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Postoperative bleeding in patients taking oral anticoagulation therapy after

'All-on-four' rehabilitation: A case-control study

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 ORIGINAL ARTICLE

Gianpaolo Sannino, Paolo Capparé, Pietro Montemezzi, Ottavio Alfieri, Giuseppe Pantaleo,
Enrico Gherlone

Postoperative bleeding in patients taking oral

anticoagulation therapy after ‘All-on-four’
rehabilitation: a case-control study

KEY WORDS 
All-on-four, bleeding, dental implants, rivaroxaban, warfarin

ABSTRACT
Purpose: The aim of this study was to estimate bleeding prevalence and postoperative peri-oral
purpura after full-arch immediate implant rehabilitation according to the ‘All-on-four’ technique,
in patients on different oral anticoagulant therapies (warfarin and rivaroxaban).
Materials and methods: A total of 120 patients (47 women, 73 men, mean age 66.4 years) pre-
sented with edentulous or partially edentulous arches. All patients were treated with immediate
full-arch fixed prostheses (28 maxillary, 34 mandibular), each supported by four implants (two
vertical, two distally tilted). Participants were divided in three groups: 40 patients under treatment
with warfarin formed group A, 40 patients under treatment with rivaroxaban composed group
B, and 40 healthy subjects composed the control group. As the primary outcome measure, mild,
moderate and severe postoperative bleeding was recorded. As the secondary outcome meas-
ure, the presence of postoperative petechiae, ecchymoses and haematomas in oral and peri-oral
­tissues was recorded.
Results: Patients under treatment with warfarin (group A) showed a higher prevalence of postop-
erative bleeding (P = 0.002) and purpura (P = 0.012) in comparison with other groups. No severe
bleeding took place and no haematomas appeared in any patient. Prefabricated metal-reinforced,
screw-retained, acrylic resin provisional restorations were delivered in all patients.
Conclusions: The preliminary results of this prospective case-control study showed how immedi-
ate rehabilitation according the ‘All-on-four’ technique could be a safe and predictable procedure
in anticoagulated patients where anticoagulation therapy is not discontinued or modified.

Conflict-of-interest statement: The authors declare they have no conflicts of interest.

Introduction the need for implant-supported rehabilitations

Implant treatment for edentulous patients has been
reported to be a safe and predictable procedure, as
well as providing function and aesthetics1. How-
ever patient compliance and local and systemic
health conditions still represent crucial factors and
must be accurately evaluated before implant treat-
ment. The incidence of cardiovascular diseases and
increase as the population ages. Oral anticoagula-
tion therapies are commonly prescribed in order to
prevent the occurrence of thromboembolic events,
such as deep vein thrombosis and pulmonary
embolism. The main adverse side effect of these
medicines lies in the bleeding risk2, which may
result in invalidating sequelae including fatal acci-
dents. In recent studies3,4, a 5.1% mortality rate at

Int J Oral Implantol 2019;12(4):499–509 499

Sannino et al   All-on-four in anticoagulated patients
30 days for extracranial haemorrhagic events was
reported in patients under warfarin therapy, and
the rate was 50% for intracranial haemorrhagic
events.
Bleeding complications, occurring either spon-
taneously or peri-operatively, have been faced for
long time, and can result in temporary therapy
modification or interruption before oral surger-
ies such as dental extractions and implant treat-
ments5. Since the thromboembolic event could
be more harmful than the eventual postoperative
bleeding, evaluation of an individual’s risk must be
performed for safe management of the patient6.
The benefits gained from temporary discon-
tinuation of oral anticoagulants do not justify the
embolic risk in cases of minor oral surgery, such
as placement of dental implants5,6. Although
bleeding risk cannot be avoided, implant place-
ment in anticoagulated patients has been proved
to be feasible in specific conditions. In a recent
study, it was concluded that dentoalveolar sur-
gery could be safely performed in anticoagulated
patients when the number of implants placed did
not exceed three7. Other studies proved dental
implant surgery to be safe in patients on oral anti-
coagulants if local haemostatic measures were set
in place accurately8,9. Al Zoman et al10 suggested
a flapless approach as elective procedure for im-
plant placement in patients under anticoagulation
therapy, while Clemm et al11 found that implant
surgery itself, whether more or less invasive, did
not increase the frequency of bleeding events in
anticoagulated patients.
Current anticoagulants consist of two basic
drugs: thrombocyte aggregation inhibitors (such
as acetylsalicylic acid and clopidogrel) and vitamin
K antagonists (such as warfarin, acenocoumarol
and phenprocoumon). The coumarin derivatives
that inhibit vitamin K (vitamin K antagonists) have
shown excellent pharmacokinetics and represent
the standard in oral anticoagulation therapy12,13.
However, their use necessitates regular dose
adjustments depending on the prothrombin time14
and they can have multiple drug and food interac-
tions15-17.
Recently, new oral anticoagulants have been
introduced in order to overcome these limitations.
500
Among these, rivaroxaban, which works by inhibit-
ing the activity of factor Xa4, allows a regular dose
intake, and continuous coagulation monitoring of
the patient is not required18. Moreover, as a direct
factor Xa inhibitor, rivaroxaban interrupts the coag-
ulation cascade (inhibiting mainly thrombin and
factor Xa); a reversal agent can be administered
for immediate effect reduction, and the majority
of anticoagulation effect (80%) reportedly disap-
pears 24 hours after the last drug intake in case
of normal renal function19. In contrast, vitamin K
inhibitors have a difficult pharmacological man-
agement, as the maximum prothrombin response
occurs 2 to 4 days after drug administration and the
effect declines at a constant rate following cessation
of the therapy13. However, laboratory testing for
precise dose administration is routinely available20.
The purpose of the present case-control study
was to estimate the bleeding prevalence and post-
operative peri-oral purpura after full-arch immedi-
ate implant rehabilitation according to ‘All-on-four’
technique in patients on different oral anticoagu-
lant therapies (warfarin and rivaroxaban).
Materials and methods
This case-control study was performed at the
Department of Dentistry, Istituto di Ricovero e
Cura a Carattere Scientifico (IRCCS, Institute of
Recovery and Cure with Scientific Characterisa-
tion), at the San Raffaele Hospital, Milan, Italy.
The investigation was approved by the appropriate
ethics committees related to the institution.
Between January 2014 and December 2017,
120 patients (47 women, 73 men) aged between
58 and 72 years (mean 66.4 ± 6.67 years) re-
quiring a full-arch implant-prosthetic rehabilitation
(because of hopeless teeth and refusal of removable
prosthesis) were enrolled in the study. The inclusion
and exclusion criteria for the study are showed in
Table 1. All patients signed informed consent.
Panoramic radiography and cone beam com-
puted tomography were used for radiographic
evaluation before the surgery. Of the 120 patients
included in the study, 40 were taking warfarin
(group A) and 40 were on the new anticoagulation
Int J Oral Implantol 2019;12(4):499–509
 Sannino et al   All-on-four in anticoagulated patients

Table 1   Inclusion and exclusion criteria for patient enrolment

Criteria Inclusion Exclusion

Edentulism
Anticoagulant therapy
(except control group)
Bone anatomy
Oral lesions
Interfering medication
Coagulopathies
History of bleeding
Systemic disease
Edentulous arch or remaining hope- Partial edentulism
less teeth
Regular warfarin or rivaroxaban Less than 1 year, irregular drug intake
administration from at least 1 year
Bone atrophy in posterior regions Sufficient residual bone height and width to place dental
of maxilla and mandible implants in posterior regions
None Lichen planus, erythroplakia, leucoplakia, recurrent aph-
thous stomatitis
None Radiation therapy, chemotherapy, radiation therapy in
head and neck regions, bone resorption inhibitor therapy
None Von Willebrand disease, haemophilia, rare coagulation
diseases
None Any previous haemorrhage, spontaneous or induced
None Diabetes mellitus, systemic lupus erythematosus

Table 2   Therapeutic indications for warfarin and rivaroxaban administration

Therapy indication Group A (warfarin) Group B (rivaroxaban)

patients, n (%) patients, n (%)
Atrial fibrillation and mitral stenosis 9 (22.5) 0 (0.0)
Myocardial infarction 16 (40.0) 6 (15.0)
Deep vein thrombosis or pulmonary embolism 6 (15.0) 11 (27.5)
Atrial fibrillation and prosthetic heart valve 4 (10.0) 0 (0.0)
Non-valvular atrial fibrillation and transitory ischaemic attack 5 (12.5) 8 (20.0)
Non-valvular atrial fibrillation and hypertension 0 (0.0) 6 (15.0)
Non-valvular atrial fibrillation and congestive heart failure 0 (0.0) 7 (17.5)
Stroke 0 (0.0) 2 (5.0)

therapy rivaroxaban (group B). The remaining
patients (40) were not taking oral anticoagulants
and formed the control group.
The international normalized ratio (INR) for
patients in group A was checked 24 hours before
surgery and ranged between 1.87 and 3.19. Man-
agement recommendations for invasive dental
treatment in patients on oral antithrombotic medi-
cation were followed. No patient in group A had
an INR ≥ 3.521.
The prothrombin time was assessed for
group B. Furthermore, an anti-factor Xa assay, i.e.
the most accurate measurement of the anticoagu-
lant effect of rivaroxaban, was always available in
case of an emergency situation or patient hospi-
talisation15,22,23.
The prothrombin time assay, with results
expressed as an INR, was also required for the
control group patients 24 hours before the surgery.
Values ranged from 0.97 to 1.28 for the healthy
patients. The Cardiothoracic Department of IRCCS
San Raffaele Hospital was informed about the type
of surgical intervention to be performed and gave
consent to operate without altering the anticoagu-
lation therapy (neither discontinued for any time
nor replaced with a different drug).
Therapeutic indications for oral anticoagu-
lant prescription in patients treated with warfarin
(group A) and patients treated with rivaroxaban
(group B) are shown in Table 2.

Int J Oral Implantol 2019;12(4):499–509 501

Sannino et al   All-on-four in anticoagulated patients
Surgical protocol
Participants in the study attended the dental
department on an outpatient basis. The support
of an anaesthesiologist allowed vital signs to be
monitored and the surgery to be performed under
conscious sedation with midazolam 5 mg/ml
administered intravenously (Hameln Pharmaceu-
ticals, Hameln, Germany).
Patients at risk of infective endocarditis were
instructed to take prophylactic amoxicillin 2 g (if
allergy reported, clarithromycin 500 mg) 1 hour
before surgery according to the American Heart
Association guidelines24. The study had a double-
blind design, with surgeons and observers (who vis-
ited patients at postoperative check-ups) unaware
regarding to which group the patients belonged.
Immediate loading rehabilitation of the eden-
tulous arches with four implants (two anterior
axial and two posterior tilted) (CSR-DAT, Sweden
& Martina, Due Carrare, Italy) supporting a screw-
retained prosthesis was performed for groups A
and B as well as for the control group25. Local
anaesthesia was induced by 4% articaine solu-
tion with adrenaline 1:100,000 (Ubistesin, 3M
Espe, St Paul, Minnesota). Atraumatic extractions
were performed where needed and a mucoperi-
osteal flap was raised to expose the crestal bone
with relieving incisions on the buccal aspects in
the posterior molar areas. In some cases, bone
shaping was performed with a round bur to level
the bone crest, and bone recontouring was per-
formed distal to the angled implants in order to
ease implant–abutment engagement.
The drilling protocol recommended by the
manufacturer (Sweden & Martina) was modified
by underpreparing the width of the implant site in
order to achieve a higher primary stability (inser-
tion torque ranging between 40 and 50 Ncm).
Dental implants were placed in the maxilla or
mandible according to the ‘All-on-four’ protocol:
two anterior straight implants in the lateral incisor
area and two posterior tilted implants with pros-
thetic emergence in the second premolar area.
Subcrestal implant placement was performed
0.5 mm below the buccal plate level. Prefabri-
cated metal-reinforced, screw-retained, acrylic
502
resin interim restorations were delivered immedi-
ately in all patients26.
Bleeding management
Various local haemostatic measures that have been
demonstrated to be effective in preventing post-
surgical bleeding were used27-29. Bone wax was
placed in fresh sockets to mechanically stop bleed-
ing from bony surfaces where necessary (Bone
Wax, Ethicon, Johnson & Johnson, New Brun-
swick, NJ, USA) and resorbable gelatin sponges
were placed into the alveoli before suturing (Spon-
gostan, Ferrosan Medical Devices, Søborg, Den-
mark). The horizontal mattress suturing technique
combined with simple stitches was performed with
3-0 resorbable sutures (Vicryl, Ethicon, Johnson &
Johnson). Compression was applied on the wound
through sterile gauzes soaked in 500 mg/5 ml
tranexamic acid (Ugurol, Rottapharm Biotech,
Monza, Italy) for 8 minutes.
Postoperative follow-up
Paracetamol was prescribed as analgesic drug (1 g
immediately after the surgery followed by 500 mg
every 6 hours over 5 days). Antibiotic therapy was
continued for 7  days after the surgery (1 g amoxi-
cillin every 12 hours or 250 mg clarithromycin every
12 hours if allergic to penicillin), and two ice packs
were given to the patient with the recommendation
to apply cold to the wound for at least 16 hours per
day for 4 days. All patients were advised to adhere
to a cold and soft diet during the first 48 hours.
Topical antiseptic mouth rinse (0.2 % chlorhexidine
gluconate) was prescribed every 8 hours for 7 days
starting from 2 days after the surgery. The presence
of bleeding and purpura was controlled by differ-
ent clinicians from those who had performed the
implant surgery. Suture removal was not necessary
in most cases; where this was necessary it was per-
formed 14 days post-surgery.
Outcome measures
The primary outcome measures were the time
of occurrence and prevalence of bleeding. Early
Int J Oral Implantol 2019;12(4):499–509
 Sannino et al   All-on-four in anticoagulated patients

Table 3   Distribution of dental implants placed according to site (maxilla or mandible and anterior or posterior regions*) and group

Group A (warfarin) Group B (rivaroxaban) Control group

Anterior maxilla implants 38 48 50
Posterior maxilla implants 38 48 50
Anterior mandible implants 42 32 30
Posterior mandible implants 42 32 30
Total 160 160 160

*Anterior region was considered from canine to canine, posterior region was considered distal to the first maxillary or mandibular
premolar.

bleeding was recorded after the surgery up to
24 hours. Delayed bleeding episodes were recorded
from the second day up to the fourteenth day
after the surgery. Concerning the prevalence, mild
bleeding was recorded when dry gauze compres-
sion with topical ice-pack application was sufficient
to stop the bleeding at home, moderate bleeding
occurred when additional local haemostatic meas-
ures were set in place by observers in the office,
and severe bleeding was considered as an episode
that required the patient’s hospitalisation.
The secondary outcome measures were as fol-
lows:
• the presence of purpura, a postoperative dis-
coloration produced by blood extravasation
under the surface of the mucosa in the oral
cavity or under the skin in peri-oral facial and
cervical areas
• petechiae, described as pinpoint, non-raised
circular red spots
• ecchymoses, considered as areas with an extent
wider than 1 cm
• haematomas, considered as large pools of
blood resulting in a palpable mass.
Statistical analysis
The statistical analysis regarding comparison of
the prevalence of bleeding and purpura between
group A, group B and the control group was evalu-
ated using the Freeman-Halton extension of the
Fisher exact probability test. An a priori power ana-
lysis run with the software G*Power30 test family
a magnitude of at least r = 0.30 between the cen-
tral target variables in 2 × 3 contingency tables),
the total sample size of the present study had to
include at least 112 patients (two-tailed tests; criti-
cal α = 0.05; power = 90%). The sample of this
study provided N = 120 patients (i.e. n = 40 for
each of the three basic cells of the research design,
or groups of patients), therefore slightly higher
sensitivity of the research design was obtained.
According to Senn33, the baseline balance of
typical subsample characteristics (e.g. age and/
or other sociodemographic characteristics usu-
ally compared among subsamples of patients at
baseline) was not tested in order to avoid an old
methodologically and statistically “unsound, of no
practical value, and also potentially misleading”
practice in clinical trials.
Results
Forty full-arch implant-supported rehabilitations
were performed in each group; 68 and 52 rehabili-
tations were performed in the maxilla and mandi-
ble, respectively (Table 3).
The occurrence of postoperative bleed-
ing is summarised in Table 4. Fifteen moderate
Table 4   Incidence of postoperative bleeding: mild, moderate
and severe events within group A (warfarin therapy), group B
(rivaroxaban therapy) and control group
Mild Moderate Severe

‘exact tests’ revealed that, in order to achieve a Group A (warfarin) 29 11 0

90% probability of detecting even relatively small Group B (rivaroxaban) 37 3 0

intervention effects31,32 (i.e. association effects of Control group 39 1 0

Int J Oral Implantol 2019;12(4):499–509 503

Sannino et al   All-on-four in anticoagulated patients
Table 5   Incidence of postoperative purpura: petechiae,
ecchymoses and haematomas within group A (warfarin
therapy), group B (rivaroxaban therapy) and control group
Petechiae Ecchymoses Haematoma
Group A 30 10 0 bleeding occurrence (spontaneously or peri-oper-
(­warfarin)
Group B 38 2 0
(­rivaroxaban)
Control group 38 2 0
bleeding events were reported (11 in group A,
three in group B, one in the control group). Of the
11 moderate bleeding events in group A, three
were delayed bleeding events. All other patients
had early bleeding events, i.e. that occurred within
24 hours following the surgery. No severe bleed-
ing occurred in any of the groups. Therefore, all
relevant statistical analyses were performed on
patients with either mild or moderate bleeding.
A Freeman-Halton extension of the Fisher exact
probability test revealed a statistically significant
association between bleeding events (mild vs.
moderate) and group of patients (drug therapy
with warfarin vs. rivaroxaban vs. control group)
(P = 0.002), such that patients treated with war-
farin tended to bleed more in comparison with
either patients treated with rivaroxaban or patients
assigned to the control group.
Postoperative purpura was recorded in all
patients, as displayed in Table 5. Fourteen ecchy-
moses were recorded (10 in group A, two in
group B, two in the control group). No patients
experienced haematoma. Therefore, all relevant
statistical analyses were performed on patients
with petechiae or ecchymoses. A statistically sig-
nificant association between purpura (petechiae
vs. ecchymoses) and groups of patients was found
(P = 0.012), such that group A patients tended
to show more purpuras than patients assigned to
group B and the control group.
Discussion
Tailored anticoagulation management should
be provided to patients undergoing oral surgical
504
procedures. At present, there is evidence that anti-
coagulant therapy interruption generates a higher
risk of suffering thromboembolic events, with
more severe morbidity than that resulting from
atively) when anticoagulation is continued5,34-36.
Nevertheless, an individual risk evaluation based
on the systemic health condition of the patient,
the invasiveness of the surgical procedure, and
the anticoagulation therapy must be performed
in order to provide the safest management of the
patient37.
In the current literature, there are no ran-
domised prospective studies evaluating bleeding
prevalence and postoperative peri-oral purpura
following implant surgery according to the ‘All-
on-four’ technique in patients on anticoagulation
therapy. The present study was conducted among
patients on warfarin or rivaroxaban therapy. War-
farin is a vitamin K antagonist; it interferes with
cyclic interconversion of vitamin K and its epox-
ide. Hence, biologically active prothrombin, which
requires the production of reduced vitamin K, is no
longer formed and the clotting pathway is inter-
rupted38. Rivaroxaban, a novel oral anticoagulant,
does not interfere with vitamin K, as it has a specific
anticoagulation action in the coagulation cascade.
It is a selective direct inhibitor of coagulation factor
Xa, which results in an independent antithrombin
effect39. No previous research has been published
comparing these different anticoagulants when
invasive surgical procedures, i.e. multiple implant
placement following extractions, were performed.
Despite the potential bleeding complications,
owing to the invasive nature of such surgical pro-
cedures, therapies were not discontinued nor
altered, in accordance with Nematullah et al40 and
Turpie et al41. An extensive literature review of
papers dealing with the management of dental
patients receiving oral antithrombotic medication,
showed that therapy cessation for simple dental
procedures (e.g. up to three dental extractions, up
to three dental implants and periodontal surgery)
was not recommended21. Moreover, no statistic-
ally significant difference in the risk of bleeding
was found in a Cochrane review42 (14 studies,
27,746 patients) that compared direct thrombin
Int J Oral Implantol 2019;12(4):499–509

inhibitors to vitamin K antagonists and low-molec-
ular-weight heparin (LMWH).
Based on current knowledge5,8,43,44, the pur-
pose of the present study was to evaluate how
the bleeding risk (measured as prevalence) could
be affected by the specific procedure and/or the
specific therapy. The INR interval at which dental
extractions and implant surgery can be safely per-
formed is still unclear and there is not yet a con-
sensus45-48. The present study involved patients
with INR values ≤ 3.5; the patient dose regimen of
oral anticoagulant therapy was kept unchanged
before, during and following the surgery. The INR
for group A was checked 24 hours before surgery
and ranged between 1.87 and 3.19. As shown by
Wahl et al5, the risk of serious embolic complica-
tions in patients whose anticoagulation is reduced
or withdrawn for dental procedures was approxi-
mately 0.8%, whereas patients undergoing dental
surgery with warfarin therapy continuation fea-
tured an approximately 6% relative risk of minor
postoperative bleeding controlled with additional
local haemostatic measures. The risk of severe
bleeding was approximately 0.6% and no perma-
nent morbidities or fatalities were reported from
postoperative bleeding when the anticoagulation
therapy was unchanged5.
Although INR values for the rivaroxaban group
were not checked since the test is not strictly
related to the anticoagulant effect produced by
the drug49, the prothrombin time was assessed for
group B. Furthermore, an anti-factor Xa assay, i.e.
the most accurate measurement of the anticoagu-
lant effect of rivaroxaban, was always available in
case of an emergency situation and the patient’s
hospitalisation15,22.
Firriolo and Hupp15 suggested that no inter-
ruption was required in rivaroxaban administration
before conventional dental treatments, in patients
with normal renal function and in absence of hae-
mostasis disorders.
In the present study, 15 moderate bleed-
ing occurrences were recorded, as follows: 11 in
patients under warfarin therapy (group A), three
patients under rivaroxaban therapy (group B), and
one in the non-anticoagulated patients (control
group). All bleeding episodes were classified as
Int J Oral Implantol 2019;12(4):499–509
Sannino et al   All-on-four in anticoagulated patients
early bleeding as they took place within 24 hours
after the surgery, except for three delayed cases
belonging to the warfarin group. A statistically sig-
nificant association (P = 0.002) between bleeding
events and groups of patients was found in war-
farin patients, who tended to have more bleeding
events compared with patients in the other groups.
No participants experienced severe postoperative
bleeding. All the postoperative bleeding complica-
tions were easily handled with local haemostatic
measures and none of the patients required more
than local measures, or hospitalisation. Local hae-
mostatic measures consisted of Bone Wax, resorb-
able gelatin sponges placed into the alveoli before
suturing, horizontal mattress technique combined
with simple stitches with resorbable sutures, and
wound compression with sterile tranexamic acid-
soaked gauzes.
In previous studies8,9, resorbable sutures were
avoided due to the variability of their pattern of
reabsorption and duration. In the present study, an
immediate prosthetic loading procedure was per-
formed after surgery and resorbable sutures were
chosen in order to reduce plaque accumulation
under the provisional restoration, since the screw-
retained fixed prostheses were removed after
4 months in function for the definitive restorative
procedure. It should be underlined that most of the
above-mentioned previous studies investigated
the effectiveness of local haemostatic measures in
anticoagulated patients who underwent different
surgical procedures50-53.
There is consensus in the literature that primary
wound closure, following implant insertion in a
healed site (according to the traditional protocol),
allows a primary flap closure that may result in
better haemostasis and a potentially lower inci-
dence of bleeding in contrast with tooth extrac-
tion8. The latter features healing by secondary
intention, which leaves the wound exposed until
clot stabilisation, while increasing the postopera-
tive bleeding risk. It should be highlighted that, in
the present study, a much more invasive surgical
procedure, i.e. tooth extraction, crest regularisa-
tion, implant insertion and immediate loading, was
performed. Nevertheless, postoperative bleeding
prevalence was in accordance with data published
505
Sannino et al   All-on-four in anticoagulated patients
in other studies8,9,54 where less invasive proced-
ures were performed. These findings confirm the
reliability of such a proposed protocol where the
use of local measures, i.e. Bone Wax, resorbable
gelatin sponges, resorbable sutures with horizontal
mattress technique combined with simple stitches
in order to enhance flap margin approximation
and closure around the abutment, and wound
compression with sterile tranexamic acid-soaked
gauzes for 8 minutes, were sufficient to control
postoperative bleeding. Concerning postopera-
tive purpura, no haematoma occurred. A statis-
tically significant association (P = 0.012) between
purpura and groups of patients was found in
warfarin patients compared to the other groups.
Therefore, patients treated with warfarin tended to
bleed more and show more purpuras than patients
treated with rivaroxaban and patients assigned
to the control group. The bleeding prevalence
recorded in the present study was in accordance
with the outcomes of similar previous studies,
but most of these failed to show any significant
difference between anticoagulated patients and
non-anticoagulated patients47,55-58. The present
findings are in agreement with Clemm et al11, who
evaluated, in a prospective clinical comparative
study, the postoperative bleeding risk of patients
continuing their different anticoagulation thera-
pies and undergoing different surgical proced-
ures. Although all the bleeding events were easily
manageable with local haemostatic measures and
no severe bleeding occurred, a statistically signifi-
cantly higher frequency of postoperative bleeding
was found in patients taking vitamin-K inhibitors
compared with non-anticoagulated patients as
well as those on rivaroxaban therapy. The post-
operative bleeding risk in patients on rivaroxaban
therapy was statistically comparable to patients
without any anticoagulation therapy. This is fur-
ther supported by Gómez-Moreno et al54, who
evaluated the incidence of bleeding complications
after dental implant placement in patients in treat-
ment by rivaroxaban without therapy interruption
or modification. No significant differences were
found between rivaroxaban patients and healthy
control subjects. However, it should be noted that
any statistically significant difference between
506
groups may have been affected by the presence of
advanced periodontal disease, i.e. inflammation of
oral mucosa and granulation tissue. A higher rate
of complications related to bleeding after tooth
extraction for periodontal reasons has previously
been described59,60.
Several medications have been shown to influ-
ence the coagulation system. In the present study,
the postoperative protocol provided amoxicil-
lin (or clarithromycin if allergic to penicillin), and
cephalosporins, macrolides and quinolones were
avoided61-66. Paracetamol was prescribed as an-
algesic medication, and non-steroidal anti-inflam-
matory drugs (NSAIDs) were avoided in order to
reduce the bleeding risk and potential invalidation
of the study67,68. Vitamin-K antagonists show sat-
isfactory pharmacokinetics13,69; however, they are
not without problems (regular monitoring required,
dose titration, multiple food and drug interactions).
Recently, a new drug, namely rivaroxaban, was
introduced as an alternative to warfarin; rivaroxa-
ban overcomes some of the limitations of warfarin,
since rivaroxaban does not require regular coagu-
lation monitoring or dose titration, and has a rapid
onset of action, a short half-life and limited food
and drug interactions. As the number of patients on
rivaroxaban therapy increases, knowledge of indi-
cations and the method of action are needed for
safe and predictable management of those patients
undergoing invasive dental procedures.
Conclusions
The preliminary results of this prospective case-
control study suggest that immediate rehabilitation
according the ‘All-on-four’ technique could be a
safe and predictable procedure in anticoagulated
patients where anticoagulation therapy is not dis-
continued nor modified. The use of local haemo-
static measures could be sufficient to prevent severe
postoperative bleeding both in anticoagulated and
non-anticoagulated subjects. Warfarin therapy may
expose the patient to a higher prevalence of moder-
ate bleeding and purpura. Since no specific proto-
cols are available concerning the management of
anticoagulated patients undergoing invasive dental
Int J Oral Implantol 2019;12(4):499–509

procedures, more observational studies and ran-
domised controlled trials are needed to confirm the
reliability of the protocol used in this study and to
further define management guidelines.
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Int J Oral Implantol 2019;12(4):499–509

Gianpaolo Sannino, DDS, PhD
Adjunct Professor, Dental School, Vita-
Salute San Raffaele University, Milan,
Italy; and Department of Dentistry, IRCCS
San Raffaele Hospital, Milan, Italy
Paolo Capparé, MD, MFS
Researcher, Dental School, Vita-Salute
San Raffaele University, Milan, Italy; and
Department of Dentistry, IRCCS San Raf-
faele Hospital, Milan, Italy
Gianpaolo Sannino
Pietro Montemezzi, DDS
Fellow MSc, Dental School, Vita-Salute
San Raffaele University, Milan, Italy; and
Department of Dentistry, IRCCS San Raf-
faele Hospital, Milan, Italy
Correspondence to:
Dr Gianpaolo Sannino, Department of Dentistry, IRCCS San Raffaele Hospital and Vita-Salute University,
Via Olgettina 48, zip code 20132, Milan, Italy. E-mail: gianpaolosannino@gmail.com
QV Att
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Sannino et al   All-on-four in anticoagulated patients
Ottavio Alfieri, MD, CTVS
Full Professor and Chairman, Cardiac Sur-
gery, Vita-Salute San Raffaele University,
Milan, Italy; and Cardiothoracic Depart-
ment of IRCCS San Raffaele Hospital,
Milan, Italy
Giuseppe Pantaleo, MA, MSc, PhD
Full Professor and Chairman, Research
Methodology, UniSR-Social.Lab, Faculty
of Psychology, Vita-Salute San Raffaele
University, Milan, Italy
Enrico Gherlone, MD, DMD
Full Professor and Chairman, Dental
School, Vita-Salute San Raffaele Uni-
versity, Milan, Italy; and Department of
Dentistry, IRCCS San Raffaele Hospital,
Milan, Italy