- Email: [email protected]
Bleeding After Aortic Valve Replacement Matters
JACC: CARDIOVASCULAR INTERVENTIONS
VOL. 10, NO. 14, 2017
ª 2017 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 1936-8798/$36.00
PUBLISHED BY ELSEVIER
http://dx.doi.org/10.1016/j.jcin.2017.06.005
EDITORIAL COMMENT
Bleeding After Aortic Valve Replacement Matters Important Mortality Risk* George D. Dangas, MD, Roxana Mehran, MD
A
ortic valve replacement (AVR) has gained
and late bleeding events and their relation to the
prominence in clinical investigation since
vascular access site and to patient mortality. The
the development of the minimally invasive
investigators should be commended for the longitu-
transcatheter AVR (TAVR) and its increasing applica-
dinal follow-up (average 3 years, maximum 5 years)
tion. Initial research was appropriately focused on
and the
device characteristics and procedure details. Because
used. Readers, however, should be alerted to possibly
periprocedural vascular and bleeding complications
questionable ascertainment of events at such depth
were quickly recognized as quite predictive of
of time post-procedure and with only yearly contact
early mortality, methods of safely obtaining vascular
beyond the initial month.
robust standardized
clinical endpoints
access were improved, and device sizes decreased
The population appears sizeable (N ¼ 926), in
progressively. Longer-term bleeding was less dili-
mostly female (53%) and indeed very elderly (mean
gently tracked and described in most of the random-
age 82.4 years) patients. These characteristics are
ized TAVR trials, which used variable bleeding
unlike the typical population included in dose finding
definitions. Stemming from our experience in coro-
and other clinical studies of antithrombotic medical
nary interventions, the old age and comorbidities of
therapy.
patients undergoing AVR are key foundations for
TAVR (and largely AVR as well) has been consensus/
the prognostic importance of bleeding complications
experience based (2) in the absence of evidence from
in these patients.
adequately powered randomized trials. SEE PAGE 1436
The paper by Piccolo et al. (1) in this issue of JACC: Cardiovascular Interventions reports the findings of a TAVR registry in central Switzerland regarding early
Adjunct
pharmacological
therapy
after
The bleeding rates documented by Piccolo et al. (1) are astonishing: 31% of the population experienced a significant bleeding event; 24% had life-threatening or major bleeding. Eighty percent of these complications occurred within 1 month (early) and were mostly access site related. The late events (20%) were mostly non-access site related; gastrointestinal and
*Editorials published in JACC: Cardiovascular Interventions reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Interventions or the American College of Cardiology. From the Icahn School of Medicine at Mount Sinai, Mount Sinai Medical Center, New York, New York. Dr. Dangas has received teaching/lecture
pericardial bleeding were at the top of a long list of variable bleeding etiologies. Interestingly, recurrent bleeding was rare (only 6%). Most access site bleeds were minor in severity, whereas most non-access site
fees from Bayer and Janssen; and is an unpaid consultant for Bayer and
bleeds were major. Life-threatening bleeds were
Daiichi-Sankyo. Dr. Mehran has received teaching fees from Bayer and
roughly one-half of the events in both categories.
Janssen; has been a consultant for CSI, Shanghai BraccoSine Pharma,
Female sex predicted access site bleeding, whereas
Medscape, Bayer (unpaid), and Daiichi-Sankyo (unpaid); has received (institutional) consulting fees from Abbott Laboratories, American Col-
chronic kidney disease and an increased operative
lege of Cardiology, Boston Scientific, CardioKinetix, and Spectranetics; is
risk score predicted non-access site bleeding.
on the advisory board (funding paid to institution) of BMS; is on the data safety monitoring board (fees paid to institution) of Watermark Research Partners; is on the executive committee of Janssen Pharma and Osprey
Mortality (mean 3.25 years from TAVR) was very high in this population: 49% among those without a
Medical; and has equity in Claret Medical and Elixir Medical; and her
bleed, 58% in those with an access site bleed, and
spouse is a consultant for Abiomed and The Medicines Company.
73% in patients with a non-access site bleeding
1448
Dangas and Mehran
JACC: CARDIOVASCULAR INTERVENTIONS VOL. 10, NO. 14, 2017 JULY 24, 2017:1447–8
Risk of High-Risk Cases: Perception or Reality?
event! All the mortality curves appeared to be
thrombosis events appear to be associated with
continuously increasing over time, without any
transient ischemic brain attacks and have caught
obvious deflection point. Therefore, these factors
broad attention (8,9). Anticoagulation appears to be
appeared to indicate a rather constant underlying
more effective in averting and treating leaflet
risk. Furthermore, non-access site bleeding appeared
thrombosis in retrospective studies (8), which pro-
to indicate a consistent mortality risk regardless of
vide no perspective on the bleeding risks of such
its severity.
regimens if applied on a large scale. The findings of
Besides the aforementioned event ascertainment,
Piccolo et al. (1), as well as other retrospective
another limitation is the absence of extensive data
studies on bleeding risks and outcomes after TAVR
on antiplatelet or anticoagulant agent use during
(3–7), indicate that we have to be concerned of the
follow-up, and especially before and around the time
possible risks of antithrombotic therapies after
of clinical events. Medical regimen was only available
TAVR. In the absence of robust evidence-based rec-
at the time of hospital discharge, and common
ommendations, clinical practice worldwide has been
knowledge supports its frequent modification over
multifragmented and essentially personalized per
time (particularly in 3- to 5-year depth of follow-up).
doctor or institution in an attempt to theoretically
The investigators document a wide variability in the
maximize benefit and limit risks for each patient.
post-TAVR antiplatelet and anticoagulant therapy,
However, the logical answer is to proceed with a set
despite the fact that this is a single-center registry.
of prospective clinical trials (10,11) to adequately
We can therefore expect an even greater worldwide
assess the risk and benefit of adjunct pharmacology
variability of adjunct pharmacological therapy after
options in TAVR patients, with full understanding
TAVR. Again, this stems from the absence of robust
that even the age group itself may pose specific
clinical evidence in the field, precluding the devel-
challenges to their pharmacological properties and
opment of uniform, evidence-based guidance (2–5).
efficacy/side-effect profiles.
For example, although dual antiplatelet therapy is widespread, several small trials and a meta-analysis
ADDRESS
do not support a major clinical benefit and tend to
Mehran, Mount Sinai Medical Center, One Gustave L.
FOR
CORRESPONDENCE:
suggest a bleeding risk in comparison to aspirin
Levy Place, Box 1030, New York, New York 10029.
alone (6,7). At the same time, rare valve leaflet
E-mail: [email protected].
Dr.
Roxana
REFERENCES 1. Piccolo R, Pilgrim T, Franzone A, et al. Fre-
5. Abdul-Jawad Altisent O, Durand E, Muñoz-
leaflet thrombosis in surgical and transcatheter
quency, timing and impact of access-site and non– access-site bleeding on mortality among patients undergoing transcatheter aortic valve replacement. J Am Coll Cardiol Intv 2017;10:1436–46.
García AJ, et al. Warfarin and antiplatelet therapy versus warfarin alone for treating patients with atrial fibrillation undergoing transcatheter aortic valve replacement. J Am Coll Cardiol Intv 2016;9: 1706–17.
bioprosthetic aortic valves: an observational study. Lancet 2017 Mar 19 [E-pub ahead of print].
2. Nishimura RA, Otto CM, Bonow RO, et al. 2017 AHA/ACC focused update of the 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2017 Mar 10 [E-pub ahead of print]. 3. Généreux P, Cohen DJ, Mack M, et al. Incidence, predictors, and prognostic impact of late bleeding complications after transcatheter aortic valve replacement. J Am Coll Cardiol 2014;64:2605–15. 4. Généreux P, Cohen DJ, Williams MR, et al. Bleeding complications after surgical aortic valve replacement compared with transcatheter aortic valve replacement: insights from the PARTNER I trial (Placement of Aortic Transcatheter Valve). J Am Coll Cardiol 2014;63:1100–9.
6. Rodés-Cabau J, Masson JB, Welsh RC, et al. Aspirin versus aspirin plus clopidogrel as antithrombotic treatment following transcatheter aortic valve replacement with a balloon-expandable valve: the ARTE (Aspirin Versus Aspirin þ Clopidogrel Following Transcatheter Aortic Valve Implantation) randomized clinical trial. J Am Coll Cardiol Intv 2017 May 11 [E-pub ahead of print]. 7. Aryal MR, Karmacharya P, Pandit A, et al. Dual versus single antiplatelet therapy in patients undergoing transcatheter aortic valve replacement: a systematic review and meta-analysis. Heart Lung Circ 2015;24:185–92. 8. Chakravarty T, Søndergaard L, Friedman J, et al., RESOLVE, SAVORY Investigators. Subclinical
9. Dangas GD, Weitz JI, Giustino G, Makkar R, Mehran R. Prosthetic heart valve thrombosis. J Am Coll Cardiol 2016;68:2670–89. 10. Dangas GD, Lefèvre T, Kupatt C, et al., BRAVO3 Investigators. Bivalirudin versus heparin anticoagulation in transcatheter aortic valve replacement: the randomized BRAVO-3 trial. J Am Coll Cardiol 2015;66:2860–8. 11. Windecker S, Tijssen J, Giustino G, et al. Trial design: rivaroxaban for the prevention of major cardiovascular events after transcatheter aortic valve replacement: rationale and design of the GALILEO study. Am Heart J 2017;184: 81–7.
KEY WORDS access-site bleeding, aortic stenosis, bleeding, non–access-site bleeding, TAVR
VOL. 10, NO. 14, 2017
ª 2017 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 1936-8798/$36.00
PUBLISHED BY ELSEVIER
http://dx.doi.org/10.1016/j.jcin.2017.06.005
EDITORIAL COMMENT
Bleeding After Aortic Valve Replacement Matters Important Mortality Risk* George D. Dangas, MD, Roxana Mehran, MD
A
ortic valve replacement (AVR) has gained
and late bleeding events and their relation to the
prominence in clinical investigation since
vascular access site and to patient mortality. The
the development of the minimally invasive
investigators should be commended for the longitu-
transcatheter AVR (TAVR) and its increasing applica-
dinal follow-up (average 3 years, maximum 5 years)
tion. Initial research was appropriately focused on
and the
device characteristics and procedure details. Because
used. Readers, however, should be alerted to possibly
periprocedural vascular and bleeding complications
questionable ascertainment of events at such depth
were quickly recognized as quite predictive of
of time post-procedure and with only yearly contact
early mortality, methods of safely obtaining vascular
beyond the initial month.
robust standardized
clinical endpoints
access were improved, and device sizes decreased
The population appears sizeable (N ¼ 926), in
progressively. Longer-term bleeding was less dili-
mostly female (53%) and indeed very elderly (mean
gently tracked and described in most of the random-
age 82.4 years) patients. These characteristics are
ized TAVR trials, which used variable bleeding
unlike the typical population included in dose finding
definitions. Stemming from our experience in coro-
and other clinical studies of antithrombotic medical
nary interventions, the old age and comorbidities of
therapy.
patients undergoing AVR are key foundations for
TAVR (and largely AVR as well) has been consensus/
the prognostic importance of bleeding complications
experience based (2) in the absence of evidence from
in these patients.
adequately powered randomized trials. SEE PAGE 1436
The paper by Piccolo et al. (1) in this issue of JACC: Cardiovascular Interventions reports the findings of a TAVR registry in central Switzerland regarding early
Adjunct
pharmacological
therapy
after
The bleeding rates documented by Piccolo et al. (1) are astonishing: 31% of the population experienced a significant bleeding event; 24% had life-threatening or major bleeding. Eighty percent of these complications occurred within 1 month (early) and were mostly access site related. The late events (20%) were mostly non-access site related; gastrointestinal and
*Editorials published in JACC: Cardiovascular Interventions reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Interventions or the American College of Cardiology. From the Icahn School of Medicine at Mount Sinai, Mount Sinai Medical Center, New York, New York. Dr. Dangas has received teaching/lecture
pericardial bleeding were at the top of a long list of variable bleeding etiologies. Interestingly, recurrent bleeding was rare (only 6%). Most access site bleeds were minor in severity, whereas most non-access site
fees from Bayer and Janssen; and is an unpaid consultant for Bayer and
bleeds were major. Life-threatening bleeds were
Daiichi-Sankyo. Dr. Mehran has received teaching fees from Bayer and
roughly one-half of the events in both categories.
Janssen; has been a consultant for CSI, Shanghai BraccoSine Pharma,
Female sex predicted access site bleeding, whereas
Medscape, Bayer (unpaid), and Daiichi-Sankyo (unpaid); has received (institutional) consulting fees from Abbott Laboratories, American Col-
chronic kidney disease and an increased operative
lege of Cardiology, Boston Scientific, CardioKinetix, and Spectranetics; is
risk score predicted non-access site bleeding.
on the advisory board (funding paid to institution) of BMS; is on the data safety monitoring board (fees paid to institution) of Watermark Research Partners; is on the executive committee of Janssen Pharma and Osprey
Mortality (mean 3.25 years from TAVR) was very high in this population: 49% among those without a
Medical; and has equity in Claret Medical and Elixir Medical; and her
bleed, 58% in those with an access site bleed, and
spouse is a consultant for Abiomed and The Medicines Company.
73% in patients with a non-access site bleeding
1448
Dangas and Mehran
JACC: CARDIOVASCULAR INTERVENTIONS VOL. 10, NO. 14, 2017 JULY 24, 2017:1447–8
Risk of High-Risk Cases: Perception or Reality?
event! All the mortality curves appeared to be
thrombosis events appear to be associated with
continuously increasing over time, without any
transient ischemic brain attacks and have caught
obvious deflection point. Therefore, these factors
broad attention (8,9). Anticoagulation appears to be
appeared to indicate a rather constant underlying
more effective in averting and treating leaflet
risk. Furthermore, non-access site bleeding appeared
thrombosis in retrospective studies (8), which pro-
to indicate a consistent mortality risk regardless of
vide no perspective on the bleeding risks of such
its severity.
regimens if applied on a large scale. The findings of
Besides the aforementioned event ascertainment,
Piccolo et al. (1), as well as other retrospective
another limitation is the absence of extensive data
studies on bleeding risks and outcomes after TAVR
on antiplatelet or anticoagulant agent use during
(3–7), indicate that we have to be concerned of the
follow-up, and especially before and around the time
possible risks of antithrombotic therapies after
of clinical events. Medical regimen was only available
TAVR. In the absence of robust evidence-based rec-
at the time of hospital discharge, and common
ommendations, clinical practice worldwide has been
knowledge supports its frequent modification over
multifragmented and essentially personalized per
time (particularly in 3- to 5-year depth of follow-up).
doctor or institution in an attempt to theoretically
The investigators document a wide variability in the
maximize benefit and limit risks for each patient.
post-TAVR antiplatelet and anticoagulant therapy,
However, the logical answer is to proceed with a set
despite the fact that this is a single-center registry.
of prospective clinical trials (10,11) to adequately
We can therefore expect an even greater worldwide
assess the risk and benefit of adjunct pharmacology
variability of adjunct pharmacological therapy after
options in TAVR patients, with full understanding
TAVR. Again, this stems from the absence of robust
that even the age group itself may pose specific
clinical evidence in the field, precluding the devel-
challenges to their pharmacological properties and
opment of uniform, evidence-based guidance (2–5).
efficacy/side-effect profiles.
For example, although dual antiplatelet therapy is widespread, several small trials and a meta-analysis
ADDRESS
do not support a major clinical benefit and tend to
Mehran, Mount Sinai Medical Center, One Gustave L.
FOR
CORRESPONDENCE:
suggest a bleeding risk in comparison to aspirin
Levy Place, Box 1030, New York, New York 10029.
alone (6,7). At the same time, rare valve leaflet
E-mail: [email protected].
Dr.
Roxana
REFERENCES 1. Piccolo R, Pilgrim T, Franzone A, et al. Fre-
5. Abdul-Jawad Altisent O, Durand E, Muñoz-
leaflet thrombosis in surgical and transcatheter
quency, timing and impact of access-site and non– access-site bleeding on mortality among patients undergoing transcatheter aortic valve replacement. J Am Coll Cardiol Intv 2017;10:1436–46.
García AJ, et al. Warfarin and antiplatelet therapy versus warfarin alone for treating patients with atrial fibrillation undergoing transcatheter aortic valve replacement. J Am Coll Cardiol Intv 2016;9: 1706–17.
bioprosthetic aortic valves: an observational study. Lancet 2017 Mar 19 [E-pub ahead of print].
2. Nishimura RA, Otto CM, Bonow RO, et al. 2017 AHA/ACC focused update of the 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2017 Mar 10 [E-pub ahead of print]. 3. Généreux P, Cohen DJ, Mack M, et al. Incidence, predictors, and prognostic impact of late bleeding complications after transcatheter aortic valve replacement. J Am Coll Cardiol 2014;64:2605–15. 4. Généreux P, Cohen DJ, Williams MR, et al. Bleeding complications after surgical aortic valve replacement compared with transcatheter aortic valve replacement: insights from the PARTNER I trial (Placement of Aortic Transcatheter Valve). J Am Coll Cardiol 2014;63:1100–9.
6. Rodés-Cabau J, Masson JB, Welsh RC, et al. Aspirin versus aspirin plus clopidogrel as antithrombotic treatment following transcatheter aortic valve replacement with a balloon-expandable valve: the ARTE (Aspirin Versus Aspirin þ Clopidogrel Following Transcatheter Aortic Valve Implantation) randomized clinical trial. J Am Coll Cardiol Intv 2017 May 11 [E-pub ahead of print]. 7. Aryal MR, Karmacharya P, Pandit A, et al. Dual versus single antiplatelet therapy in patients undergoing transcatheter aortic valve replacement: a systematic review and meta-analysis. Heart Lung Circ 2015;24:185–92. 8. Chakravarty T, Søndergaard L, Friedman J, et al., RESOLVE, SAVORY Investigators. Subclinical
9. Dangas GD, Weitz JI, Giustino G, Makkar R, Mehran R. Prosthetic heart valve thrombosis. J Am Coll Cardiol 2016;68:2670–89. 10. Dangas GD, Lefèvre T, Kupatt C, et al., BRAVO3 Investigators. Bivalirudin versus heparin anticoagulation in transcatheter aortic valve replacement: the randomized BRAVO-3 trial. J Am Coll Cardiol 2015;66:2860–8. 11. Windecker S, Tijssen J, Giustino G, et al. Trial design: rivaroxaban for the prevention of major cardiovascular events after transcatheter aortic valve replacement: rationale and design of the GALILEO study. Am Heart J 2017;184: 81–7.
KEY WORDS access-site bleeding, aortic stenosis, bleeding, non–access-site bleeding, TAVR