ars.els-cdn.com · Web viewCHA 2 DS 2-VASc score is a clinical prediction rule which predicts the...

Anticoagulation in Thrombocytopenic Patients with Hematological Malignancy:

A Multinational Clinical Vignette-based Experiment

SUPPLEMENTARY MATERIAL

Content:

1) Supplemental Table 1 (Characteristics of interviewed physicians) Pg. 2

2) Supplemental Table 2 (Selection process for case attributes and levels) Pg. 3-6

3) Supplemental Table 3 (List of variables comprising each case vignette) Pg. 7-9

4) Supplemental Table 4 (Details on institutional protocols) Pg. 10

5) Supplemental Table 5 (Absolute frequencies of management choices) Pg. 11

6) Supplemental Figure 1 (Efficiency of the fractional factorial design) Pg. 12

7) Supplemental Figure 2 (Study design) Pg. 13-14

8) Supplemental Figure 3 (RRs for different LMWH dose reductions) Pg. 15

9) Introduction to the questionnaire Pg. 16-17

1

1) Supplemental Table 1: Characteristics of interviewed physicians

Physician No.

Position Primary clinical expertise Years of clinical experience

Country of practice

1 Senior physician, management position

Hematopoietic stem cell transplantation

>20 Israel


Lymphoma >20 Israel


Thrombosis and hemostasis 13 Israel


Lymphoma 10 Israel


Acute leukemia 5 Israel


General malignant hematology

>20 The Netherlands

7 Senior physician Transfusion medicine >20 The Netherlands

8 Senior physician General malignant hematology

2 The Netherlands

9 Fellow General malignant hematology

3 The Netherlands


1 The Netherlands


1 Israel

This table shows the characteristics of the 11 physicians who participated in interviews aimed at identifying

which variables should be evaluated in this case-vignette study. Each physician practiced at one of three

academic medical centers in Israel or the Netherlands. The interviewees were asked: “which variables

influence your management of anticoagulation in these patients?”; “which management strategies would you

consider?”.

2

2) Supplemental Table 2: Selection process for case attributes and levels

Attributes Level Cumulative weight, n (%) a

Decision Main reason for decision Comment

Duration of TCP b < 1 week 8 (73%) Include Weight Represented by “diffuse large B cell lymphoma treated by R-CHOP”

~ 2-3 weeks 8 (73%) Include Weight Represented by “acute leukemia treated with intensive chemotherapy”

Long term 5 (45%) Exclude Less probable with the selected diseases. Variability over time

-

Depth of TCP 20,000/µL - 30,000/µL 7 (64%) Include 20,000/µL

Weight. VTE guidelines use platelet counts of 20-25,000/µL and 50,000/µL to guide management

These cutoffs had varying effects on management choices

40,000/µL - 50,000/µL 7 (64%) Include 40,000/µL

≥ 55,000/µL 11 (100%) Exclude Redundant level, since all hematologists would continue therapy

-

Dynamics of TCP Decreasing counts 1 (9%) Exclude Weight. Complexity -

Increasing counts

Chronic, stable

Etiology of TCP Treatment-induced 1 (9%) Exclude Weight. Clinical relevance -

Disease-related

3



Disease-related bleeding and thrombotic risk c

High risk 5 (45%) Partial inclusion (only AML and ALL included)

Weight. Feasibility. Hard to cover all the fields and disconnect from the risk posed by treatment

e.g. AML, APL, myelofibrosis, MM, PCNSL.

Low risk Include Weight e.g. diffuse large B cell lymphoma

Anticancer drug-related thrombotic risk c

Higher risk(e.g. Adriamycin, asparaginase, lenalidomide, thalidomide)

7 (64%) Include Weight. Asparaginase was chosen over lenalidomide or thalidomide as high risk because of its combined bleeding and thrombotic risk and its use in ALL (selected as a disease attribute)

Represented by asparaginase with chemotherapy in “ALL treated with asparaginase-based intensive chemotherapy regimen”

Lower risk (e.g. chemotherapy only or no chemotherapy)

Include Represented by chemotherapy only in “AML with high dose cytarabine consolidation”

Drug related bleeding risk c

High risk 2 (18%) Partial inclusion (only asparaginase)

Weight. Ibrutinib not relevant in the selected diseases

e.g. asparaginase, ibrutinib, NSAID, steroids

Lower risk Inclusion Weight Chemotherapy only

Type of antithrombotic regimen d

AC only 9 (91%) Include Weight -

AC and aspirin 3 (27%) Include Weight

Type of AC VKA 4 (36%) Exclude Weight and lack of effect on primary management (i.e. hold, continue, transfuse)

AC will not be specified and can be LMWH/DOAC/VKA. Different management options for different types of AC will be given, after the primary management is selected

LMWH 2 (18%) Exclude

DOAC 2 (18%) Exclude

4



Drugs with antidote vs. those without

5 (45%) Exclude Antidotes eventually anticipated for all drugs

-

Indication for AC d AF 10 (91%) Include Weight -

VTE 10 (91%) Include Weight -

Mechanical heart valve

6 (55%) Exclude Rare scenario. Limited physician experience to guide decisions

-

Primary VTE prophylaxis

3 (27%) Exclude Redundant level, because 100% would stop AC

-

None 1 (9%) Exclude Weight. Redundant (stopping AC = standard of care)

Will emphasize that the indication for AC was clear and reassessed, in all cases

VTE-specific indication for AC e

Lower risk site 4 (36%) Include Weight. Pulmonary embolism was chosen as high risk since it is the most common higher risk VTE. Guidelines for VTE in TCP differentiate between and lower recurrence risks

Represented by “catheter-related upper extremity DVT”

Higher risk site Include Represented by “symptomatic pulmonary embolism”. Other options: sinus or splanchnic vein thrombosis, massive pulmonary embolism

Unprovoked popliteal DVT

1 (9%) Exclude Redundant. Management and risk is similar to pulmonary embolism

-

AF-specific indication for AC f

Lower thrombotic risk 7 (64%) Include Weight. A CHA2DS2-VASc score cutoff above and below 3 was mentioned

Represented by “CHA2DS2-VASc = 2”, since there is still a clear indication for AC with this score

Higher thrombotic risk Include Represented by “CHA2DS2-VASc = 6”

Recent stroke 2 (18%) Exclude Part of the CHA2DS2-VASc score -

5



Time since the AC indication-defining event

6 months 6 (55%) Include Weight. 1 month, 3 month and 5-6 month cutoffs mentioned. VTE guidelines (with and without TCP) suggest different management at each of these timeframes

May be a larger tendency to stop therapy (>6 months = secondary prevention)

2 months Include Dose reduction more likely

2 weeks Include Guidelines suggest platelet infusion to enable full dose AC, as an option

Prior major bleeding g

Yes vs. never 7 (64%) Include Weight Central nervous system and GI bleeding were mentioned. GI was selected because it is more common

Time since bleeding g

Sub-acute / remote 3 (27%) Include Weight. Counterbalances the attribute “time since the AC indication-defining event”

Represented by “4 months earlier”

Recent Represented by “3 weeks earlier”

Source of prior bleeding identified or treated g

No 4 (36%) Constant h Weight. Lower priority than cancer-specific attributes

-

Age 50 years 1 (9%) Constant h Weight. Not unique to cancer and TCP. Introduces too much variability

-

Renal function Normal 1 (9%) Constant h -

Surgery None (current/recent) 1 (9%) Constant h Weight. Lower priority -

AC dose Full 11 (100%) Constant h Redundancy This is linked to “indication for AC”. Without TCP, the standard of care for all indications is full dose AC

DIC None 2 (18%) Constant h Associated with thrombotic events in acute myeloid leukemia. Too complex to incorporate different levels

-

6



Cancer-related prognosis

Favorable vs. poor 1 (9%) Exclude Weight -

Performance status Good vs. poor 1 (9%) Exclude Weight -

Malignant venous occlusion

Yes vs. no 1 (9%) Exclude Weight -

Life-threatening VTE

Yes vs. no 2 (18%) Exclude Weight. Linked to “VTE-specific indication for AC”

-

Recurrent thrombosis

Yes vs. no (first event) 1 (9%) Exclude Weight. Not cancer-specific -

Thrombosis during TCP

Yes vs. no 1 (9%) Exclude Weight. Questionable clinical relevance -

Immobilization Yes vs. no 2 (18%) Exclude Lower priority than cancer specific factors. Weight

-

Indwelling venous catheters

Yes vs. no 2 (18%) Partially include

Weight. Incorporated in “catheter-related upper extremity DVT”, which is one of the levels of “indication for AC”

Relevant only for venous thrombosis

HASBLED score High vs. low 1 (9%) Exclude Weight -

Risk of fall Yes vs. no 1 (9%) Exclude Weight -

Liver disease Yes vs. no 1 (9%) Exclude Weight -

This table shows all the attributes (i.e. variable groups) that were mentioned at least once during the 11 preparatory interviews with Dutch and Israeli physicians, along with the reasons for including or excluding each attribute in the case vignette study. All the interviews were semi-structured and were conducted by a member of the research team (AL) in person or by telephone conference.

7

a Number of physicians (%) who mentioned this attribute/level as a variable which could influence management, during the preparatory interviews (n=11). As a rule, only variables selected at least twice (i.e. 18%) were considered

b This attribute was converted to “hematological malignancy and treatment” which is the main driver of duration of TCP. Two physicians (18%) selected “hematological malignancy and treatment” as a separate attribute

c This attribute was merged with the attribute “hematological malignancy and treatment” (duration of TCP) to prevent implausible combinationsd These two attributes (“type of antithrombotic regimen” and indication for AC”) were linked to create the attribute “indication and type of antithrombotic regimen”, to

prevent implausible combinationse This attribute was merged with “indication for AC” within the level of VTEf This attribute was merged with “indication for AC” within the level of AFg These attributes were merged into the attribute “major GI bleeding from an unidentified source” (levels: never, 4 months earlier, 3 weeks earlier)h Case constants are attributes which potentially influence decisions but were not included in modeling the cases vignettes. Single levels of these attributes were used as

constants across all cases to eliminate ambiguityAC, anticoagulation; AF, atrial fibrillation; ALL, Acute lymphoblastic leukemia; AML, Acute myeloid leukemia; APL, acute promyelocytic leukemia; DIC, disseminated intravascular coagulation; DOAC, direct oral anticoagulant; DVT, deep vein thrombosis; GI, gastrointestinal; LMWH, low molecular weight heparin; MM, multiple myeloma; NSAID, non-steroidal anti-inflammatory drugs; PCNSL, primary central nervous system lymphoma; R-CHOP, rituximab cyclophosphamide doxorubicin vincristine prednisone; TCP, thrombocytopenia; VKA, vitamin K antagonist; VTE, venous thromboembolism3) Supplemental Table 3: List of variables comprising each case vignette a

Survey Version

Case no. b

Attributes and levels (level number)

Hematological malignancy and treatment

Depth of Thrombocytopenia

Indication and type of antithrombotic regimen

Time since the anticoagulation indication-defining event

Major GI bleeding from an unidentified source

A 1 AML with high dose cytarabine consolidation (3)

20,000/µL (2) AF and CHA2DS2-VASc = 2, with AC only (1)

2 weeks (3) 3 weeks earlier (3)

2 Diffuse large B cell lymphoma with R-CHOP treatment (1)

20,000/µL (2) Symptomatic PE with AC only (4)

2 months (2) 3 weeks earlier (3)

3 AML with high dose cytarabine consolidation (3)


2 months (2) 4 months earlier (2)

4 Diffuse large B cell lymphoma with R-CHOP

20,000/µL (2) Symptomatic PE with AC, and aspirin due to ischemic stroke


8

Survey Version

Case no. b







treatment (1) 4 months earlier (5)

5 ALL with Asparaginase-based chemotherapy (2)

40,000/µL (1) Catheter-related UE-DVT with AC only (3)

2 weeks (3) None (1)

B 6 AML with high dose cytarabine consolidation (3)





2 weeks (3) 4 months earlier (2)





20,000/µL (2) Symptomatic PE with AC, and aspirin due to ischemic stroke 4 months earlier (5)

2 months (2) None (1)




C 11 ALL with Asparaginase-based chemotherapy (2)






9

Survey Version

Case no. b
















D 16 ALL with Asparaginase-based chemotherapy (2)















E 21 Diffuse large B cell 40,000/µL (1) Symptomatic PE with AC, and 2 weeks (3) 3 weeks earlier (3)

10

Survey Version

Case no. b







lymphoma with R-CHOP treatment (1)

aspirin due to ischemic stroke 4 months earlier (5)













F 26 Diffuse large B cell lymphoma with R-CHOP treatment (1)












30 AML with high dose 20,000/µL (2) Symptomatic PE with AC, and 6 months (1) None (1)

11

Survey Version

Case no. b







cytarabine consolidation (3)

aspirin due to ischemic stroke 4 months earlier (5)

This table shows the variable combinations comprising each of the 30 vignettes selected for this study (each row representing one vignette), and how these vignettes were split into 6 questionnaire versions (i.e. blocks A thru F), each with 5 vignettes. Consecutive participants were assigned with sequential questionnaire versions in ascending order (A thru F and again A thru F, and so forth).a All cases were preluded by the following introduction: „The patient is a 50 year old male, with no current bleeding or planned invasive procedures.

Fibrinogen, PT, PTT and renal function are all normal. All antithrombotic medication is mentioned below. The chemotherapy regimen has been maximized for efficacy and risk of thrombocytopenia”

b Each case was comprised of one of the 2-5 levels from each of the 5 attributes, and was presented in tabular form in the survey, similar to this table.AC, anticoagulation; AML, Acute myeloid leukemia; ALL, Acute lymphoblastic leukemia; AF, atrial fibrillation; GI, gastrointestinal; No., number; PE, pulmonary embolism; PT, prothrombin time; PTT. Partial thromboplastin time; R-CHOP, rituximab cyclophosphamide doxorubicin vincristine prednisone; UE-DVT, upper extremity deep vein thrombosis

4) Supplemental Table 4: Details on institutional protocols for management of cancer patients with AC and hypoproliferative thrombocytopenia

Maastricht University Medical Center, The Netherlands

Hospital Papa Giovanni XXIII, Bergamo, Italy

Rabin Medical Center, Petah Tikva, Israel

General management Discontinue AC if the indication allows

No institutional protocol No institutional protocol

Anticoagulation dose reductions not specified per-protocol

12

Standard prophylactic platelet transfusion target (without AC or other high risk parameters)

10,000/µL

Prophylactic platelet transfusion target, if AC continued

50,000/µL

This table provides details on institutional protocols for management of cancer patients with AC and hypoproliferative thrombocytopenia, at the 3

primary study centers. The general platelet transfusion guidelines from these protocols are not shown. Details on the protocols at the other

participating centers were not available, because of the anonymous design.

AC, anticoagulation

13

5) Supplemental Table 5: Absolute frequencies of management choices underlying the relative risk, stratified by country

Attribute Level Step A (n=773) Step B (n=607) Step C (n=497)

Continue AC, n=607

Hold AC, n=166

RR a

Platelet Tx support or modify the AC regimen, n=497

Continue without change, n=110

RR b

Platelet Tx support, n=119

Modifying AC, n=378

RR c

Country of practice

Israel 174 68 ref 149 25 ref 36 113 ref

Italy 230 36 1.2 188 42 1 21 167 0.5

The Netherlands

175 50 1.1 137 38 0.9 57 80 1.7

USA 10 10 0.7 7 3 0.8 1 6 0.6

Spain 18 2 1.5 16 2 1 4 12 1

This table shows the absolute numbers of cases assigned by responders to each management strategy, for each country. Unadjusted RRs for choosing

one management strategy over the other are also shown for each level, compared to the reference. This is shown for each of the 3 management steps

(A,B,C). The physician from Haiti answered only one case (in which anticoagulation was held) and was excluded from this analysis.

a Unadjusted RR for continuing AC over holding

b Unadjusted RR for platelet transfusion support or modifying the AC regimen over continuing without change

c Unadjusted RR for platelet transfusion support over modifying AC

AC, anticoagulation; RR, relative risk; Tx, transfusion; USA, United States of America

14

6) Supplemental Figure 1: Efficiency of the fractional factorial design

This figure shows the D and G efficiencies of the reduced design matrix. Each point in the chart represents

the D or G efficiencies (in blue or black, respectively) with a given number of vignettes in the fractional

factorial design. The solid lines are smoothing splines, which were used to give an estimate of the D and G

efficiencies (blue and red, respectively) as a function of the number of vignettes used. The vertical dotted

line shows a D-efficiency of 99.5% and G-efficiency of 94.7% for 30 case vignettes, as chosen for this study.

15

7) Supplemental Figure 2: Study design

16

This figure depicts the study design. First, attributes and levels were identified (panel A). Next, the vignettes were created and piloted (panel B).

† Variables selected at least twice during the interview phase, were considered. The list was further refined using a literature review. If there

was no variability of levels within a given attribute, it was not selected.

‡ The full factorial matrix of 270 possible permutations of the attributes and levels was reduced to a balanced & efficient design of 30 cases,

using the Federov exchange algorithm implemented in R (in the ‘AlgDesign’ package by Wheeler).

§ The 'optBlock' algorithm (also in the 'AlgDesign' package) was used to split the 30 cases into 6 diagonal blocks or questionnaire versions, each

with 5 cases.

¶ Depending on the primary management choice, there were secondary management choices.

†† The survey was piloted to detect implausible variable combinations, ambiguity, and missing management options.

‡‡ Physicians were questioned on the management of patients with hematological malignancy, disease or treatment related thrombocytopenia and

an indication for anticoagulant therapy.

AC, anticoagulation; IVC, inferior vena cava

17

8) Supplemental Figure 3: RRs for reducing LMWH dose by 50% over using prophylactic dose

This figure shows forest plots with RRs (95% CI, p value), derived from a cluster robust Poisson regression

model, for reducing therapeutic LMWH dose by 50% over using prophylactic dose, for each patient or

physician variable in comparison to their reference variables. Reference variables are signified by symbols

adjacent to each variable.

* Diffuse large B cell lymphoma, R-CHOP treatment

† 40,000/µL

‡ AF, CHA2DS2-VASc = 2, AC only

§ 6 months

ǁ No prior GI bleeding

η Academic tertiary referral center

δ No institutional management protocols

AC, anticoagulation; AF, atrial fibrillation; AML, acute myeloid leukemia; ALL, acute lymphoblastic

leukemia; DVT, deep vein thrombosis; GI, gastro-intestinal; LMWH, low molecular weight heparin; PE,

pulmonary embolism; R-CHOP, rituximab cyclophosphamide doxorubicin vincristine prednisone; RR,

relative risk; UE, upper extremity

18

n=116 (51%)n=112 (49%)

9) Introduction to the questionnaire

Dear Participant. We thank you for your valuable time and opinion, in completing this questionnaire.

This questionnaire includes 8 case vignettes of patients with a hematological malignancy undergoing active treatment with chemotherapy. In addition, these patients are currently receiving varying antithrombotic regimens (anticoagulation or antiplatelet medication or both) for various indications, for varying durations. Due to newly-developed treatment related thrombocytopenia, you are requested to reassess the management of the antithrombotic therapy. In each case vignette there will be differing values for the following case variables: Type of hematological malignancy and type of treatment; Depth of Thrombocytopenia; Indication and type of antithrombotic regimen; Time since the anticoagulation/antiplatelet indication-defining event; Prior Bleeding Event.

After the case variables, for each case vignette, you will be given a multiple choice question with options for management of the antithrombotic regimen. Please consider each case on its own, irrespective of how rare or common such a scenario may be, and choose the most suitable management option. Based upon the initial choice you make, additional options will appear, including dose and antithrombotic drug modification, supportive measures such as platelet transfusion and mechanical interventions such as inferior vena cava filters, among others. Please choose only one answer for each question (your ideal choice). In addition, for each case, you will be asked to assess the bleeding risk and thrombotic risk on a scale of 1 to 10, whereby 1 represents a negligible chance of bleeding or thrombosis and 10 represents the highest risk. It is not possible to skip questions, and therefore all cases and questions must be answered.

The following case details are constants and do not vary from one case to another. For your convenience, you will be able to re-access this list while reading each case vignette, by clicking on the corresponding links:Case constants

The patient in question is a 50 year old male. Fibrinogen, PT, PTT and Renal Function are all normal. Single agent antiplatelet therapy = low-dose aspirin or clopidogrel "Anticoagulation" refers to full dose anticoagulation with either a vitamin K antagonist (VKA), low molecular

weight heparin (LMWH) or a direct oral anticoagulant (DOAC). Options for agent-specific management will be given.

After reevaluation there is still an indication for antithrombotic therapy. The patient is not receiving any additional antithrombotic medication, unless mentioned in the case vignette. There is no current bleeding and there are no recent or planned invasive (e.g. surgical) procedures. CHA2DS2-VASc score is a clinical prediction rule which predicts the risk of stroke in patients with non-rheumatic

atrial fibrillation. A score of 2 predicts an annual stroke risk of 4%, while a score of 6 predicts an annual risk of 18.2%.

Management constants (which won't be addressed in the response options)

Assume that this is the nadir of thrombocytopenia and that if the thrombocytopenia deepens you will be allowed to modify your management as you deem fit.

Treatment modifications made due to thrombocytopenia are relevant only for the period with platelet counts similar to those stated in the vignette. Once the platelet count rises, you may revert to previous or another dose/treatment.

The chemotherapy regimen has already been maximized for efficacy and risk of thrombocytopenia.

19

It is possible to remove peripherally-inserted central catheters if deemed appropriate. The use of Intermittent Pneumatic Compression (IPC) devices is allowed if deemed appropriate.

The decision can be made after discussing the case with a consultant from the field targeted by the antithrombotic

therapy (or the prescribing physician)

20

Date post:	12-Oct-2020
Category:	Documents
Upload:	others
View:	0 times
Download:	0 times

ars.els-cdn.com · Web viewCHA 2 DS 2-VASc score is a clinical prediction rule which predicts the...

Documents