Patient Population: The study population included adult patients with cancer and symptomatic or incidental proximal lower-limb deep-vein thrombosis (DVT) or pulmonary embolism (PE). Key exclusion criteria were as follows: age <18 years old, an Eastern Cooperative Oncology Group (ECOG) status of III or IV, life expectancy of less than 6 months, basal-cell or squamous-cell carcinoma of the skin, primary brain tumor, known intracerebral metastases, acute leukemia, indication for anticoagulation therapy other than the trial inclusion criteria, creatinine clearance <30 mL/min, and severe liver dysfunction.

Intervention: 576 patients received apixaban 10 mg orally twice daily for the first 7 days, then 5 mg twice daily for a total of six months.

Comparison: 579 patients received dalteparin 200 International Units/kg subcutaneously once daily for 1 month, then 150 International Units/kg daily (maximum daily dose of 18,000 International Units) for a total of six months.

Outcome: The primary outcome included recurrent venous thromboembolism (VTE) over a six-month period, while the primary safety outcome was major bleeding.

Citation: Apixaban for the Treatment of Venous Thromboembolism Associated with Cancer. N Engl J Med. 2020;382(17):1599-1607. doi: 10.1056/NEJMoa1915103.

Healthcare Professional Summary

The CARAVAGGIO trial evaluated the efficacy and safety of apixaban compared to dalteparin for the treatment of cancer-associated venous thromboembolism. It was a multi-national, randomized, controlled, open-label, noninferiority trial, with a low percentage of patients who were lost to follow up. The trial applies to patients who are older than 18 years of age with active cancer or a history of cancer with a new diagnosis of symptomatic or incidental proximal lower-limb DVT or PE. The statistical analysis of a non-inferiority study should consist of an intention-to-treat analysis and per-protocol analysis. However, in this study, the primary efficacy data was analyzed with a modified intention to treat principle and consisted of all patients who had undergone randomization and received at least one dose of trial drug. The absolute risk reduction of the primary outcome was found to be 2.3%, with a relative risk reduction of 29%. Apixaban was found to be noninferior to injectable dalteparin for the treatment of cancer-associated VTE, with no significant difference in major bleeding. Oral apixaban may serve as an alternative to LMWH in patients with cancer for the treatment of venous thromboembolism who prefer oral therapy over subcutaneous injections, though clinicians should be aware that apixaban is a P-glycoprotein and CYP3A4 substrate and may interact with other drugs. Patients with gastrointestinal and genitourinary cancers may be at higher risk of bleeding with the use of the DOACs. Gastrointestinal bleeding was not a prespecified trial outcome for this trial, and the sample size was not large enough to make a definitive conclusion on bleeding. For patients with gastrointestinal or genitourinary cancers, the bleeding risk must be weighed against benefits when deciding on the appropriate anticoagulant to prescribe. Additional limitations of the study include the open-label trial design and the short duration of six months.

Patient Summary

Apixaban, a prescription medication, is a blood thinner that is taken by mouth. Apixaban should be taken two times daily to prevent clots. Patients with certain types of cancer are at risk for clots in the veins (deep vein thrombosis or DVT) and lungs (pulmonary embolism or PE). Apixaban was compared to dalteparin, another blood thinner that must be injected under the skin, for the treatment of DVT or PE in cancer patients. The study showed that apixaban was not worse than dalteparin for preventing another clot. The risk of bleeding appears to be similar between the two blood thinners. Apixaban may be an option to prevent future clots in cancer patients who have lower bleeding risks. Ultimately, the choice of the blood thinner should be decided by healthcare provider with consideration for the risks of bleeding and developing a new clot, along with considering patient values.

Tiffany Khieu, PharmD, is a 2021 graduate of Marshall B. Ketchum University, College of Pharmacy. Dr. Khieu has no conflicts of interest to disclose.

Genene Salman, PharmD, BCCCP, BCPS, CNSC, is an Assistant Professor at Marshall B. Ketchum University, College of Pharmacy. Dr. Salman has no conflicts of interest to disclose.

Noelle de Leon, PharmD, BCPS, BCCCP, is a clinical pharmacist specializing in cardiovascular critical care and anticoagulation management at UC San Francisco Medical Center and an Assistant Clinical Professor at the UC San Francisco School of Pharmacy in San Francisco, CA. Dr. de Leon has no conflicts of interest to disclose.

Cynthia Jackevicius, BScPhm, PharmD, MSc, BCPS, BCCP, FCSHP, FAHA, FCCP, FCCS, FACC, a Professor of Pharmacy Practice at Western University of Health Sciences, is the Evidence-Based Practice Section Editor. Dr. Jackevicius teaches evidence-based practice skills to health care professionals. She advocates for the adoption of an evidence-based practice, incorporating the best available evidence, patients’ values and preferences, and clinicians’ expertise into clinical decision-making. She has no conflicts of interest to report.

1.
Raskob
GE,
van Es
N,
Verhamme
P,
Carrier
M,
Di Nisio
M,
Garcia
D,
Grosso
MA,
Kakkar
AK,
Kovacs
MJ,
Mercuri
MF,
Meyer
G,
Segers
A,
Shi
M,
Wang
TF,
Yeo
E,
Zhang
G,
Zwicker
JI,
Weitz
JI,
Büller
HR;
Hokusai VTE Cancer Investigators
.
Edoxaban for the Treatment of Cancer-Associated Venous Thromboembolism
.
N Engl J Med
.
2018
Feb
15
;
378
(
7
):
615
624
. doi: .
2.
Streiff
MB,
Holmstrom
B,
Angelini
D,
Ashrani
A,
Bockenstedt
PL,
Chesney
C,
Fanikos
J,
Fenninger
RB,
Fogerty
AE,
Gao
S,
Goldhaber
SZ,
Gundabolu
K,
Hendrie
P,
Lee
AI,
Lee
JT,
Mann
J,
McMahon
B,
Millenson
MM,
Morton
C,
Ortel
TL,
Ozair
S,
Paschal
R,
Shattil
S,
Siddiqi
T,
Smock
KJ,
Soff
G,
Wang
TF,
Williams
E,
Zakarija
A,
Hammond
L,
Dwyer
MA,
Engh
AM.
NCCN Guidelines Insights: Cancer-Associated Venous Thromboembolic Disease, Version 2.2018
.
J Natl Compr Canc Netw
.
2018
Nov
;
16
(
11
):
1289
1303
. doi: .
3.
Key
NS,
Khorana
AA,
Kuderer
NM,
Bohlke
K,
Lee
AYY,
Arcelus
JI,
Wong
SL,
Balaban
EP,
Flowers
CR,
Francis
CW,
Gates
LE,
Kakkar
AK,
Levine
MN,
Liebman
HA,
Tempero
MA,
Lyman
GH,
Falanga
A.
Venous Thromboembolism Prophylaxis and Treatment in Patients With Cancer: ASCO Clinical Practice Guideline Update
.
J Clin Oncol
.
2020
Feb
10
;
38
(
5
):
496
520
. doi: .
4.
Farge
D,
Frere
C,
Connors
JM,
Ay
C,
Khorana
AA,
Munoz
A,
Brenner
B,
Kakkar
A,
Rafii
H,
Solymoss
S,
Brilhante
D,
Monreal
M,
Bounameaux
H,
Pabinger
I,
Douketis
J;
International Initiative on Thrombosis and Cancer (ITAC) advisory panel
.
2019 international clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer
.
Lancet Oncol
.
2019
Oct
;
20
(
10
):
e566
e581
. doi: .
5.
Young
AM,
Marshall
A,
Thirlwall
J,
Chapman
O,
Lokare
A,
Hill
C,
Hale
D,
Dunn
JA,
Lyman
GH,
Hutchinson
C,
MacCallum
P,
Kakkar
A,
Hobbs
FDR,
Petrou
S,
Dale
J,
Poole
CJ,
Maraveyas
A,
Levine
M.
Comparison of an Oral Factor Xa Inhibitor With Low Molecular Weight Heparin in Patients With Cancer With Venous Thromboembolism: Results of a Randomized Trial (SELECT-D)
.
J Clin Oncol
.
2018
Jul
10
;
36
(
20
2017
2023
. doi: .