Managing antiplatelet therapy in thrombocytopenic patients with hematological malignancy

 

Introduction

The use of antiplatelet therapy (APT), prescribed for acute and chronic ischemic arterial disease, is frequently encountered in cancer patients1. APT following acute atherothrombotic events and dual APT (DAPT) in particular, puts patients at a substantial risk of bleeding2-4. Patients with active malignancy undergoing anticancer treatment also have episodes of thrombocytopenia of variable duration and intensity5 which pose a substantial risk of bleeding 6. At the same time, patients presenting with active cancer have an increased risk of atherothrombotic events as well as adverse outcomes7,8. Importantly, thrombocytopenia does not provide protection against arterial thrombosis 9 and is in fact associated with adverse outcomes following ischemic heart disease (IHD) or stroke9-11, making this a high risk population. Retrospective cohort studies of cancer patients with thrombocytopenia and acute coronary syndrome (ACS) suggest that aspirin increases survival, without increasing bleeding10,12. Nevertheless, aspirin is often not utilized in thrombocytopenic cancer patients with ACS10,12. With one exception13, formal IHD and stroke guidelines do not provide recommendations for management of thrombocytopenic cancer patients. In order to clarify current practice, we aimed to identify the patient and physician characteristics associated with APT management in patients with thrombocytopenia and hematological malignancy14.

 

Design

A clinical vignette-based experiment was designed to mimic the clinical scenarios in which decision-making occurs14. Our population of interest was adult patients with hematological malignancy who have disease or treatment-related thrombocytopenia and any indication for APT. First, eleven hematologists were interviewed and asked to determine the variables influencing their management of APT in this population as well as the management strategies they would consider. The variable list was refined based on a literature review. This led to the selection of five variable categories potentially influencing management of APT, each with 2-3 levels (Figure 1).

 


 

Figure 1: List of selected attributes and levels.

* Reference level.

ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; GI, gastrointestinal; STEMI, ST elevation myocardial infarction.


Next, using computer algorithms, 18 case vignettes were produced, each comprising one level from each of the 5 attributes (Figure 2).


 

Figure 2: Case vignette example

 


These vignettes were further divided into six survey versions, comprising three vignettes each. Surveys were distributed to hematologists and thrombosis specialists in three countries, each randomly assigned one version. For each vignette, physicians were required to make three management decisions:

A: continue any APT versus holding all APT.

B (for those continuing any anti-platelet regimen): give platelet transfusion support versus no transfusion support.

C (for those continuing APT, with or without platelet transfusion support) in DAPT cases: holding either aspirin or clopidogrel versus continuation of DAPT.

In addition, when platelet transfusion support was used, a 30,000/µL platelet target was compared with 50,000/µL.

Multivariate regression models were used to calculate relative risks (RR) of using one management option over the other for each variable in comparison to a reference variable (level 1 in Figure 1).

  

Results

145 physicians addressed 434 cases. Doctors who participated were from Italy (48), Israel (46), the Netherlands (44), Spain (4) and the United States (3). 73 (50%) physicians worked in academic tertiary referral centers, 49 (34%) in academic community hospitals, and 23 (16%) in non-academic community hospitals. 122 (84%) were senior physicians. 60 (41%) reported expertise in thrombosis, 30 (20%) in general hematology, 25 (17%) in general malignant hematology, while 30 (22%) reported other expertise. Physicians estimated seeing a median of 5 (IQR = 8) patients with thrombocytopaenia and either APT or anticoagulation per month. Institutional protocols guiding management of these patients were reported by 56 (39%) of physicians.

Physicians elected to continue APT (± platelet transfusion or change in APT regimen) in 349 cases (80%). DAPT due to ST elevation MI (STEMI) and a drug eluting stent (DES) made it 31% more likely that a physician would continue APT than when single APT was used for conservatively treated unstable angina (95% CI: 1.18-1.45). In addition, continuing APT was 15% more likely when there were institutional protocols guiding management (RR 1.15, 95% CI: 1.03-1.27). On the other hand, holding all APT was preferred over continuing if platelets were 20,000/µL, in case of major gastro-intestinal bleeding 3 weeks earlier, and when the physician worked at a university-affiliated community hospital. Platelet transfusion was chosen to support APT in 120 cases (34%). Platelet transfusion support was preferred if platelet counts were 20,000/µL, in case of DAPT due to STEMI with DES, and when the physician had expertise in general malignant hematology. There was no clear preference towards either of the transfusion targets. Among the DAPT cases continuing APT, continuing DAPT was preferred over single APT when the DAPT indication was 2 weeks earlier (vs. 2 months earlier).

 

Summary and recommendations

The management of thrombocytopenic patients with hematological malignancy and APT is affected by platelet count, APT indication, time since indication and prior GI bleeding, as well as physician demographics and practice setting. APT is usually continued, and platelet transfusions are frequently chosen to support APT although no evidence supports this practice. In summary, the decision process is complex and affected by multiple patient and physician characteristics. This underlines the need for ongoing research15 and consistent guidelines.

 


References

  1. Vinholt PJ, Alnor A, Nybo M, Hvas A. Prediction of bleeding and prophylactic platelet transfusions in cancer patients with thrombocytopenia. Platelets 2016;27:547-554
  2. Ng FH, Wong SY, Chang CM, et al. High incidence of clopidogrel-associated gastrointestinal bleeding in patients with previous peptic ulcer disease. Aliment Pharmacol Ther 2003;18:443-449
  3. Ng W, Wong W, Chen W, et al. Incidence and predictors of upper gastrointestinal bleeding in patients receiving low-dose aspirin for secondary prevention of cardiovascular events in patients with coronary artery disease. World J Gastroenterol 2006;12:2923-2927
  4. Généreux P, Giustino G, Witzenbichler B, et al. Incidence, predictors, and impact of post-discharge bleeding after percutaneous coronary intervention. J Am Coll Cardiol 2015;66:1036-1045
  5. Liebman HA. Thrombocytopenia in cancer patients. Thromb Res 2014;133 Suppl 2:63
  6. Stanworth SJ, Estcourt LJ, Powter G, et al. A no-prophylaxis platelet-transfusion strategy for hematologic cancers. N Engl J Med 2013;368:1771-1780
  7. Velders MA, Boden H, Hofma SH, et al. Outcome after ST elevation myocardial infarction in patients with cancer treated with primary percutaneous coronary intervention. Am J Cardiol 2013;112:1867-1872
  8. Navi BB, Reiner AS, Kamel H, et al. Risk of arterial thromboembolism in Patients With Cancer. J Am Coll Cardiol 2017;70:926-938
  9. Del Prete C, Kim T, Lansigan F, Shatzel J, Friedman H. The epidemiology and clinical associations of stroke in patients with acute myeloid leukemia: A review of 10,972 admissions from the 2012 national inpatient sample. Clin Lymphoma Myeloma Leuk 2018;18:77.e1
  10. Feher A, Kampaktsis PN, Parameswaran R, Stein EM, Steingart R, Gupta D. Aspirin is associated with improved survival in severely thrombocytopenic cancer patients with acute myocardial infarction. Oncologist 2017;22:213-221
  11. McCarthy CP, Steg G, Bhatt DL. The management of antiplatelet therapy in acute coronary syndrome patients with thrombocytopenia: A clinical conundrum. Eur Heart J 2017;38:3488-3492
  12. Sarkiss MG, Yusuf SW, Warneke CL, et al. Impact of aspirin therapy in cancer patients with thrombocytopenia and acute coronary syndromes. Cancer 2007;109:621-627
  13. Iliescu C, Grines CL, Herrmann J, et al. SCAI expert consensus statement: Evaluation, management, and special considerations of cardio-oncology patients in the cardiac catheterization laboratory (endorsed by the cardiological society of india, and sociedad latino americana de cardiologıa intervencionista). Catheter Cardiovasc Interv 2016;87:895-899
  14. Leader A, Ten Cate V, Ten Cate-Hoek AJ, et al. Managing Anti-Platelet Therapy in Thrombocytopaenic Patients with Haematological Malignancy: A Multinational Clinical Vignette-Based Experiment. Thromb Haemost. 2019 Jan;119(1):163-174.
  15. Management and outcomes of anti-thrombotic medication use in thrombocytopenia - full text view - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03288441. Accessed Jan 25, 2018.

 

  • Avi Leader

    Avi Leader

    Cardiovascular Research Institute Maastricht (CARIM), Medical Center, Maastricht University, Maastricht, the Netherlands; Institute of Hematology, Davidoff Cancer Center, Rabin Petha Tikva, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel;
    view profile
  • Eilon Krashin

    Eilon Krashin

    Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; Translational Hemato-Oncology Laboratory, Meir Medical Center, Kfar-Saba, Israel
    view profile
  • Hugo ten Cate

    Hugo ten Cate

    Professor in Clinical Thrombosis and Hemostasis, Thrombosis Expertise Center and Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, the Netherlands
    view profile

Rate this article

Login or register to leave a comment or rate this article


Register