Keywords
venous thromboembolism - cancer - apixaban
Introduction
Cancer and venous thromboembolism (VTE), which includes deep vein thrombosis (DVT)
and pulmonary embolism (PE), are linked by a two-way association.[1] Indeed, approximately 15% of patients with cancer experience one or more episodes
of VTE during the course of their disease,[2] while approximately 20% of patients with VTE have cancer at the time of the presentation
of VTE.[3] In addition, approximately 4% of patients with VTE are newly diagnosed with cancer
at the time of the presentation of VTE or in the year thereafter.[4] Patients with cancer and VTE have a high risk of recurrent VTE and bleeding complications
during anticoagulant treatment compared with patients without cancer[5]
[6] and this makes cancer patients a distinct population which requires specific clinical
trials on the treatment of VTE.
For the treatment of VTE in patients with cancer, international guidelines recommend
low-molecular-weight heparin (LMWH) for at least 3 to 6 months over LMWH followed
by vitamin K antagonists (VKAs)[7]
[8]
[9]
[10]
[11] ([Table 1]). In the CLOT study, dalteparin was associated with a statistically significant
52% reduction in the risk of recurrent VTE over 6 months' treatment compared with
LMWH followed by VKAs (conventional treatment) with a comparable rate of major bleeding
and death.[12] In the CATCH trial, a non-statistically significant 35% risk reduction of recurrent
VTE in favour of tinzaparin was observed compared with the conventional treatment
without differences in the rates of major bleeding and death.[13] A meta-analysis which included six studies in patients with cancer and VTE showed
a statistically significant 44% risk reduction for recurrent VTE in favour of LMWH
compared with the conventional treatment with a non-significant 7% increase in major
bleeding.[14] Although recommended by guidelines, treatment with LMWH in cancer-associated VTE
has several limitations. These include the inconvenience of subcutaneous injections
for at least 6 months in patients who are already receiving complex anti-cancer treatment
and the risk for heparin-induced thrombocytopaenia. Furthermore, treatment with LMWH
is associated with the same risk for major bleeding as conventional treatment.
Table 1
Recommendations from international guidelines on anticoagulant treatment of VTE in
cancer patients
|
Initial treatment
|
Long-term treatment
|
Optimal duration
|
|
ESMO, 2011[7]
|
Weight-adjusted LMWH or UFH
If creatinine clearance is
< 25–30 mL/min anti-Xa monitoring is proposed
|
LMWH or VKA
|
For at least 3–6 months
For patient with metastatic disease, receiving neoadjuvant CHT, the optimal duration
should be individually assessed.
For cancer patients receiving chemotherapy in palliative setting, an indefinite treatment
should be proposed
|
|
NCCN, 2011[8]
|
Weight-adjusted LMWH, UFH or fondaparinux
|
LMWH is preferred for the first 6 months as monotherapy; or VKA
|
Minimum time of 3–6 months for DVT and 6–12 months for PE
Indefinite anticoagulation is proposed in patients with active cancer or persistent
risk factors
|
|
ASCO, 2015[9]
|
LMWH is recommended for the initial 5–10 days
|
LMWH
|
For at least 6 months
|
|
ITAC, 2016[10]
|
First 10 days: LMWH are recommended (1B); UFH and fondaparinux can be also used (2B)
|
LMWHs are preferred over VKA (1A)
|
For a minimum of 3 months (1A). After 3–6 months, termination or continuation of anticoagulation
should be based on individual assessment of the benefit-to-risk ratio
|
|
ACCP, 2016[11]
|
LMWH are suggested over VKA (2B) or DOAC (2C)
|
LMWH are suggested over VKA(2B) or DOAC (2C)
|
For at least 3 months
In patients with VTE and active cancer, and who do not have a high bleeding risk,
extended anticoagulation (no scheduled stop date) is recommended.
In patients with VTE and active cancer, and who have a high bleeding risk, extended
anticoagulation (no scheduled stop date) is suggested
|
Abbreviations: CHT, chemotherapy; DOAC, direct oral anticoagulant; DVT, deep vein
thrombosis; LMWH, low-molecular-weight heparin; PE, pulmonary embolism; UFH, unfractionated
heparin; VKA, vitamin K antagonist; VTE, venous thromboembolism.
Direct oral anticoagulants (DOACs) were tested in six phase III studies on the treatment
of acute VTE and were shown by meta-analyses to be at least as effective as and safer
than the conventional treatment.[15]
[16] Based on these results, DOACs are currently recommended as first line treatment
in the majority of patients with VTE.[11] Sub-group analyses in cancer patients included in the phase III trials on VTE treatment
showed encouraging results both in terms of efficacy and safety.[17]
[18]
[19]
[20] A meta-analysis on cancer patients included in the phase III trials showed similar
efficacy and safety profiles of DOACs in comparison with VKAs for the treatment of
acute VTE.[21] However, DOACs are currently not recommended for the treatment of VTE in cancer
patients mainly because the phase III clinical trials included only a limited number
of these patients. Furthermore, patients with cancer for whom treatment with LMWH
was deemed appropriate were excluded from these studies. The patients with cancer
included in phase III clinical trials with DOACs also had lower rates of metastatic
disease and lower mortality than those included in the CATCH and CLOT trials, with
limited data regarding active cancer treatments which could have affected both efficacy
and safety of DOACs.
Given the limitations of LMWH and the potential advantages of DOACs, several trials
on the treatment of VTE in cancer patients have recently been published or are currently
on-going. The recently published Hokusai VTE cancer in 1,050 patients with VTE and
cancer showed an incidence of the composite of recurrent VTE and major bleeding of
12.8% in the edoxaban group and 13.5% in the dalteparin group (hazard ratio [HR],
0.97; 95% confidence interval [CI], 0.70–1.36; p = 0.006 for non-inferiority).[22]
[23] In this study, rates of recurrent VTE were of 7.9 and 11.3% in the edoxaban and
dalteparin groups, respectively, and major bleeding rates were of 6.9 and 4.0%, respectively.
Findings from the recently presented pilot study Select-D in 406 patients with VTE
and cancer indicate an increase in bleeding with rivaroxaban.[24] The observed increase in bleeding in the DOAC arms of these studies underscores
the need for further studies evaluating other DOACs or DOAC regimens in the treatment
of cancer-associated VTE.
We report here the design of the Caravaggio study, a trial comparing the direct factor
Xa inhibitor apixaban with the LMWH dalteparin for the treatment of acute VTE in patients
with cancer (NCT03045406).
Aim of the Study
The aim of this study is to assess whether oral apixaban is non-inferior to subcutaneous
LMWH dalteparin for the treatment of newly diagnosed proximal DVT and/or PE in patients
with cancer.
Study Design
The Caravaggio study is an investigator-initiated, multi-national, prospective, randomized,
open-label with blind end-point evaluation (PROBE), non-inferiority clinical trial.
The study compares 6-month treatment with oral apixaban or subcutaneous dalteparin
in consecutive cancer patients with newly diagnosed proximal DVT and/or PE ([Fig. 1]). The study has been planned to be conducted in 140 centres in 10 European countries
and in the United States.
Fig. 1 Study design.
Rationale for the Prospective Randomized Open-Label Blind Evaluation design
The PROBE design was chosen for the Caravaggio study as double-blinding would have
required daily subcutaneous injection of placebo in the apixaban recipients. Ethically,
the use of daily injectable placebo and the related inconvenience for patients that
already need complex treatment for cancer are difficult to justify. The assessment
of the study outcomes made by a central independent adjudication committee unaware
of study treatment allocation is a reasonable guarantee of the appropriateness as
well as the consistency of the assessment of study outcome events in the two treatment
groups.
Study Population and Eligibility
Study Population and Eligibility
Consecutive adult cancer patients with a newly diagnosed symptomatic or incidental
proximal lower-limb DVT or symptomatic or incidental PE or both DVT and PE are eligible
for the study.
DVT is defined as proximal if located in the popliteal or a more proximal vein. For
the purpose of this study, incidental DVT or PE are unsuspected events detected by
imaging performed for cancer diagnosis or staging and not to confirm the clinical
suspicion of VTE. To be included in the study, patients with incidental DVT need to
have thrombosis located in the popliteal or a more proximal vein and incidental PE
emboli involving a segmental or more proximal pulmonary artery. The criteria required
for the diagnosis of DVT and PE are listed in [Supplementary Table S1] (available in the online version).
Patients with any type of confirmed cancer other than basal-cell or squamous cell
carcinoma of the skin, primary brain tumour, known intra-cerebral metastases or acute
leukaemia are eligible for the study.
For the purpose of this study, patients with active cancer are those with cancer diagnosed
within the past 6 months, those receiving treatment for cancer at the time of inclusion
or during 6 months prior to randomization, or those with recurrent locally advanced
or metastatic disease. Patients with a history of cancer are defined as those with
cancer diagnosed within 2 years before the study inclusion and not fulfilling the
criteria for active cancer.
Exclusion criteria, classified into four categories including patient characteristics
(age, Eastern Cooperative Oncology Group stage and life expectancy), issues related
to anticoagulant treatment, issues related to bleeding risk and standard exclusion
criteria for clinical trials with anticoagulant agents, are listed in [Table 2].
Table 2
Eligibility criteria
|
Inclusion criteria
|
|
A newly diagnosed, objectively confirmed symptomatic or unsuspected proximal lower-limb
DVT or symptomatic PE or unsuspected PE in a segmental or more proximal pulmonary
artery
|
|
Any type of cancer (other than basal-cell or squamous-cell carcinoma of the skin,
primary brain tumour or intra-cerebral metastases and acute leukaemia) that meets
at least one of the following:
• Active cancer defined as diagnosis of cancer within 6 months before the study
inclusion, or receiving treatment for cancer at the time of inclusion or any treatment
for cancer during 6 months prior to randomization, or recurrent locally advanced or
metastatic cancer
• Cancer diagnosed within 2 years before the study inclusion (history of cancer)
|
|
Signed and dated informed consent
|
|
Exclusion criteria
|
|
Related to patient
|
Age < 18 years
|
|
ECOG performance status III or IV
|
|
Life expectancy of less than 6 months
|
|
Related to anticoagulant treatment
|
Administration of therapeutic doses of LMWH, fondaparinux or unfractionated heparin
(UFH) for more than 72 hours before randomization
|
|
Three or more doses of a vitamin K antagonist before randomization
|
|
Thrombectomy, vena cava filter insertion or thrombolysis used to manage the index
episode
|
|
Indication for anticoagulant treatment for a disease other than the index VTE
|
|
Concomitant use of strong inhibitors or inducers of both cytochrome P-450 3A4 and
P-glycoprotein[a]
|
|
Related to bleeding risk
|
Concomitant thienopyridine therapy (clopidogrel, prasugrel or ticagrelor) or aspirin
over 165 mg daily or dual anti-platelet therapy
|
|
Active bleeding or a high risk of bleeding contraindicating anticoagulant treatment
|
|
Recent (in the last 1 month prior to randomization) brain, spinal or ophthalmic surgery
|
|
Haemoglobin level lower than 8 g/dL (5.0 mmol/L) or platelet count < 75 × 109/L or history of heparin induced thrombocytopaenia
|
|
Creatinine clearance < 30 mL/min based on the Cockcroft–Gault equation
|
|
Acute hepatitis, chronic active hepatitis, liver cirrhosis or an alanine aminotransferase
level three times or more and/or bilirubin level two times or more the upper limit
of the normal range
|
|
Uncontrolled hypertension (systolic BP > 180 mm Hg or diastolic BP > 100 mm Hg despite
anti-hypertensive treatment)
|
|
Standard criteria
|
Bacterial endocarditis
|
|
Hypersensitivity to the study drugs or to any of their excipients
|
|
Patient's participation in other pharmacotherapeutic program with an experimental
therapy that is known to affect the coagulation system
|
|
Women of childbearing potential (WOCBP) who do not practice a medically accepted highly
effective contraception during the trial and 1 month beyond
|
|
Pregnancy, or breast feeding
|
|
Any condition that as judged by the investigator would place the subject at increased
risk of harm if he/she participated in the study
|
Abbreviations: BP, blood pressure; DVT, deep vein thrombosis; ECOG, Eastern Cooperative
Oncology Group; EHRA, European Heart Rhythm Association; LMWH, low-molecular-weight
heparin; PE, pulmonary embolism; VTE, venous thromboembolism.
a For details see EHRA guidelines.[47]
Rationale for Inclusion of Patients with a History of Cancer
Sub-analyses of the Hokusai and AMPLIFY studies[19]
[20] showed a similar risk of recurrence in patients with active cancer and those with
history of cancer diagnosed within 2 years before inclusion in the study. In the AMPLIFY
study, the rate of recurrence in the conventional treatment arm was 6.4 and 6.3% in
patients with active cancer and history of cancer, respectively.[19] Based on these observations, the Caravaggio study will allow the randomization of
patients diagnosed with history of cancer as defined by the study protocol.
Rationale for Inclusion of Cancer Patients with Incidental VTE
In patients with cancer, both DVT and PE may be detected in those undergoing imaging
for purposes of cancer diagnosis, staging, re-staging or surveillance and not be clinically
suspected at the time of detection. Patients with incidental VTE may not necessarily
be asymptomatic, as they often report symptoms and signs that are due to VTE but are
attributed to cancer disease or anti-cancer therapy. In cohort studies, the risks
of recurrence, anticoagulation-related bleeding and death were reported to be similar
in patients with incidental and symptomatic VTE events.[25]
[26]
[27] Therefore, guidelines recommend treating the majority of patients with incidentally
detected VTE with anticoagulation as would be done for patients with symptomatic VTE.[7]
[8]
[9]
[10]
[11]
Including patients with incidental VTE as well as those with a history of cancer broadens
the spectrum of randomized patients towards more closely approximating clinical practice
and enhances the external validity of the Caravaggio study.
Study Treatments and Treatment Allocation
Study Treatments and Treatment Allocation
All patients included in the Caravaggio study receive anticoagulant treatment after
the diagnosis of DVT and/or PE has been confirmed. Administration of therapeutic doses
of LMWH, fondaparinux or unfractionated heparin is allowed for a maximum of 72 hours
before study randomization.
After providing informed consent, patients are randomized on a 1:1 basis to receive
monotherapy with either apixaban or dalteparin ([Fig. 1]). The study treatments are given for 6 months.
Apixaban is given orally at a dose of 10 mg twice daily for the first 7 days (starting
12 hours after the last injection of LMWH, if given before randomization) and then
5 mg twice daily thereafter for the remainder of the 6-month treatment period. The
regimen chosen for apixaban is the same as validated for the treatment of VTE in the
AMPLIFY study.[28]
Dalteparin is administered subcutaneously, at a dose of 200 IU/kg for the first month,
after which the dose is reduced to 150 IU/kg once daily for the following 5 months.
The maximum daily dose allowed for dalteparin is 18,000 IU. The regimen chosen for
dalteparin is the same as validated in the CLOT study.[12] Since the study was extended to the United States, an amendment to the protocol
was submitted to adjust the dose of dalteparin in patients with platelet count between
50 and 100 × 109/L according to the label of the drug in this country.
No further dose adjustment of the study drugs is foreseen but these can be temporarily
withhold in case of a platelet count lower than 50 × 109/L or an any condition associated with an increased bleeding risk, including surgery,
procedures or deterioration of renal function.
Randomization of eligible patients is centrally performed through an interactive web-based
randomization system. Randomization is stratified by the type of VTE (symptomatic
vs. incidental) and the category of cancer (active cancer vs. history of cancer),
allowing for a balanced proportion of patients with incidental VTE or history of cancer
in the two treatment groups. The maximum proportion of patients entering the strata
of incidental VTE or history of cancer is set at 20% of the overall study population
for each of the strata as only a limited proportion of these patients were included
in randomized clinical trials on VTE treatment in cancer patients.
Study Outcomes
The primary outcome of the study is objectively confirmed recurrent DVT or PE occurring
during the study treatment period, which includes proximal DVT of the lower limbs
(symptomatic or incidental), symptomatic DVT of the upper limbs and PE (symptomatic,
incidental or fatal).
All deaths are to be adjudicated concerning their causes by the central independent
adjudication committee. PE is to be adjudicated as the cause of death based on objective
diagnostic testing made before death or autopsy or when PE is the most probable cause
of a sudden and unexplained death.
To adjudicate an incidental PE as an outcome event, there must be one or more new
filling defects in segmental or more-proximal arteries on pulmonary computed tomography
angiography, which is (are) evident on the adjudication study images and was (were)
not present on the index or interval study images. The criteria required for the diagnosis
of recurrent VTE are listed in [Supplementary Table S2] (available in the online version).
Several secondary efficacy outcomes are to be analysed including symptomatic recurrent
VTE and quality of life. The secondary efficacy outcomes are shown in [Supplementary Table S3] (available in the online version).
The principal safety outcome is major bleeding defined according to the guidelines
of the International Society of Thrombosis and Haemostasis as acute clinically overt
bleeding associated with one or more among the following: a decrease in haemoglobin
of 2 g/dL or more, a transfusion of two or more units of packed red blood cells, bleeding
that occurs in at least one of the following critical sites (intra-cranial, intra-spinal,
intra-ocular, peri-cardial, intra-articular, intra-muscular with compartment syndrome
or retroperitoneal), bleeding that is fatal (defined as a bleeding event that the
independent central committee adjudicate as the primary cause of death or contributing
directly to death) and bleeding that necessitates surgical intervention. The list
of the secondary safety outcomes is shown in [Supplementary Table S4] (available in the online version).
A central independent adjudication committee whose members are unaware of treatment
allocation will adjudicate all suspected study outcomes and all deaths occurring during
the study period.
Surveillance and Follow-Up
Surveillance and Follow-Up
The study requires the following scheduled visits: enrolment, 4 weeks, 3 months, 6
months and 7 months after randomization. Additional visits are performed if new symptoms
and/or signs of VTE or major bleeding occur during the study period or anytime it
is deemed necessary by the investigator. Clinical examination, laboratory and diagnostic
imaging are performed if the patient develops symptoms or signs suggestive of recurrent
VTE.
Sample Size of the Study
The study hypothesis is that apixaban is non-inferior to dalteparin with respect to
the primary study outcome (recurrence of VTE) with a pre-specified non-inferiority
margin of 2.00 for the upper limit of the two-sided 95% CI of the HR. Assuming an
estimated 6-month incidence of the primary efficacy outcome of 7% with dalteparin,
934 patients will be required to have 80% power to show the non-inferiority of apixaban
at a one-sided α level of 0.025. This sample is increased to 1,168 patients to account for up to 20%
loss in total patient-years. This estimate is consistent with a drop-out rate of 40%
assuming patients discontinue uniformly during the follow-up (mean discontinuation
time equal to 3 months).
Expected VTE Recurrence Rate in the Comparison Treatment Arm (Dalteparin)
The reference values for the expected incidence of recurrent VTE with dalteparin are
derived from the results of the CLOT and CATCH trials.[12]
[13] Similarly to Caravaggio, these two studies adopted a PROBE design, compared LMWH
(dalteparin or tinzaparin, respectively) with warfarin and had study treatment duration
of 6 months. The incidence of recurrent VTE was 8.0% with dalteparin in the CLOT study
and 7.2% with tinzaparin in the CATCH trial. Furthermore, the recurrence rate in LMWH-treated
patients was 7% in a meta-analysis on cancer patients enrolled in the phase III trials
on the treatment of VTE.[14] The 6-month VTE rate seen with dalteparin in the Hokusai VTE cancer study was 8.8%,
confirming the relative stability over time of the risk of recurrent VTE in LMWH-treated
cancer patients.[23] This recurrence rate was confirmed by a recently presented large health care insurance
claims databases analysis from January 2011 to September 2016.[29] Therefore, the 7% recurrence rate assumed in the Caravaggio study for patients randomized
to receive dalteparin is based on consistent evidence.
Expected Recurrence Rate with Apixaban
In a post hoc analysis of the AMPLIFY study, 169 patients had active cancer and 365
a history of cancer without active cancer at baseline.[19] Among patients with active cancer, recurrent VTE occurred in 3.7 and 6.4% of patients
who received apixaban or conventional treatment, respectively (relative risk, 0.56,
95% CI, 0.13–2.37). Among patients with a history of cancer, recurrent VTE occurred
in 1.1 and 6.3% of evaluable patients in the apixaban and conventional treatment groups,
respectively (relative risk, 0.17, 95% CI, 0.04–0.78). Based on these figures, that
are supported by a network meta-analysis,[30] it is expected that the recurrent VTE rate in the apixaban-treated patients will
not be significantly higher than the rate observed in the LMWH-treated patients.
Rationale for Non-Inferiority Margin (Delta) Choice
The objective of Caravaggio is to demonstrate that oral apixaban is non-inferior to
the subcutaneous LMWH dalteparin for the treatment of VTE in patients with cancer.
The results of this study could lead to a more tolerable treatment (both for the patients
and caregivers) and, in some countries, less expensive therapy than the currently
recommended LMWH. These objectives deal with unmet clinical needs in the setting of
the VTE treatment in cancer patients. The choice of a relatively large delta for efficacy
is accepted in exchange for the convenience and potential compliance benefits, provided
that a putative superiority to placebo is not left in doubt (EMEA/CPMP/EWP/2158/99
Document. Guideline on the choice of non-inferiority margin. July 27, 2005). The considerations
related to convenience and compliance are particularly cogent in patients with cancer
that require complex and difficult cancer treatment. The values and the limitations
of the non-inferiority design in clinical trials have been recently reviewed.[31] The non-inferiority design appears reasonable when evaluating new treatments that
offer greater convenience for the patients while providing similar efficacy. Based
on these assumptions, the upper limit of the two-sided 95% CIs of the HR below the
pre-specified margin of 2.00 planned for our study is considered as acceptable from
a clinical and methodological point of view. Moreover, the non-inferiority margins
set for the Caravaggio study are of the same order of magnitude to those used in pivotal
trials on VTE therapy with DOACs.[28]
[32]
[33]
[34]
[35]
[36] These studies were accepted by the European Medicines Agency and Food and Drug Administration
(FDA) for the registration of DOACs for the indication ‘treatment of VTE’.
Statistical Analysis
The primary efficacy dataset will consist of all randomized subjects who received
at least one dose of study drug (modified intention-to-treat [ITT] population). The
safety dataset (as-treated) will consist of all treated subjects (randomized subjects
who received at least one dose of study drug).
Secondary efficacy datasets will consist of all randomized subjects (ITT) and the
per-protocol (PP) population as defined in the pre-defined statistical analysis plan.
Briefly, the PP population will consist of all randomized patients who complete the
study fully compliant with the protocol and without any major violation or deviation.
Secondary efficacy analyses based on the ITT and PP populations will be considered
as supportive.
The time to first event of the primary outcome during the 6-month study period will
be analysed using a Cox's proportional hazard model including the treatment group
and stratification factors as covariates. The evaluation of the primary objective
will be done by considering the time from randomization to the first recurrent VTE
(primary study outcome) or to the occurrence of death unrelated to VTE (competing
event) or to the last follow-up if neither a recurrent VTE or a competing event occur
within the 6-month follow-up (censored time). The apixaban-to-comparator HR adjusted
for the competing risk of death unrelated to VTE will be computed with associated
two-sided 95% CI by resorting to the Fine and Gray regression model.[37] Superiority of apixaban in comparison to dalteparin will be tested as a secondary
analysis of the primary end-point only after non-inferiority has been demonstrated
for the experimental treatment group (apixaban) relative to the control group (dalteparin).
The rate of major bleeding (the primary safety outcome) and clinically relevant non-major
bleeding in patients treated with apixaban or dalteparin will be compared by using
the safety dataset.
Rationale for Using a Competing Risk Analysis
A significant proportion of patients with cancer included in clinical trials on the
treatment of VTE ultimately die due to cancer progression during the study period.
The 6-month mortality was 39 and 32% in CLOT and CATCH studies, respectively,[12]
[13] and the 12-month mortality was approximately 45% in the Hokusai cancer study.[23] In the CLOT study, 90% of death in each group was due to the progression of cancer.
Due to the high mortality rate in patients with cancer and VTE, the standard statistical
method of Kaplan–Meier to evaluate time to recurrence is limited when death is considered
a censored event. The Kaplan–Meier method handles death as censored observation, which
conceptually implies that the subjects retain the probability of recurrence even after
death. As the risk of VTE recurrent is zero in a dead patient, by ignoring the effect
of death as a competitive risk, the method of Kaplan–Meier over-estimates the cumulative
incidence of VTE. A more appropriate statistical analysis accounts for both death
and VTE as competitive risks.[38] The competitive risk analysis handles the competing events as actual events rather
than censoring observations and recognizes that death terminates the ability to observe
a VTE. Therefore, the probability of experiencing a recurrence is adjusted for a competing
event (death) that occurred prior to the development of the VTE outcome. The Gray's
test is considered the more appropriate test to assess differences between two study
groups when competing risks are present.
The issue of competing risks is well recognized in the oncology literature although
it has been applied inconsistently to the analysis of clinical studies assessing anti-thrombotic
treatments in cohorts with a high incidence of death such as cancer patients. Comparisons
between treatment groups in the CATCH study accounted for deaths not due to fatal
PE as a competing risk.[13]
All data summaries and listings will be performed using the SAS System version 9.4
under Windows 10 PRO operating system.
Study Organization
The study is performed in accordance with the provisions of the Declaration of Helsinki
and local regulations. Protocol and amendments have to be approved by the Institutional
Review Board or Ethic Committee at each study centre.
The promoter of Caravaggio is Federazione delle Associazioni dei Dirigenti Ospedalieri
Italiani (FADOI) Foundation. The study is co-ordinated by the Clinical Research Unit
of the University of Perugia in Italy, by the Research Department of FADOI Foundation
and the Steering Committee of the study. Data are collected, maintained and will be
analysed by Exom Group in Italy under the supervision of the Steering Committee members.
The study is supported by a grant in aid by Bristol-Myers Squibb and Pfizer. Apixaban
will be supplied by Bristol-Myers Squibb and dalteparin by Pfizer. Bristol-Myers Squibb
and Pfizer did not have any role in study design, and does not have any role in the
study conduction, data collection and analysis.
Study Committees
The structure of the Caravaggio study includes a Steering Committee, a central independent
adjudication committee and a Data and Safety Monitoring Board (DSMB).
Steering Committee
The Steering Committee of the study is composed by the National Coordinators of the
participating countries and by members of the University of Perugia and FADOI. The
study was designed by the Steering Committee members. The Steering Committee members
have the final responsibility for the conduction of the study as well as the verification
and analyses of all the study data. All the members of the Steering Committee have
access to the study data, vouch for their accuracy and completeness; they will contribute
to the interpretation of the results, approve the final version of the manuscript
verifying the fidelity of the article to the study protocol and make the decision
to submit the manuscript for publication. The writing committee, composed by members
of the Steering Committee, will write the manuscript and vouch for the accuracy and
completeness of the reported data.
Adjudication Committee
A central independent adjudication committee, whose members are unaware of treatment
allocation, adjudicates all suspected outcome events and the qualifying diagnosis,
the anatomical extent of the initial DVT or PE. The Central Adjudication Committee
is composed of medical specialists in oncology, radiology and vascular medicine.
Data and Safety Monitoring Board
An independent DSMB periodically reviews the study outcomes with all information available
concerning treatment allocation. A DSMB charter was provided to the board members
before the start of the study. The DSMB is composed of three expert clinicians with
experience in the conduction and monitoring of clinical trials.
Study Monitoring
Monitoring procedures are followed to comply with Good Clinical Practice guidelines.
The risk for the occurrence of quality and safety issues is regularly and centrally
monitored through the use of a “Risk Based Monitoring and Management” platform. Study-specific
risk indicators and related scores were defined and are closely and centrally monitored
during the entire study period for each of following six risk categories: (1) site
management quality, (2) data quality, (3) data timeliness, (4) source documents verification,
(5) milestone delay and (6) subject safety. Caravaggio is a paperless study which
utilizes integrated clinical data management and remote data capture solutions that
include functionalities in key areas such as drug supply and randomization, data collection
and serious adverse event (SAE) reporting. An Oracle database enables management of
all clinical trial data in a single system, improving accuracy, visibility and data
integrity.
Adverse Event Reporting
This study follows a targeted approach to collection and reporting of adverse events
(AEs) and SAEs. All AEs occurring after the subject signs the informed consent form
and through month 6 or the end of treatment date, whichever occurs first, whether
observed by the investigator or reported by the patient, are recorded on the AEs section
of the electronic case report from.
AEs are described using the Medical Dictionary for Regulator Activities.
On-Going Studies Comparing DOACs with LMWH for the Treatment of Cancer-Associated
VTE
On-Going Studies Comparing DOACs with LMWH for the Treatment of Cancer-Associated
VTE
Several trials aimed at improving the anticoagulant treatment in patients with cancer-associated
VTE by comparing DOACs with LMWH are currently on-going ([Table 3]).
Table 3
On-going trials with DOACs versus LMWH on treatment of VTE in cancer patients
|
Trial (ref)
|
Sample size (N)
|
Study design
|
DOACs
|
Comparator
|
Primary outcome (s)
|
Treatment duration
|
|
CANVAS[39]
|
940
|
Randomized, open label
|
Any DOAC
|
LMWH or fondaparinux alone or with VKA
|
VTE recurrence
|
6 months
|
|
CARAVAGGIO
|
1,126
|
Randomized, open label, blinded end-point (PROBE), non-inferiority
|
Apixaban
|
Dalteparin
|
VTE recurrence Major bleeding
|
6 months
|
|
CASTA-DIVA[40]
|
200
|
Randomized, open label
|
Rivaroxaban
|
Dalteparin
|
VTE recurrence
Major bleeding
|
3 months
|
|
ADAM VTE[41]
|
300
|
Randomized, open label, superiority
|
Apixaban
|
Dalteparin
|
Major bleeding
|
6 months
|
|
CONKO[42]
|
450
|
Randomized, open label
|
Rivaroxaban
|
LMWH
|
Patient-reported treatment satisfaction
|
3 months
|
Abbreviations: DOAC, direct oral anticoagulant; LMWH, low-molecular-weight heparin;
VKA, vitamin K antagonist; VTE, venous thromboembolism.
CANVAS is a 940-patient study with the primary objective of evaluating whether DOACs
are as effective as one of the FDA-approved injectable agents (dalteparin, enoxaparin
or fondaparinux), given alone or transitioned to VKAs (NCT02744092).[39] Any of the four DOACs approved for the treatment of VTE (apixaban, dabigatran, edoxaban
or rivaroxaban) could be used in the DOACs arm.
The CASTA DIVA investigators randomize 200 cancer patients with VTE to receive either
rivaroxaban or dalteparin to assess the 3-month rate of recurrence and major bleeding
(NCT02746185).[40]
The main aim of the ADAM-VTE trial is to test the hypothesis that apixaban is associated
with a significantly lower rate of major bleeding compared with dalteparin in the
treatment of 300 patients with acute VTE and active malignancy.[41]
The CONKO study is a randomized, open-label study designed to evaluate the treatment
satisfaction in 450 patients with VTE and cancer treated with rivaroxaban or dalteparin.[42]
Anticipated Results and Implications for Clinical Practice
Anticipated Results and Implications for Clinical Practice
It is anticipated that the Caravaggio study will demonstrate that apixaban is non-inferior
compared with dalteparin for the treatment of DVT and PE in patients with cancer.
The Caravaggio study has the potential, along with other studies with similar objective
and design, to improve the treatment of VTE in patients with cancer by making VTE
management simpler and less cumbersome for patients who are already receiving complex
anti-cancer treatment and management. An additional potential advantage associated
with the oral administration of apixaban, as of other DOAC, could be the improvement
of treatment adherence and persistence. Indeed, adherence to and persistence on guideline-recommended
LMWH given for long-term VTE treatment in patients with cancer is quite low and much
less than generally appreciated by clinicians. Most patients are discontinuing LMWH
after 2 to 3 months and either continuing with VKA, which is less effective or definitively
stopping anticoagulation, and thus, they are at increased risk of recurrent VTE.[43]
[44]
[45]
To increase the external validity of the study, we include in the study patients affected
by the large majority of cancers. Although in patients with primary brain cancer or
brain metastases anticoagulant treatment is not contraindicated, these patients are
excluded from the study as there are not even preliminary data on the use of DOACs
in these patients. The same applies to patients with acute leukaemia.
In the Hokusai VTE Cancer study, major bleeding was found to be increased in patients
who entered the study with gastrointestinal cancer. Patients with gastrointestinal
cancer (including the upper gastrointestinal tract) are not excluded from Caravaggio
and are expected to account for approximately 20% of the entire study population.
The type of gastrointestinal malignancy, location and stage of cancer disease in these
patients will be formally and carefully scrutinized and compared with the Hokusai
cancer population in a pre-specified analysis as reported in the Statistical Analysis
plan. To ensure patient safety, the DSMB received a mandate to monitor bleeding (and
its severity) in patients with gastrointestinal cancer. The apixaban regimen evaluated
in Caravaggio is the same evaluated in the Amplify study. This is the only DOAC regimen
which was not associated with an increase in gastrointestinal bleeding in the phase
III trials of VTE treatment.[16] The inclusion of patients with gastrointestinal cancer in Caravaggio has substantial
clinical implications for clinical practice. Indeed, should the bleeding associated
with apixaban in these patients be as excessive as that seen with edoxaban in the
Hokusai VTE cancer (in comparison with the conventional treatment), this finding will
definitively indicate that patients with gastrointestinal cancer should be denied
DOACs for the treatment of VTE. On the other hand, if an increase in bleeding in these
patients is not seen, this observation will be of remarkable clinical importance and
patients with gastrointestinal cancer will be able to safely take advantage of an
oral treatment that does not require monitoring. This observation could also reinforce
the need for specific studies on the effect of the different DOACs on the gastrointestinal
system.
In the Caravaggio study, apixaban is given as a single drug approach, validated in
the Amplify study, which involves a higher dose given for the first 7 days. This difference
in DOAC regimens has remarkable implications. It is possible that, in cancer patients
who have high risk of early recurrence, this approach may not be as effective as some
period of LMWH treatment, either because the dose of apixaban is not high enough or
the period of more intense dosing is not long enough. On the other hand, a more balanced
regimen could reduce the risk of bleeding seen in Hokusai VTE cancer study. A time-course
analysis of the thromboembolic and bleeding events similar to that made in the Amplify
study could be helpful in understanding the time course of the thromboembolic and
bleeding events.[46] In addition, the knowledge achieved from the Caravaggio study will provide evidence
for improving the design of further studies and updating current practice guidelines.
What is known about this topic?
-
Cancer patients with venous thromboembolism (VTE) are at increased risk of recurrence
and bleeding during anticoagulant treatment.
-
For the treatment of VTE in patients with cancer, international guidelines recommend
low-molecular-weight heparin (LMWH) for at least 3 to 6 months over LMWH followed
by vitamin K antagonists.
-
Direct oral anticoagulants are an effective and safe treatment for VTE, but limited
data are currently available with these agents in patients with concomitant cancer.
What does this paper add?
-
This paper reports details on the design of the Caravaggio study.
-
The Caravaggio study will assess whether oral apixaban is non-inferior to subcutaneous
LMWH dalteparin for the treatment of newly diagnosed proximal DVT and/or PE in patients
with cancer.
-
The Caravaggio study has the potential to make the management of VTE less cumbersome
in patients with cancer by replacing parenteral with oral anticoagulation.
