The endothelial dysfunction associated with vascular endothelial growth factor pathway inhibitors (VPIs) would seem to be the most plausible explanation for such events: it causes thromboembolic events and cardiovascular complications.

1. 117Zenoni D, et al. Eur J Hosp Pharm 2020;27:117–120. doi:10.1136/ejhpharm-2019-001879
Aortic dissection after ramucirumab infusion
Davide Zenoni ‍ ‍,1
Flavio Niccolò Beretta,2
Vanessa Martinelli,1
Alessandro Iaculli,3
Maria Teresa Benzoni Fratelli,1
Delia Bonzi1
Case report
To cite: Zenoni D,
Beretta FN, Martinelli V, et al.
Eur J Hosp Pharm
2020;27:117–120.
1
Hospital Pharmacy
Department,ASST Bergamo
EST,Alzano Lombardo, Italy
2
Scuola di Specializzazione
Farmacia Ospedaliera,
Università degli Studi di
Milano, Milan, Italy
3
Oncology Department,ASST
Bergamo EST, Seriate, Italy
Correspondence to
Dr Davide Zenoni, Hospital
Pharmacy,ASST Bergamo EST,
Alzano Lombardo, Italy; ​davide.​
zenoni@​asst-​bergamoest.​it
Received 7 February 2019
Accepted 20 March 2019
Published Online First
14 June 2019
© European Association of
Hospital Pharmacists 2020. No
commercial re-­use. See rights
and permissions. Published
by BMJ.
SUMMARY
A female patient in her seventies affected by a
signet-­ring cell carcinoma G3pT4N3 (24/29), with
lymphovascular invasion, HER2-­negative.After
completing three cycles of first-­line systemic treatment in
combination with cisplatin (CDDP) + 5-­fluorouracil (5FU),
a new systemic therapy line with paclitaxel + Cyramza
(ramucirumab) was planned. On the day after the first
administration the patient manifested a Standford type A
aortic dissection (AD), with a diameter of around 6.5 cm
and dissection flap originating in the ascending aorta
below the brachiocephalic trunk, extended to the whole
descending aorta until the carrefour.
The causal relationship between adverse drug
reactions and Cyramza, calculated using the Naranjo
algorithm, led to a result of ’probable’ correlation
between ramucirumab and AD.The endothelial
dysfunction associated with vascular endothelial
growth factor pathway inhibitors (VPIs) would seem
to be the most plausible explanation for such events:
it causes thromboembolic events and cardiovascular
complications.
BACKGROUND
Aortic dissection (AD) is a relatively rare vascular
disease, encoded within acute aortic syndromes1
and characterised by a high mortality rate.2
The
pathogenesis of AD derives from laceration of the
intima that exposes the underlying medium layer
(which is almost always damaged by predisposing
factors) to the intraluminal pressure forces,1
thus
creating a 'false lumen'.3
AD is a relatively rare
event, with an estimated prevalence of 3/100 000
cases per year.4
It is more common in males than
in females,5
in the presence of predisposing factors
such as hypertension, smoking, atherosclerotic
vasculopathy, diabetes or Marfan syndrome.6
Ramucirumab (IMC-­1121B) is a fully human
IgG1 monoclonal antibody, produced by recombi-
nant DNA in the murine cell line (NSO).7
Cyramza
has been approved by the European Medicines
Agency and the US Food and Drug Administra-
tion for the treatment of gastric or advanced
gastro-­oesophageal junction adenocarcinoma, in
monotherapy or in combination with paclitaxel
in patients with progressive or refractory disease
after treatment with fluoropyrimidine or platinum-­
containing chemotherapy, for the treatment of
advanced colon-­rectal cancer in combination
with fluorouracil, levofolinic acid and irinotecan
(FOLFIRI therapeutic scheme) in patients with
progressive disease after oxaliplatin, fluoropyrimi-
dine and bevacizumab treatments and in non-­small
cell lung cancer in combination with docetaxel.8
In Italy the drug received reimbursement from the
Italian Medicines Agency (AIFA) only for the first of
these indications.9
The development of ramucirumab began with
the identification of a high-­affinity antibody against
vascular endothelial growth factor receptor 2
(VEGFR-2) (clone 1121) from a library of Fab frag-
ments from unimmunised human donors, through a
highly rigorous affinity maturation process. Initially
the IMC-1121 chimeric antibody was developed,
then it was subsequently fully humanised to become
the IMC-­1121B (ramucirumab).10
Ramucirumab selectively binds to the VEGFR-2,
with an eight-­fold higher affinity compared with
the natural VEGF-­A ligand.11
Vascular endothelial
growth factor A (VEGF-­A) plays a central role in
the regulation of tumour angiogenesis, stimulating
– when activated – proliferation and migration
of endothelial cells and improving microvascular
permeability, thus being important for revascular-
isation during neoplastic progression. For these
reasons, VEGF-­A and its VEGFR-2 receptor are key
targets in cancer therapy.
CASE PRESENTATION
The patient is a woman in her seventies with a
history of systemic arterial hypertension and carotid
atherosclerosis (with non-­haemodynamically signif-
icant stenosis) and a previous cerebellar stroke in
2016, with no history of drug allergies. For these
comorbidities, she takes acetylsalicylic acid 100 mg,
lansoprazole, nebivolol hydrochloride/hydrochlo-
rothiazide and lormetazepam.
Given the appearance, in the previous 3 months,
of postprandial epigastric pain with a sense of early
fullness and moderate weight loss, in January 2017
she underwent an oesophagogastroduodenoscopy
that showed a gastric antral stenosis; histological
examination of the biopsy showed a signet-­ring cell
adenocarcinoma G3, HER2 1+.
The thorax-­abdomen computed tomography
(CT) scan revealed a >9 cm expansion of filling
tissue into the antro-­pyloric region, associated with
multiple perivisceral adenopathies.
On January 2017, the patient underwent explor-
atory laparotomy, during which the liver scan
showed no suspicious lesions, subtotal gastrectomy
with lymphadenectomy (LDACT) D2 and omen-
tectomy. Histological examination of the surgical
biopsy demonstrated a signet-­ring cell carcinoma
G3pT4N3 (24/29), with lymphovascular invasion,
HER2-­negative. After subsequent oncological eval-
uation, positron emission tomography of the chest
and abdomen revealed two dubious mediastinal
lymph nodes (SUV max 3.6) and millimetric uptakes
in the hilar area and in the abdominal wall; taking
into account the stage and risk class, and after the
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2. 118 Zenoni D, et al. Eur J Hosp Pharm 2020;27:117–120. doi:10.1136/ejhpharm-2019-001879
Case report
Figure 1 Computed tomography (CT) shows the dissection flap marked there by the red arrow.
insertion of a central venous catheter port, adjuvant systemic
chemotherapy was started in March 2017 in combination with
FOLFOX412–14
of which, in August 2017, the first seven cycles
were completed, and were well tolerated by the patient.
Given the absence of suspicious signs of disease progres-
sion after the thorax-­abdominal CT/PET scans performed in
September 2017, treatment was continued, completing 11
/12 cycles of the initially established treatment regimen, until
November 2017, when treatment was interrupted at the patient's
request.
The chest-­abdomen CT on 2 February 2018 did not show
pulmonary nodules, mediastinal adenopathies, visceral metas-
tasis or detectable abdominal locations, but reported hydrouret-
eronephrosis on the left, with kinking and ureteral strincture in
the distal tract.
The PET scan (January 2018) showed unchanged shades
and dubious mediastinal lymph nodes, with no other detect-
able hyper-­accumulations in particular in the pulmonary and
abdominal-­pelvic area. In the absence of evident signs of disease
progression and of hyper-­accumulations in the pelvic-­abdominal
area despite the CT scan, the tomographic data were again
checked after a short interval, repeating the chest-­abdomen CT
scan 3 months later.
Examination (April 2018) showed a marked worsening of
hydronephrosis on the left side, with the presence of hydro-
ureteronephrosis also on the right side and a conglobate aspect
of the ileal loops. The cancer antigen CA 19.9 level was 142.
The patient was evaluated by a urologist, who having observed
a retained renal function, excluded nephrostomy, instead
suggesting creatinine monitoring and renal dilatation ultra-
sound. Taking into account the documented peritoneal progres-
sion, the patient's good general health, the previous treatments
and the biomolecular profile, and excluding the need to perform
nephrostomies, first-­line systemic treatment with a combination
of cisplatin (CDDP) with 75% dosage + 5-­fluorouracil (5FU) was
performed. On August 2018, three cycles had been completed,
the first and third of which were complicated by gastrointestinal
toxicity g.3 (Common Terminology Criteria for Adverse Events
CTCAE).15
Taking into account the reported toxicities, before restarting
treatment, restaging was anticipated; the thorax-­abdominal CT
performed on September 2018 reported substantial stability of
the pathological para-­aortic tissue infiltration, again with uret-
eral infiltration on the left side, even if with lower hydrouretero-
nephrosis. However, the CA 19.9 level was markedly increased
(472). The renal function parameters were within normal limits.
Given the patient's good general condition and their mediocre
tolerance of the previous treatment schedule, a new systemic
therapy line with paclitaxel + ramucirumab was planned, the
initial administration of which was completed on the end of
September 2018. The day after the therapy, the patient arrived
in the emergency room with epigastric pain with retrosternal
and interscapular irradiation, which was subsequently associated
with pallor, cold sweating and hypotension with lipothymia. An
electrocardiogram showed left axial deviation, incomplete right
bundle branch block, and non-­specific repolarisation disorders.
Thorax-­abdominal CT with and without contrast medium
excluded signs of pulmonary thromboembolism, but a Standford
type A AD2
[figure 1] was documented, with a diameter of around
6.5 cm and dissection flap originating in the ascending aorta
below the brachiocephalic trunk with no apparent involvement
of the aortic valvular plane, extended to the whole descending
aorta to the carrefour; the epiaortic trunks, the celiac tripod, the
superior mesenteric artery, the common iliac arteries and both
renal arteries appeared to originate from the true lumen, while
the inferior mesenteric artery originated from the false lumen.
INVESTIGATIONS
Through MEREAFaPS 5.0 project (Monitoraggio degli Eventi e
delle Reazioni Avverse da farmaci in Ambito Poli-­Specialistico),
an active pharmacovigilance project conducted in North Italian
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3. 119Zenoni D, et al. Eur J Hosp Pharm 2020;27:117–120. doi:10.1136/ejhpharm-2019-001879
Case report
Hospitals, integrated with the pharmacovigilance system of
ASST Bergamo Est Hospital, an adverse drug reaction was found
following administration of a biological drug. The analysis of
causality and interactions was carried out by means of the Soft-
ware Intercheck Web managed by ‘Mario Negri’ Pharmacolog-
ical Research Centre. Micromedex and Codifa were consulted as
data banks. The physician was interviewed and the clinical folder
was analysed in order to collect more information.
TREATMENT
Evaluated by the vascular surgeon, and considering the extension
of the dissection and the prognosis, the patient was not subjected
to further intervention; no signs of cardiocirculatory or respira-
tory decompensation were documented, and an antalgic therapy
associated with deep sedation with morphine hydrochloride
subcutaneously (induction 4 mg), midazolam intravenous (15
mg/day) and haloperidol (2–4 mg/day) was performed.
Outcome and follow-up
The patient was hospitalised in the Department of Medicine in
order to stabilise the clinical and haemodynamic parameters;
during the subsequent hours there were episodes of vomiting
followed by loss of consciousness, hypotension and oligo-­anuria.
Death was recorded during the night of hospitalisation.
DISCUSSION
The pharmacodynamic characteristics of multiple vascular endo-
thelial growth factor pathway inhibitors (VPIs), now widely used
in the treatment of many solid neoplasms in adults, are associ-
ated with toxicity risks, especially in the cardiovascular system,16
with modalities and recurrence rates widely observed in the
recorded studies for each different molecule.
VEGF, in fact, plays a key role in the growth and functional
maintenance of the vascular system, whose integrity is essen-
tial for cardiocirculatory function.16
Hypertension, sometimes
severe, is the most common adverse event for this pharmaco-
logical class.8 17 18
For this reason, it is always advisable, and is
routinely applied, to carry out a careful monitoring of blood
pressure before the administration of ramucirumab, and during
the treatment period, as well as for other anti-­angiogenics. A
Japanese retrospective study, performed on the basis of the Japa-
nese Adverse Drug Event Report (JADER), revealed a potential
direct correlation between VPIs use and AD. The reported study
documented the adverse reactions that occurred following the
use of various VPIs, and therefore the associated cardiovascular
risk would represent a class effect related to the mechanism of
action of these drugs.
The endothelial dysfunction associated with these drugs
would seem to be the most plausible explanation for such events:
it causes vasoconstriction, atherosclerosis, platelet aggregation
and coagulation, all factors favouring arterial thromboembolic
events and cardiovascular complications.16
Analysing the spontaneous reports of adverse drug reac-
tions between April 2004 and October 2015, it emerged that
out of 16 441 subjects with malignant neoplasms treated with
a systemic VPIs drug, 49 (0.3%) developed AD, 25 (51%) of
which presented with hypertension, while out of 74 614 patients
presenting with malignant neoplasms not treated with VEGF
inhibitors, 10 (0.01%) developed AD.19
In the literature there are case reports that associate AD with
the anti-­angiogenic tyrosine kinase inhibitor, sunitinib20 21
or with
the anti-­VEGF monoclonal antibody, bevacizumab;22
however,
ramucirumab-­related cases are not reported in the literature,
perhaps due to the small number of case series compared with
the other VPIs. To date, there are no reports of AD in the RNF
(National Pharmacovigilance Network) related to ramucirumab
administration in Italy. The assessment of a causal link between
ramucirumab and AD was calculated using the Naranjo algo-
rithm, a probability scale consisting of 10 questions that assigns,
based on the answers, a score that allows the establishment of a
category of probability (certain ≥9, probable 5–8, possible 1–4,
doubtful <1).23
The probable correlation (score of 5) is related
to the lack of dechallenge and rechallenge data. However, the
temporal correlation data remain strong. Although the hyperten-
sive picture, a highly correlated factor with AD, was known in
the months before the patient commenced treatment, during the
access to Emergency Room (ER) and just before ramucirumab
administration, the blood pressure was always well controlled by
antihypertensive treatment performed at home (nebivolol and
hydrochlorothiazide); conversely, no traumatic events that could
have facilitated the event were detected.
We believe that ramucirumab may have contributed to DA
manifestation in a patient who presented with predisposing
factors, comprising arterial hypertension and atherosclerotic
vasculopathy.
We hypothesise that hypertension can be a side effect that
also occurs in the short-­medium term; for hypertensive patients
in therapy with VPIs, although blood pressure compensated,
therefore we believe that intensive monitoring of blood pres-
sure (Holter) can be useful, at least in the days before treatment
commences and after first administration.
The authors have not declared a specific grant for this research from any funding
agency in the public, commercial or not-­for-­profit sectors.
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
ORCID iD
Davide Zenoni http://​orcid.​org/​0000-​0002-​1060-​5252
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