PCI Complications: Bleeding, Stent Thrombosis, and Restenosis

PCI Complications: Bleeding, Stent
Thrombosis, and Restenosis
Roxana Mehran, MD
Professor of Medicine (Cardiology)
Director, Interventional Cardiovascular Research and Clinical
Trials
Mount Sinai School of Medicine
Chief Scientific Officer
Cardiovascular Research Foundation


Disclosure Statement of Financial Interest
Within the past 12 months, I or my spouse/partner have had a
financial interest/arrangement or affiliation with the organization(s)
listed below.
Affiliation/Financial Relationship

Company

• Grant/Research Support

• Sanofi/BMS, TMC-

• Consulting/ Advisory

• Astra Zeneca, Regado

Significant

Biosciences, Ortho McNeal,
Abbott Vascular

The Dilemmas
During PCI

ischemic
events

bleeding


Issues in Pharmacotherapy and PCI:

Stent Thrombosis

bleeding
Bleeding


Bleeding: The New Risk Factor


Bleeding and Mortality
Major Bleeding

Hypotension

Cessation of
ASA/Clop

Transfusion

Ischemia

Stent Thrombosis

Inflammation

Mortality

Bhatt DL. In Braunwald EB, Harrison’s
Online. 2005.


Impact of In-hospital Bleeding in ACS
34,146 Pts with ACS in the OASIS-1/2 and CURE

Major bleeding occurred in 2.3% of pts

Mortality (%)

12

12.8%

P<0.0001

10

Bleeding

8
6
4

2.5%

2
0

5

10

15

20

25

P=0.002

6

4.6%

4

Bleeding

2.9%

2

No bleeding

No bleeding

0

Landmark analysis, 1-6 mo

8

Mortality (%)

First 30 days

14

0
30

0

Days
No. at Risk
No bleeding 33376 33419 33157 32990 32879 32769 32710
Bleeding
470

459
440
430
420
410
408

Adj. HR [95%CI] = 5.37 [3.97, 7.26]
P<0.0001

30

60

90

120

150

180

Days
32634
560

32491 32161 31981 31166 30316 29238
559
554
548

533
519
489

Adj. HR [95%CI] = 1.54 [1.02, 2.36]
P=0.047
Eikelboom JW. Circulation 2006;114:774–782


Definitions of Major/Severe Bleeding
in Randomized Controlled Clinical Trials
GUST
O

TIMI
phase I

TIMI
phase
II

REPLACE2

OASIS-5
ESSENC
E

CURE

STEEPL

E

ACUITY
HORIZON
S

PLAT
O

Intracranial/intracereb
ral

+

+

+

+

+

+

+

+

+

Intraocular

-

-

-

+

+

+

+

+

+

Retroperitoneal

-

-

-

+

+

+

+

+

-

Bleeding causing
hemodynamic
compromise

+

-

-

-

-

+

+

-

+

Cardiac tamponade

-

+

+

-

-

-

-

-

+

Bleeding requiring
surgical intervention

-

-

-

-

-

+

+

+

+

Hematoma >5cm at
the puncture site

-

-

-

-

-

-

-

+

-

≥1

≥1

≥1

≥2

≥2

≥2

≥1

≥1

≥4

Decrease in Hgb with
overt bleeding, g/dL

-

≥5.0*

≥3.0

≥3.0

≥3.0

-

≥3.0

≥3.0

≥5.
0

Decrease in Hgb
without overt
bleeding, g/dL

-

-

-

≥4.0

-

≥5.
0

-

≥4.0

-

Type of bleeding

Transfusion, units

*Or decrease in Hct ≥15%


Bleeding Definitions
TIMI Major

Bleeding with >5 g/dL fall in hgb
Intracranial bleeding
Intraocular bleeding
Access site bleed requiring intervention
≥ 5 cm hematoma at puncture site
Reoperation for bleeding
Blood product transfusion

ACUITY
and HORIZONS
Major Bleeding

Hgb ⇓ ≥3g/dL with an overt source

TIMI Minor

Hgb ⇓ ≥4g/dL w/o overt source
Retroperitoneal bleeding
Gross hematuria or hematemesis
Rao AK et al. JACC 1988;11:1-11; Stone GW et al. NEJM 2006;355:2203-16


Influence of Bleeding Severity within 30 Days After PCI
on the Risk of Death Over 1 Year
Baseline covariate-adjusted time-updated Cox multivariable model
HR (95% CI)

Pvalue

Attributable
deaths
within 1 yr

TIMI major bleed

4.85 (3.56-6.60)

<0.001

53

ACUITY major (non TIMI
major) bleed with
transfusion*

2.98 (2.10-4.24)

<0.001

40

ACUITY major (non TIMI
major) bleed without
transfusion*

1.79 (1.09-2.93)

0.02

17

Hematoma ≥5 cm only

1.30 (0.58-2.92)

0.53

6

Type of Bleed

HR (95%CI)
Mehran, et al. JACC Int 2011- In-Press
* Excluding hematomas if the only criteria

Each patient is represented only once according to their most severe bleed


How Does Access Site Impact Major
Bleeding Rates in PCI Patients?
• Meta-analysis of 18 randomized trials (5 had no bleeding
events) of femoral versus radial access involving 4,458
patients undergoing angiography or PCI
Major Bleeding

Radial access reduced
major bleeding by
73%, with a trend for
reductions in the
composite of death,
MI, or stroke (2.5%
vs 3.8%, P = .058)

Jolly SS. Am Heart J 2009;157:132-40.


Percent Protocol Major Bleed

Non-CABG Major Bleeding in
PCI-Treated ACS Patients

ACUITY
30 Days

TRITON

3 Days

EARLY ACS SYNERGY
120 hours
30 Days

88%
Femoral
Access

84%
Radial
Access

OASIS 5
9 Days

ABOARD
30 Days


Sources and Incidence of Bleeding
Among 17,393 PCI Patients

5.3% (n=925)

5.2%

Non- access
site bleeds

3.3% are 61.4% of
TIMI bleeding
events
1.6%
2.1%

Access site
only accounts
for 38.6%

Verheugt JACC Cardio Interv 2011;4:191-7:


Relative Risk of 1-year Mortality Associated
with Bleeding and Source (unadjusted)
P<0.0001 for all bleeding versus none

Verheugt JACC Cardio Interv 2011;4:191-7:


Standardized Bleeding Definitions for
Cardiovascular Clinical Trials: A Consensus
Report from the Bleeding Academic
Research Consortium (BARC)
•  
Roxana Mehran, MD, Sunil V. Rao, MD, Deepak L. Bhatt, MD,
MPH, C. Michael Gibson, MS, MD, Adriano Caixeta, MD,
PhD, John Eikelboom, MD, MBBS, Sanjay Kaul, MD,
Stephen D. Wiviott, MD, Venu Menon, MD, Eugenia Nikolsky,
MD, PhD, Victor Serebruany, MD, PhD, Marco Valgimigli,

MD, PhD, Pascal Vranckx, MD, David Taggart, MD, PhD,
Joseph F. Sabik, MD, Donald E. Cutlip, MD, Mitchell W.
Krucoff, MD, E. Magnus Ohman, MD, Philippe Gabriel Steg,
MD, and Harvey White, MB ChB DSc

Circulation 2011 In-press


Discharge Medication Use in Patients who
Bleed: PREMIER Registry (STEMI)
1433 STEMI pts treated with primary stenting

P=0.001
P=0.002

P<0.001

Wang TY et. al. Circulation 2008;118:2139-2145

P=0.05


Discharge Medication Use in Patients who
Bleed: HORIZONS-AMI (STEMI)
3,345 STEMI pts in whom primary PCI was performed

P=0.12

P=0.05
P<0.0001

P<0.0001


Issues in PCI :

Stent Thrombosis

48 months
bleeding

Restenosis


Pathology

In-Stent Restenosis = Intimal Hyperplasia


Drug-Eluting Stents….
Late loss = 0

BMS

DES

DES

Giant cells

Angioscopy

BMS

48 months

Delayed Healing!
Incomplete
apposition

Late stent
thrombosis

40 mos

Eos
Inflammation

IVUS

Abn Vasomotion

*P<0.001 *vs. control

*

Sirolimus
Control


Mechanisms of DES Restenosis
•

Biological factors
Drug resistance
Hypersensitivity

•

Mechanical factors
Non uniform stent strut distribution
Stent fractures
Polymer peeling
Non uniform drug deposition

•

Technical factors
Incomplete stent expansion
Stent gaps or “misses” (uncovered lesion segments)
Barotrauma to unstented segments


DES Fractures
a

a’

Post

Follow-up
b’

b
Stent
c

c’

Restenosis

Aoki J. et al. CCI 2007;69: 380-6


Technical Factors
Stent Underexpansion


Technical Factors
Gap

Incomplete stent
coverage

Stent edge restenosis is frequently associated with local trauma
outside the stent. In-stent restenosis occurs as a localized lesion,
commonly associated with a discontinuity in stent coverage.
Lemos A. et al. Circulation 2003;
108: 257-60


Patterns of In-stent Restenosis Predict

Outcomes in the BMS Era

TLR @ 1 Year

% Frequency

282 lesions reviewed; restenosis patterns
classified by angiography and confirmed by IVUS

Mehran et al. Circulation 1999;
100:1872-1878