Yes No
In managing bleeding in LVAD patients, there is a careful balance between resolving the
bleed and increasing the risk of thrombosis through prolonged holding of anticoagulation
Suarez, J., et al. Am. Heart Assoc. 2011, No. Circ Heart Fail. 2011;4:779-784, 4:779–784.
13
14. 0 2 4 6 8 10 12 14 16 18
None
Marginal
Moderate
Significant
Perception of a Need for a Novel Therapeutic
Cardiology Hematology Gastroenterology
Physician survey supports the conclusion
that there is an unmet clinical need
The “underlying pathophysiology induced by the VAD fosters the on-going
formation of AVMs. So even if some are found and treated, they invariably recur
as the underlying physiologic changes are still present”
Dr. Wild, Gastroenterologist, Duke Medical School
“We don’t want our patients bleeding all the time but we also don’t want to mess up
the pump by keeping them off anticoagulation forever. Is a tough balance.”
Dr. Russell, Cardiologist, Johns Hopkins
“If we had better tolerated, more effective preventive medical therapies, that
would be ideal.”
Dr. Draper, Gastroenterologist, Stanford
14
16. Assumptions from KOL feedback
The majority of physicians are interested in and willing to
prescribe a new medication to stop bleeding due to LVAD
implantation. It is agreed that there is a great medical
need.
Contrary to secondary literature research, KOL interviews
indicate that LVAD implantation is used increasingly as a
destination therapy, rather than a bridge to transplant.
Regardless of improvements in pump technology,
bleeding will continue to be a serious complication for
LVAD patients.
16
17. LVADs increase survival rates
• In most patients without an LVAD, the one-year survival rate is 10%
• Most doctors interviewed have recommended LVAD implantation as a
destination therapy
Because of the increase in survival rates in patients with end stage heart failure due to
LVAD implantation, we can assume that market will continue to increase
Intermacs Quarterly Statistical Report. 2015.
Dr. Tiede, Interview, 2015; Dr. Arabia, Interview, 2015.
0
20
40
60
80
100
0 10 20 30 40 50 60 70
% survival
months after device implantation
Kaplan-meier survival plot
BTT
BTC
DT
17
17
18. LVAD implant incidence and adverse events
.
Table: Adverse event June 2008 to Dec 2014 in first 12 month Post Implant (N=12,030)
Adverse event 2008-2011
(events)
2008-2011
(Rate)
2012-2014
(Events)
2012-2014
(Rate)
P-value
Bleeding 3,932 9.41/100
patients
4,420 7.79/100
patients
<0.001
0
200
400
600
800
1000
1200
1400
2006 2007 2008 2009 2010 2011 2012 2013 2014 2015
Implants per year by device type
BTT
BTC
DT
BR
Even with the improvement in technology of LVADs, bleeding is still a significant risk
Intermacs Quarterly Statistical Report. 2015.
18
19. Survey results support business assumptions regarding
improved pump designs
0 2 4 6 8 10 12 14
None
Marginal
Moderate
Significant
Impact of Improvement in Pump Design
Cardiology Cardiothoracic Surgery
19
19
20. Reasons to believe this is an attractive market
LVADs are highly underutilized
• 3,000 heart transplants are performed each year worldwide
• 15,000 patients are on waiting lists for transplants
Improvement in
technology
Increase in
adoption rate
Larger market
for AVWS
“I know 2 different devices (HeartWare and HeartMate) that are different in the
way blood is pumped through, but the AVWS occurs similarly with both. I am not
aware of an LVAD that doesn’t cause AVWS.”
- Dr.Tiede interview, 2015
20
22. Analysis of current clinical studies regarding LVAD
patients,AVWS, and GI bleeding
Unmet Need
• Pump design:
Moderate impact
• Novel therapy: a
significant
requirement (61%)
• Dissatisfaction
with current AVWS
treatment options
Case
Studies
• 18 trials reviewed
• Trials pertaining to
LVADs and GI
bleeding,
AVWS/VWD, and
general GI
bleeding
• Trial comparison
Challenges
• Total enrollment in
trial
• Defining
primary/secondary
endpoints
• Endpoint
satisfaction
• Bleeding definition
• Trial sites
No clinical trial currently exists that combines both BioMarin’s target
patient population and a new therapeutic strategy
22
23. Research outcomes indicated differences in
current trial parameters
• History of two or more severe GI bleeding episodes associated
with either a drop in hemoglobin of ≥ 2 g/dl or requiring red blood
cell transfusion or treatment with VWD concentrate
• Internal or external bleeding leading to death or prolonged
hospitalization or requiring re-hospitalization
Bleeding
• Treatment success will be defined as a mean efficacy rating score
of < 2.5 for a participant´s bleeding episodes treated with the
investigational product while in a treatment period.
• Cessation of Bleeding [Time Frame: 52 months ]
Primary
outcomes
• Need for transfusion [ Time Frame: 48 hours post administration ]
• von Willebrand study and protein electrophoresis; multimer
analysis
• Proportion of VAD Patients with Gastrointestinal bleeding as
Assessed by HemoQuant Fecal Occult Blood Testing
Secondary
outcomes
https://clinicaltrials.gov
23
23
24. Important considerations in designing trial
Bleeding criteria is useful and relevant to
physicians
Differentiation of post-operative bleeding and
device-related bleeding
• Larger sample size would increase costs and difficulty
Trial sites and patient recruitment
• Could skew trial results
• Increase risk of adverse events: thrombosis
Predictability of development of AVWS
24
24
25. Summary
Unmet Need
•GI bleeding is a
significant
complication for
LVAD patients
•Current therapeutic
approach is
inadequate
•61% of doctors
perceive a significant
need for a new
therapeutic
Business
Opportunity
•A greater number of
LVADs are needed
than are implanted
•Improvements in
pump design
technology
•Market for
therapeutic targeting
AVWS from LVADs is
growing
Clinical Trials
•No current equivalent
clinical trial
•Specifics such as
bleeding criteria and
outcomes were
complied from 18
separate but related
trials
25
Recommendation
The clinical need and market opportunity clearly indicate that this project holds great
potential for BioMarin and should be further developed
29. Timeline of Deliverables
Aug Sep Oct Nov Dec Jan Feb Mar Apr
Clinical Landscape
Literature Research
KOL Interviews
Business Opportunity
Physician Survey
Clinical Trial Concepts
KOL Interviews
29
29
30. Primary Research - KOL Interviews
KOL Interviews
Phone interviews
with 9 KOLs
4 Main specialties
• Gastroenterology (2)
• Cardiothoracic
Surgery (4)
• Cardiology (1)
• Hematology (1)
1 research
scientist – VWF
30
30
32. Current Treatment Options
Desmopressin
Indication Manage spontaneous or trauma-induced bleeds in patients with
hemophilia A or von Willebrand's disease Type I
Dosage forms Oral
Intranasal
Parenteral (IV)
Half-Life Oral: 1.5-2.5 hours
Intranasal: 3.3-3.5 hours
Injection: Initial = 7.8 minutes, terminal = 0.4-4 hours
Protein binding 50%
Prices Apo-Desmopressin 0.1 mg Tablet = $0.83
Ddavp 0.01% nasal spray = $50.76
Ddavp 0.1 mg/ml Soltuion = $21.26
Ddavp 0.2 mg tablet = $2.98
32
33. Current Treatment Options
VWF-containing Factor
VIII concentrate
Indication For the treatment of hemophilia A, von Willebrand disease
and Factor XIII deficiency
Dosage forms Powder for solution
Half-Life 8.4-19.3 hrs
Clearance 4.1 mL/h•kg [Previously treated pediatric patients]
Prices $1.20 - $1.68/vial
33
34. Current Treatment Options
Recombinant
Factor VIIa
Indication For treatment of hemorrhagic complications in hemophilia A and B
Dosage forms Powder for injection
Volume of
Distribution
121 ± 30 mL/kg [adults]
153 ± 29 mL/kg [children]
280 to 290 mL/kg [congenital Factor VII deficiency]
Clearance 33 – 37 mL/h x kg [healthy]
1375 +/- 396 mL/hr [severe hemophilia A male children]
57.3 +/- 9.5 mL/hr/kg [severe hemophilia A male children]
2767 +/- 385 mL/hr [severe hemophilia A men]
37.6 +/- 13.1 mL/hr/kg [severe hemophilia A men]
Price $1.64/vial
34
35. Current Treatment Options
Anti-
fibrinolytics
Tranexamic Acid Aminoaproic Acide
Indication For use in patients with hemophilia
for short term use (two to eight
days) to reduce or prevent
hemorrhage
For use in the treatment of
excessive postoperative bleeding
Dosage forms Cream
Solution
Tablet
Solution
Syrup
Tablet
Half-life ~3 hours ~2 hours
Volume of
Distribution
9 to 12 L 23.1 ± 6.6 L
Clearance 110 – 116 mL/min 169 mL/min
Price $1.30 - $8.80/unit $2.28 - $7.17/unit
35
37. Survey Design
- Initial page assesses demographic information and
speciality
- Different survey design based on speciality
- Logic designed to terminate survey if respondent did not
have sufficient knowledge in the area
- 41 respondents so far
- Followed up with 11 respondents to further assess unmet
needs
37
37
38. Arizona, 1
California, 15
Colorado, 3
Florida, 1
Maryland, 5
New York, 1
North Carolina, 12
Pennsylvania, 1
Texas, 2
Q1: In which state is your primary practice located? (n=41)
38
39. 12
19
4
3 3
0-9 years 10-19 years 20-29 years 30-39 years 40+ years
Q2: How long have been practicing medicine? (n=41)
39
40. 0 0
6
40
1
Private practice Group practice Hospital based Academic medicine Other (please specify)
Q3: Which of the following best describes your practice (select all that
apply)? (n=41)
40
46. 1 1
4
1 1
0
0-1 year 1-2 years 2-3 years 3-4 years 4-5 years >5 years
Q9: How long on average is a patient on an LVAD as
destination therapy? (n=8)
46
49. 9
5
0 0 0
Heartmate (II, XVE) Heartware Jarvik 2000 Novacor Other
Q12: Which of the following LVAD pumps do you encounter
most often? (n=14)
49
50. 0
1 1
2
1
2
7
<1 in 50 1 in 40 1 in 30 1 in 20 1 in 15 1 in 10 1 in 5
Q13: In what fraction of your patients with LVADs does non-
surgical GI bleeding occur? (n=14)
50
51. 2
1
0 0
3
4 4
Never Rarely Occasionally Always
Q14: Please rank your involvement in the
management of non-surgical GI bleeding in LVAD
patients. (n=14)
0.00 1.00 2.00 3.00 4.00 5.00 6.00
Please rank your involvement in the management of non-surgical
GI bleeding in LVAD patients.
51
52. 0 2 4 6 8 10 12
None
Marginal
Moderate
Significant
Q15: What impact do you think the improvement of pump design
will have, if any, on the problem of GI bleeding? (n=14)
52
53. 0 2 4 6 8 10 12
None
Marginal
Moderate
Significant
Q16: To what extent do you perceive there to be a need to develop a novel therapy
specifically for the management of GI bleeding in LVAD patients with AVWS?
(n=14)
53
59. 0 0 0
1 1 1
0-1 year 1-2 years 2-3 years 3-4 years 4-5 years >5 years
Q21: How long on average is a patient on an LVAD as destination
therapy? (n=3)
59
62. 3
2
0 0
1
Heartmate (II, XVE) Heartware Jarvik 2000 Novacor Other (please specify)
Q24: Which of the following LVAD pumps do you encounter
most often? (n=6)
62
63. 0 0 0
2
0
2 2
<1 in 50 1 in 40 1 in 30 1 in 20 1 in 15 1 in 10 1 in 5
Q25: In what fraction of your patients with LVADs does non-
surgical GI bleeding occur? (n=6)
63
64. 1
0 0 0
1
3
1
Never Rarely Occasionally Always
Q26: Please rank your involvement in the
management of non-surgical GI bleeding in
LVAD patients. (n=6)
0.00 1.00 2.00 3.00 4.00 5.00 6.00
Please rank your involvement in the management of non-
surgical GI bleeding in LVAD patients.
64
65. 0 1 1 2 2 3 3 4
None
Marginal
Moderate
Significant
Q27: What impact do you think the improvement of pump
design with have, if any, on the problem of GI bleeding? (n=6)
65
67. 0 0 0 0 0
1
2
Not familiar Moderately
familiar
Very Familiar
Q28: Familiarity with AVWS - Hematology
(n=3)
0.00 1.00 2.00 3.00 4.00 5.00 6.00 7.00 8.00
Please rank your familiarity with Acquired von Willebrand
Syndrome.
67
68. 1
2
0 0 0 0 0
<1 in 50 1 in 40 1 in 30 1 in 20 1 in 15 1 in 10 1 in 5
Q29: What fraction of your patients with GI bleeding have
LVADs? (n=3)
68
69. 0 0 0 0
3
0 0
Never Rarely Occasionally Always
Q30: Please rank your involvement in the
management of non-surgical GI bleeding in
LVAD patients. (n=3)
0.00 1.00 2.00 3.00 4.00 5.00 6.00
Please rank your involvement in the management of non-
surgical GI bleeding in LVAD patients.
69
70. 0
1
0
1
0 0
1
Desmopressin Plasma-derived VWF
concentrate
Recombinant VWF
concentrate
Antifibrinolytics Intravenous
Immunoglobulin
N/A Other (please
specify)
Q31: Which of the following treatments do you use most often
for patients with GI bleeding due to LVADs? (n=3)
Series1
70
71. 0 0 0
2
1
0 0
Not satisfied Neutral Very satisfied
Q32: Please rank your satisfaction with
current treatment options for AVWS. (n=3)
0.00 0.50 1.00 1.50 2.00 2.50 3.00 3.50 4.00 4.50 5.00
Please rank you satisfaction with current treatment
options for AVWS.
71
72. 0
2
0
1
None Marginal Moderate Significant
Q34: To what extent do you perceive there to be a need to develop a novel therapy
specifically for the management of GI bleeding in LVAD patients with AVWS? (n=3)
72
74. 1
0 0
6
1 1
4
Not familiar Moderately
familiar
Very Familiar
Q35: Familiarity with AVWS - Gastroenterology
(n=13)
0.00 1.00 2.00 3.00 4.00 5.00 6.00
Please rank your familiarity with Acquired von Willebrand
Syndrome.
74
75. 1
3
0
1
0
4
0
<1 in 50 1 in 40 1 in 30 1 in 20 1 in 15 1 in 10 1 in 5
Q36: What fraction of your patients with GI bleeding have
LVADs? (n=9)
75
76. 0 0
1
0
4
3
1
Never Rarely Occasionally Always
Q37: Please rank your involvement in the
management of non-surgical GI bleeding in
LVAD patients. (n=9)
0.00 1.00 2.00 3.00 4.00 5.00 6.00
Please rank your involvement in the management of non-
surgical GI bleeding in LVAD patients.
76
77. 1 1
6
0
1
0
Cauterization Hemostatic clips Argon plasma
coagulation
Hemospray N/A Other
Q38: Which of the following treatments do you use most often
for patients with GI bleeding due to LVADs? (n=9)
77
78. 4
1
0
2 2
0 0
Not satisfied Neutral Very
satisfied
Q39: Please rank your satisfaction
with current treatment options for
AVWS. (n=9)
0.00 0.50 1.00 1.50 2.00 2.50 3.00
Please rank your satisfaction with current treatment
options for AVWS.
78
79. 0 1 2 3 4 5 6
None
Marginal
Moderate
Significant
Q41: To what extent do you perceive there to be a need to develop a
novel therapy specifically for the management of GI bleeding in LVAD
patients with AVWS? (n=9))
79
Font size (RM) – not sure which size he wants?(HP)
Current State
Recurrent GI bleeding is a significant medical problem in patients following implantation of LVADs
Presence of LVAD induces Acquired Von Willebrand Syndrome (AVWS)
No current therapy specifically indicated for GI bleeding due to AVWS
03272016
Recurrent GI bleeding is a significant clinical complication in patients following implantation of LVADs
Currently, an optimal therapy is lacking to specifically address this type of bleeding
*Assign slide time limits to try and keep everything on track* (try and get to 1 minute per slide as possible)
Source: Aggarwal, A. Annual thoracic surgery 2010.
03272016
Typo under device related…..
Shear stress induced (please highlight or underline it)
Mention that GI bleeding is the predominant risk in patients with LVADs (based on intermacs)
I would recommend adding a picture slide of LVADS before this slide, can lead to a greater impact since the picture usually show where it is placed inside a patient. You can allot less than 30 seconds to the slide
03282016
Introducing vWF and change in structure following LVAD implantation
Note that there is no mention of AVWS or ADAMTS13
Just emphasizing that shear force leads to vWF structure change and decrease in multimers
Type1 : autosomal dominant
Type2 : mostly autosomal dominant, can be recessive
Type3 : most severe
Highlight that AVWS is identical to Type 2A genetic disease (RM)
Explain vWF role in the bleeding cascade
03282016
In acquired VWD, increased shear forces induce conformational change and unravel VWF and increase susceptibility to ADAMTS13 proteolysis
It’s okay if it is a bit redundant, you are emphasizing change in vWF structure due to LVADs
Alternatively, you could use this slide.
Dr. Slaughter, Interview 2015; Dr. Tiede, Interview 2015
Tiede, A.; Rand, J. H.; Budde, U.; Ganser, A.; Federici, A. B. How I Treat the Acquired von Willebrand Syndrome. Blood 2011, 117 (25), 6777–6785.
Velik-Salchner, C.; Eschertzhuber, S.; Streif, W.; Hangler, H.; Budde, U.; Fries, D. Acquired von Willebrand Syndrome in Cardiac Patients. J. Cardiothorac. Vasc. Anesth. 2008, 22 (5), 719–724.
SUCHI FIX THIS PLEASE
Whitlow, C. B. Endoscopic Treatment for Lower Gastrointestinal Bleeding. Clin. Colon Rectal Surg. 2010, 23 (1), 31–36.
Cerulli, M. A. Upper Gastrointestinal Bleeding Treatment & Management: Approach Considerations, PPIs, Therapeutic Endoscopy. Medscape 2015.
Tiede, A.; Rand, J. H.; Budde, U.; Ganser, A.; Federici, A. B. How I Treat the Acquired von Willebrand Syndrome. Blood 2011, 117 (25), 6777–6785.
Geisen, U.; Heilmann, C.; Beyersdorf, F.; Benk, C.; Berchtold-Herz, M.; Schlensak, C.; Budde, U.; Zieger, B. Non-Surgical Bleeding in Patients with Ventricular Assist Devices Could Be Explained by Acquired von Willebrand Disease. Eur. J. Cardiothorac. Surg. 2008, 33 (4), 679–684.
03272016
Typo in title ……case studies
Is the column on the right for long term treatment?
Increasing incidence of bleeding after LVAD beyond that of normal anticoagulation therapy
Claims of higher risk of bleeding than the risk of thromboembolism
Close patient monitoring required to maintain the proper balance between anticoagulation and thrombosis
Third point; please modify to maintenance of VWF multimers instead of inhibition of enzymatic cleavage of VWF (RM) – DONE(HP)
The potential for market expansion into genetic VWD exists with the success of the maintenance of VWF multimers
03272016
2nd point: Contrary to secondary literature research, KOL interviews indicates that LVAD …………..
LVADs significantly increase survival in patients
These are being implanted, they are well tolerated change the title
Intermacs source
Interviews sources
Historically, when an improved pump is introduced, the number of implants increases, but the number of complications did not decrease.
Insert Intermacs graphs here
Source: Intermacs and Rajeevs slides/paper
The discrepancy between the number of LVADs needed and the number actually implanted
Miller paper, INTERMACS
Improvements in future technology will not decrease bleeding to an extent where this will not be a serious issue
Physician survey response and Miller interview
With improvements in technology, the incidence of implants increases, leading to a growing market in this area
500,000 new cases of heart failure per year. break it down by stage
Strict criteria, unfamiliarity
Better clinical trial data increased implants from <500LVADS a year to <3000
With improvements in technology, the incidence of implants increases growing market
Pump design: talk about the heartmate 3 as an example
Novel therapy: can say that 71.43 % of cardiologists surveyed believe that it is a significant requirement
Dissatisfaction: Gastroenterologists are 1000% not satisfied with current treatment options for AVWS.
Post implantation factors for bleeding include: antiplatelet therapy, infection, and pump speed, which takes us back to shear stress due to which a loss in multimers is seen. Further taking us back to the first point, moderate impact.
Case studies: our first aim was to look for trials that have already been conducted or ongoing trials similar to that of what BioMarin is trying to do. This comparison was important because we needed to determine specific aspects of patient recruitment that might have to be considered that has never been done before.
Trial sites: there are no AVWS centers in the US, the closest thing to it are the hemophilia sites. But the hemophilia sites do not necessarily cover LVAD sites.
Add which specific trials
Define what a significant bleed is bleeding criteria
Give more details of the reference studies
Trial sites:
-INTERMACS listed centers
- LVAD centers
Hemophilia centers
Inclusion / Exclusion criteria:
- Post implantation bleeding
- Level of multimers loss
Font size (RM) – not sure which size he wants?(HP)
Current State
Recurrent GI bleeding is a significant medical problem in patients following implantation of LVADs
Presence of LVAD induces Acquired Von Willebrand Syndrome (AVWS)
No current therapy specifically indicated for GI bleeding due to AVWS
03272016
Recurrent GI bleeding is a significant clinical complication in patients following implantation of LVADs
Currently, an optimal therapy is lacking to specifically address this type of bleeding
Things worked on over TMP work week:
1.DT & GI bleeding risks
2. Prevalence and incidence (we could have it for the faculty and not for BioMarin’s)
3.Survey
4. Clinical trials: an overview on this slide and go into details later
islam - gastro
lonardo - gasteroenterology
slaughter - surgery
lopez — what specialty????
lau - surgery
czar - cardio
arabia - surgery
tiede - hemotology
miller - cardio
All calculations include all three trial phase and were made with Sample Size Calculator: http://www.surveysystem.com/sscalc.htm