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CLINICAL NEWS
On Location 2015 ASH Annual Meeting
rivaroxaban use for CAT (including dosing guidelines in
the setting of thrombocytopenia, advanced age, and hepatic
dysfunction). They then began offering patients rivaroxaban
as an alternative to enoxaparin, acknowledging that clinical
trials had not established the superiority of either drug and
that “the only reason to switch to rivaroxaban would be
convenience,” Dr. Mantha explained.
Results from the first 100 patients (out of a planned
200) who had been treated for at least six months or
had reached an endpoint (new or recurrent pulmonary
embolism [PE], symptomatic proximal lower-extremity
deep-vein thrombosis [DVT], major bleeding, clinically
relevant non-major bleeding leading to discontinuation of
rivaroxaban, or death), were presented.
Patients were not treated with rivaroxaban i f they
had active gastrointestinal or genitourinary lesions or
had undergone gastric resection due to anticipated excess bleeding risk or reduced absorption – representing
less than 5 percent of patients.
All patients had PE or symptomatic proximal DVT and
a full course of anticoagulation with rivaroxaban (allowing
up to 3 days of initial parenteral anticoagulation).
At six months, the cumulative incidences for study
endpoints were:
• Death: 14.4% (95% CI 6.8-21.4%)
• New or recurrent VTE: 4.3% (95% CI 0.1-8.4%)
• Major bleeding: 1.1% (95% CI 0-3.1%)
• Clinically relevant non-major bleeding leading to
rivaroxaban discontinuation: 7.9% (95% CI 2.113.3%)
“Major or life-threatening bleeding risk was only 1.1
percent at the six-month timepoint, which is quite low,” Dr.
Mantha said. “The low rate of major bleeding is influenced
likely by the exclusion of patients with active gastrointestinal or genitourinary lesions, who would be expected to
have a high bleeding risk with an oral direct anticoagulant.”
Anticipating that older patients (≥75 years old) would
have reduced drug clearance and an increased risk of
bleeding with rivaroxaban, the investigators reduced the
dose in these patients, which “did not appear to be associated with any loss in efficacy.”
The six-month follow-up of the remaining 100 patients
was completed in December 2015, with the rates of major
bleeding and recurrent VTE expected to remain non-inferior to LMWH, but with a lower burden of treatment. “It’s
all about quality of life,” Dr. Mantha said. ●
REFERENCES
Miao Y, Soff GA, Parameswaran R, et al. Enoxaparin dose reduction for thrombocytopenia in patients
with cancer: a quality assessment study. Abstract #429. Presented at the 2015 ASH Annual Meeting,
December 7, 2015; Orlando, Florida.
Mantha S, Miao Y, Sarasohn D, et al. Safe and effective use of rivaroxaban for treatment of cancerassociated venous thromboembolic disease: a quality improvement initiative. Abstract #431.
Presented at the 2015 ASH Annual Meeting, December 7, 2015; Orlando, Florida.
Are Clinical Trial Exclusion Criteria Too Strict?
New research suggests that eligibility
criteria for randomized controlled trials
(RCTs) in hematologic malignancies
might be too strict, limiting their applicability to real-world clinical practice.
The research, conducted by Abby Statler,
MPH, MA, from Taussig Cancer Institute
at Cleveland Clinic in Cleveland, Ohio,
and colleagues looked at the exclusion
criteria among published RCTs articles
and whether or not these criteria reflected
expected or observed adverse event (AE)
rates among enrolled patients.
“We have this push and pull between
internal and external validity – between
the trial’s ability to demonstrate a causeeffect relationship and the actual generalizability of those results,” Ms. Statler
said in an interview with ASH Clinical
News. “It’s a challenge to balance these
two things, so we asked, ‘Are we compromising external validity by focusing on
internal validity?’”
To maximize the potential for
registration, Ms. Statler and colleagues
wrote, “eligibility criteria for RCTs
may be overly restrictive so as to avoid
toxicities that may be attributed to the
study drug.” To test their hypothesis
that RCTs exclude patients regardless
of the AEs that would be expected (or
ultimately observed) based on drug
class, the authors identified 98 phase II
and III RCTs in hematologic malignancies that were published in high-impact
medical journals (an impact factor ≥5)
between January 2010 and January 2015.
Of these 98 trials, 32 (33%) were
leukemia trials, 27 (28%) were lymphoma,
34 (35%) were multiple myeloma, and 5
(5%) were myelodysplastic syndromes
or myelofibrosis. The majority of studies
were phase III (n=77; 79%), multi-center
(n=92; 94%), and/or multi-national
(n=63; 64%). Twelve trials contributed
pivotal data leading to a label change or
48
ASH Clinical News
new FDA approval for eight drugs.
The researchers collected AE data
from package inserts or published manuscripts for the following drug classes:
alkylators, antimetabolites, anthracyclines,
topoisomerase inhibitors, microtubule
inhibitors, proteasome inhibitors, and
monoclonal antibodies. Toxicities of these
drug classes were then compared with
corresponding trial exclusion criteria using the exact binomial test.
Using the threshold applied in medication labels (reported AEs that occurred
in ≥10% of trial participants), Ms. Statler
calculated the binomial probability for
each AE, particularly those relevant to the
most commonly used organ function exclusion criteria (hepatic, kidney, cardiac,
and neurologic).
The most commonly applied exclusion
criteria were:
• medical comorbidities (e.g., active
or prior cancer, previous cardiac
conditions, HIV infection, hepatitis,
or psychiatric disease): 97% of studies
• inadequate organ function: 89%
• poor performance status: 67%
“Exclusion criteria relevant to baseline
organ function did not reflect established
safety profiles,” the authors noted, with the
proportion of studies excluding patients
with specific organ dysfunction far outweighing the proportion of drug classes
with known toxicities in these realms:
• Hepatic toxicities: 87% (proportion of
studies with organ-specific exclusion
criteria) vs. 75% (proportion of drugs
classes with known toxicities), p=.007
• Cardiac toxicities: 74.5% vs. 62.5%,
p=0.02
• Renal toxicities: 73.5% vs. 50%,
p<0.0001
Interestingly, the proportion of studies
excluding patients with neurologic deficits
was actually lower than the proportion
Number of Trials Reporting Adverse Events
Versus Expected to Report Adverse Events
FIGURE.
of drug classes with known neurologic
toxicities: 22 percent versus 50 percent
(p<0.0001), respectively.
Given the toxicity profile of the
investigational products in these RCTs,
the widespread use of restrictive eligibility
criteria seems inappropriate, Ms. Statler
and co-authors concluded. “The proportion of RCTs in hematologic malignancies
published in high-impact medical journals
excluding patients with como rbidities and/
or organ function abnormalities does not
reflect the expected or observed AEs in
these patients. [Landmark RCTs], with an
eye to registration, may be overly conservative in using restrictive exclusion criteria.”
However, the authors added, the number
of studies that reported grade ≥1 toxicities in
≥10 percent or more participants was considerably lower than expected, assuming study
treatments lead to an AE in 10 percent of
patients (FIGURE). The difference was lowest
for clinical trials that excluded patients with
peripheral neuropathy (14 vs. 11; p=0.95).
“We were quite surprised by this. Our
hypothesis was that we would see fewer
studies report toxicities than we expected,
but we did not anticipate that the difference
would be so dramatic,” Ms. Statler said.
“What may be driving this is the inclusion
and exclusion criteria – we are enrolling
patients who are very clinically fit and,
therefore, do not have many toxicities.”
Although the strict eligibility criteria result in “very good safety data,” she
added, they may not accurately reflect
what occurs in daily practice. “We may be
able to expand exclusion criteria a little
bit to include more patients and we would
not significantly impact the safety data of
the investigational product.” ●
REFERENCE
Statler A, Radivoyevitch T, Siebenaller C, et al. Eligibility criteria
are not associated with expected or observed adverse events in
randomized controlled trials (RCTs) of hematologic malignancies.
Abstract #635. Presented at the 2015 ASH Annual Meeting,
December 7, 2015; Orlando, Florida.
January 2016