CATT Trial Compares AMD Drugs Bevacizumab and Ranibizumab

AJAY DUDANI
MUMBAI RETINA CENTRE
PROF K J SOMAIYA MEDICAL COLLEGE
COOL
CATT

 ‘WE KNEW THE WORLD WOULD NOT BE THE
SAME. A FEW PEOPLE LAUGHED, A FEW PEOPLE
CRIED, MOST PEOPLE WERE SILENT. I
REMEMBERED THE LINE FROM THE HINDU
SCRIPTURE, THE BHAGWAD GITA. VISHNU IS
TRYING TO PERSUADE THE PRINCE THAT HE
SHOULD DO HIS DUTY, AND TO IMPRESS HIM
TAKES ON HIS MULTIARMED FORM AND SAYS
NOW I AM BECOME DEATH, THE DESROYER OF
WORLDS. I SUPPOSE WE ALL THOUGHT THAT,
ONE WAY OR ANOTHER.’
 ROBERT OPPENHEIMER
2

TAKE HOME THE CATT
 FIRST COMPARATIVE EFFECTIVENESS STUDY
 AVASTIN vs LUCENTIS -1200 PATIENTS
 MONTHLY vs PRN
 250000 AMD ANNUALLY IN USA
 MEDICARE- 60%AVASTIN 40%LUCENTIS
 BOTH DRUGS EFFECTIVE
 AS NEEDED DOSE ALSO EFFECTIVE
 BUT MONTHLY EXAM & OCT MUST
 ADVERSE EVENTS MEDIAN AGE 80 YEARS

CONTD CATT
 DEATHS STROKE MI ETC LOW ,
 24 %IN AVASTIN 19% IN LUCENTIS
 ½ LIFE LUCENTIS SHORTER
 AVASTIN DOSE 500TIMES LESS THAN IN CANCER
 CHOICE BY PATIENT AND DOCTOR
 SYSTEMIC DISEASE,COST,PERSONAL PREF
 ECONOMY AND HEALTH POLICY
 2ND YEAR RESULTS IN MID 2012
4

The CATT trial
 Prospective, multicenter, randomized, single-blinded, 2-year trial1
 The largest ongoing head-to-head trial, enrolling around 1200 patients with
wet AMD
 The purpose of the study was to evaluate the relative efficacy and safety of
treatment of neovascular AMD with:1
 Ranibizumab (0.5 mg) on a fixed schedule (monthly dosing)
 Bevacizumab (1.25 mg) on a fixed schedule (monthly dosing)
 Ranibizumab (0.5 mg) on a variable schedule (PRN)
 Bevacizumab (1.25 mg) on a variable schedule (PRN)
 The initial 1-year results described here form the primary endpoint of
the study
 Final 2-year results are expected in early 2012
 Funded by the National Eye Institute, USA1
1. www.ClinicalTrials.gov Accessed 30 November 2010. PRN, pro re nata (as needed)
5

CATT: inclusion / exclusion criteria
Inclusion criteria:1
 Active choroidal neovascularization (CNV)
 Any component of lesion under centre of fovea
 Fibrosis < 50% of total lesion area
 Visual acuity in the range 20/25 to 20/320
Exclusion criteria:1
 Previous treatment for CNV in study eye
 Other progressive retinal disease likely to compromise visual acuity
 Contraindications to injections with ranibizumab or bevacizumab
Compared with ranibizumab trials, the upper visual acuity limit for study entry to
CATT suggested the inclusion of some patients with lesser visual impairment
(20/25 in CATT, compared with 20/40 in MARINA2, ANCHOR3 and PIER4)
1. www.ClinicalTrials.gov Accessed 30 November 2010.
2. Rosenfeld PJ, et al. N Engl J Med 2006; 355: 1419–31.
3. Brown DM, et al. Ophthalmology 2009;116:57–65 e5.
4. Regillo CD, et al. Am J Ophthalmol 2008; 145: 239–48.
6

CATT (USA) study design
One dose at the beginning then PRN, monthly follow-up
Ranibizumab
0.5 mg, mtl.
Randomized 300 patients in
each of the 4 arms
Monthly treatment
Bevacizumab
1.25 mg, PRN
Ranibizumab
0.5 mg, PRN
Bevacizumab
1.25 mg, mtl.
Ranibizumab 0.5 mg
50% to PRN
50% remain on mtl.
One dose at the beginning then PRN, monthly follow-up
Primary end point,
after 1 year
Monthly treatment
Bevacizumab 1.25 mg
2 years
50% to PRN
50% remain on mtl.
7

CATT: re-treatment criteria (for PRN groups)
 CATT protocol states, “Treatment is warranted if there are
signs of active CNV… driven by the presence or absence
of fluid (sub-retinal or intra-retinal) on OCT”
 Eyes with fluid on OCT should be treated, unless there has been
no decrease in fluid after 3 consecutive monthly injections
 If there is no fluid on OCT, but there are other signs of active CNV,
the eye should be treated
 Patients who present for a ‘non-scheduled’ visit may be treated if
they meet re-treatment criteria and at least 4 weeks has elapsed
since last injection
8

CATT: primary and secondary endpoints
 Primary endpoint:
 Mean change in visual acuity after 1 year with a
non-inferiority limit of 5 letters (ETDRS)
 Secondary endpoints:
 Number of injections
 Mean visual acuity change after 2 years
 3-line visual acuity change (15 letters on ETDRS)
 Changes in sub- and intra-retinal fluid on OCT
 Changes in lesion size on fluorescein angiography
 Systemic and ocular adverse events
 Comparison of cost of treatment
ETDRS: Early Treatment Diabetic Retinopathy Study
OCT: Optical Coherence Tomography
10

Overview
 Design, objectives and methods
 Results
 Baseline characteristics
 Efficacy
 Safety
 Conclusions
11

12
CATT is a non-inferiority trial
 A non-inferiority trial is designed to show that the experimental treatment is no less
effective than an existing treatment, by more than a pre-specified, small amount1
 This amount is known as the non-inferiority margin, or Δ
 To show non-inferiority, the 2-sided CI (99.2% in this study) should lie entirely to the right
of the value –Δ (-5 letters in this study )
 Showing non-inferiority does not necessarily mean the two treatments are equivalent,
but that the experimental treatment is not significantly worse than the comparator
1. CHMP. Guideline on the choice of the non-inferiority margin. EMA 2005.

13
 The trial design of CATT means that efficacy differences between the
two drugs are unlikely to be observed
 5 letter non-inferiority limit (i.e. –Δ)
 Unconventional PRN regimen
Potential concerns in the interpretation of
non-inferiority trials
There is a danger that if non-inferiority is observed in the head-to-
head trials, this could be misinterpreted as meaning that the efficacy
of ranibizumab and bevacizumab is the same

Baseline characteristics and comorbidities:
The groups were relatively homogeneous at baseline
Baseline characteristics and
concomitant diseases†
Ranibizumab
monthly
Bevacizumab
monthly
Ranibizumab
PRN
Bevacizumab
PRN
N 301 286 298 300
Age (mean) 79.2±7.4 80.1±7.3 78.4±7.8 79.3±7.6
Male (%) 39.2 37.1 37.9 38.7
Race – white (%) 98.7 98.3 99.3 98.0
History of myocardial infarction
(%)
11.3 14.0 10.1 12.0
History of stroke (%) 4.7 6.3 7.4 5.3
History of transient ischemic
attack (%)
4.0 8.7 4.0 6.3
† Plus-minus values are means ± SD
15

Baseline visual acuity and anatomical characteristics
Baseline characteristics† Ranibizumab
monthly
Bevacizumab
monthly
Ranibizumab
PRN
Bevacizumab
PRN
Visual acuity score, n (%)
68–82 letters 111 (36.9) 94 (32.9) 116 (38.9) 103 (34.3)
53–67 letters 98 (32.6) 118 (41.3) 108 (36.2) 119 (39.7)
38–52 letters 67 (22.3) 53 (18.5) 58 (19.5) 58 (19.3)
23–37 letters 25 (8.3) 21 (7.3) 16 (5.4) 20 (6.7)
Mean visual acuity score 60.1±14.3 60.2±13.1 61.5±13.2 60.4±13.4
Total thickness at fovea*, µm 458±184 463±196 458±193 461±175
Foveal centre involvement, n (%)
Choroidal neovascularization 176 (58.5) 153 (53.5) 176 (59.1) 183 (61.0)
Fluid 85 (28.2) 81 (28.3) 77 (25.8) 72 (24.0)
Hemorrhage 20 (6.6) 24 (8.4) 24 (8.1) 25 (8.3)
Other 18 (6.0) 20 (7.0) 15 (5.0) 18 (6.0)
No choroidal neovascularization or
not possible to grade
2 (0.7) 8 (2.8) 6 (2.0) 2 (0.7)
*Includes retina, subretinal fluid, choroidal neovascularization, and retinal pigment epithelial elevation
16

Mean number
of injections
11.7
11.9
6.9
7.7
Efficacy:
Mean change in visual acuity at 12 months
 Monthly bevacizumab was non-inferior to monthly ranibizumab (8.0-letter gain
versus 8.5-letter gain, respectively)
 PRN bevacizumab was non-inferior to PRN ranibizumab (5.9-letter gain versus
6.8-letter gain, respectively)
17
Mean
change
in
visual-acuity
score
from
baseline
(no.
of
letters)
Follow-up (week)
0
3
6
9
12
15
0 4 12 24 36 52
Ranibizumab monthly
Bevacizumab monthly
Ranibizumab PRN
Bevacizumab PRN
Mean change in
visual acuity at
Week 52 (letters)
8.5
8.0
6.8
5.9

Efficacy:
Differences between study group pairs in mean VA change at 12 months
 The comparison between PRN bevacizumab and monthly ranibizumab ( also
monthly bevacizumab) was inconclusive (failed to demonstrate non-inferiority)
 The number of injections for the PRN bevacizumab arm was 7.7 compared
to 6.9 for the ranibizumab arm (p = 0.003)
18
Bevacizumab monthly
Bevacizumab PRN
Bevacizumab PRN
Ranibizumab PRN
Bevacizumab PRN
Ranibizumab PRN
Ranibizumab monthly
Ranibizumab PRN
Ranibizumab monthly
Bevacizumab monthly
Bevacizumab monthly
Ranibizumab monthly
-5 0 5
-0.5
-3.9 2.9
-0.8
-4.1 2.4
-1.7
-4.7 1.3
-2.1
-5.7 1.6
-1.2
-4.5 2.1
-2.6
-5.9 0.8
Group 1 Group 2 Difference in mean change in visual-acuity score
(no. of letters)
Group 2 better Group 1 better

Efficacy:
Mean change in total retinal thickness at fovea at 12 months
 Mean decrease in retinal thickness (total foveal thickness) was significantly
greater in the ranibizumab monthly group compared with all other treatment
groups (p = 0.03)
19
Mean
change
in
total
thickness
at
fovea
from
baseline
(µm)
Follow-up (week)
0
50
100
150
200
Mean change in
foveal thickness
at Week 52 (µm)
-152
-164
-168
-196

Summary of 12-month CATT efficacy results
Efficacy endpoint† Ranibizumab
monthly
Bevacizumab
monthly
Ranibizumab
PRN
Bevacizumab
PRN
P value*
Mean change in visual acuity
at Month 12 versus baseline
8.5±14.1 8.0±15.8 6.8±13.1 5.9±15.7 ns
Number of injections 11.7±1.5 11.9±1.2 6.9±3.0 7.7±3.5 <0.001
≥15-letter gain in visual acuity 34.2% 31.3% 24.9% 28.0% ns
Change in total foveal
thickness (µm)
-196±176 -164±181 -168±186 -152±178 0.03
Absence of dye leakage on
angiogram no (%)
167 (58.8) 153 (57.7) 133 (46.7) 111(41.0) <0.001
Mean change in lesion area
from baseline
0.0±2.1 0.1±1.9 0.2±2.5 0.5±2.6 0.047
* P values are for the test of the hypothesis of equality among the four study groups
20

Safety (1 of 2)
Serious systemic events after 1 year
 There were more deaths among bevacizumab-treated patients (p = ns; n = 15 vs 9)
 Patients treated with bevacizumab had a higher risk of experiencing at least one serious
systemic adverse event compared with those given ranibizumab (p = 0.04; n = 141 vs 114)
21
Adverse event
Ranibizumab
monthly
(N = 301)
Bevacizumab
monthly
(N = 286)
Ranibizumab
PRN
(N = 298)
Bevacizumab
PRN
(N = 300)
Ranibizumab
total
(N = 599)
Bevacizumab
total
(N = 586)
P value
(excl. total columns)
Number of patients (percent)
Among
groups
Between
drugs
Serious systemic event
Death from any cause 4 (1.3) 4 (1.4) 5 (1.7) 11 (3.7) 9 (1.5) 15 (2.6) 0.18 0.22
Arteriothrombotic event 7 (2.3) 6 (2.1) 6 (2.0) 8 (2.7) 13 (2.2) 14 (2.4) 0.97 0.85
Nonfatal myocardial
infarction
2 (0.7) 2 (0.7) 3 (1.0) 1 (0.3) 5 (0.8) 3 (0.5) 0.78 0.73
Nonfatal stroke 3 (1.0) 2 (0.7) 1 (0.3) 2 (0.7) 4 (0.7) 4 (0.7) 0.88 1.00
Death from vascular
causes†
2 (0.7) 2 (0.7) 2 (0.7) 5 (1.7) 4 (0.7) 7 (1.2) 0.57 0.38
Venous thrombotic event 0 4 (1.4) 2 (0.7) 1 (0.3) 2 (0.3) 5 (0.9) 0.08 0.28
Transient ischemic attack 1 (0.3) 0 2 (0.7) 3 (1.0) 3 (0.5) 3 (0.5) 0.48 1.00
Hypertension 0 2 (0.7) 0 0 0 2 (0.3) 0.06 0.24
≥1 Serious systemic event 53 (17.6) 64 (22.4) 61 (20.5) 77 (25.7) 114 (19.0) 141 (24.1) 0.11 0.04
Multiple events in the same category were counted only once. MedDRA denotes Medical Dictionary for Regulatory Activities.
‡ Data are listed only for system organ classes with 20 or more events.
Table adapted from Martin, DF et al, NEJM 2011

Safety (2 of 2)
Serious systemic events and ocular events in study eye after 1 year
22
Multiple events in the same category were counted only once. MedDRA denotes Medical Dictionary for Regulatory Activities.
‡ Data are listed only for system organ classes with 20 or more events.
Adverse event
Ranibizumab
monthly
(N = 301)
Bevacizumab
monthly
(N = 286)
Ranibizumab
PRN
(N = 298)
Bevacizumab
PRN
(N = 300)
Ranibizumab
total
(N = 599)
Bevacizumab
total
(N = 586)
P value
(excl. total columns)
Number of patients (percent)
Among
groups
Between
drugs
MedDRA system
organ class‡
Cardiac disorder 10 (3.3) 16 (5.6) 12 (4.0) 13 (4.3) 22 (3.7) 29 (4.9) 0.61 0.32
Infection 6 (2.0) 11 (3.8) 12 (4.0) 18 (6.0) 18 (3.0) 29 (4.9) 0.09 0.10
Nervous system
disorder
6 (2.0) 9 (3.1) 12 (4.0) 9 (3.0) 18 (3.0) 18 (3.1) 0.54 1.00
Injury or procedural
complication
7 (2.3) 11 (3.8) 8 (2.7) 9 (3.0) 15 (2.5) 20 (3.4) 0.76 0.39
Benign or malignant
neoplasm
7 (2.3) 5 (1.7) 10 (3.4) 9 (3.0) 17 (2.8) 14 (2.4) 0.62 0.71
Surgical or medical
procedure
4 (1.3) 6 (2.1) 4 (1.3) 8 (2.7) 8 (1.3) 14 (2.4) 0.57 0.20
Gastrointestinal
disorder
3 (1.0) 6 (2.1) 2 (0.7) 9 (3.0) 5 (0.8) 15 (2.6) 0.11 0.02
Any other system
organ class
18 (6.0) 26 (9.1) 16 (5.4) 28 (9.3) 34 (5.7) 54 (9.2) 0.14 0.03
Ocular event in the
study eye
Endophthalmitis 2 (0.7) 4 (1.4) 0 0 2 (0.3) 4 (0.7) 0.03 0.45
Pseudoendophthalmitis 1 (0.3) 0 0 0 1 (0.2) 0 1.00 1.00
Table adapted from Martin, DF et al, NEJM 2011

Summary of systemic safety
23
Adverse events
Ranibizumab
monthly
(N = 301)
Bevacizumab
monthly
(N = 286)
Ranibizumab
PRN
(N = 298)
Bevacizumab
PRN
(N = 300)
Ranibizumab
total
(N = 599)
Bevacizumab
total
(N = 586)
n (%) n (%) n (%) n (%) n (%) n (%)
All Yes 235 (78.1) 232 (81.1) 238 (79.9) 251 (83.7) 473 (79.0) 483 (82.4)
No 66 (21.9) 54 (18.9) 60 (20.1) 49 (16.3) 126 (21.0) 103 (17.6)
Severity ≥ 2 Yes 141 (46.8) 152 (53.2) 154 (51.7) 171 (57.0) 295 (49.2) 323 (55.1)
No 160 (53.2) 134 (46.9) 144 (48.3) 129 (43.0) 304 (50.8) 263 (44.9)
Severity ≥ 3 Yes 59 (19.6) 64 (22.4) 64 (21.5) 81 (27.0) 123 (20.5) 145 (24.7)
No 242 (80.4) 222 (77.6) 234 (78.5) 219 (73.0) 476 (79.5) 441 (75.3)
Severity ≥ 4 Yes 10 (3.32) 13 (4.55) 11 (3.69) 20 (6.67) 21 (3.5) 33 (5.6)
No 291 (96.7) 273 (95.5) 287 (96.3) 280 (93.3) 578 (96.5) 553 (94.4)
Severity levels
1 Mild, little clinical significance
2 Moderate, causing some limitations; minimal/no intervention required
3 Severe
4 Life-threatening or disabling
5 Death

Death from any cause: differences between
study drugs
 Bevacizumab (15)
 Cerebral hemorrhage (3)
 Malignant glioma
 Hypertensive heart disease
 Cardiac arrest (2)
 Failure to thrive
 Cardio-respiratory arrest (2)
 Sepsis (2)
 Fall
 Metastatic renal cancer (2)
 Ranibizumab (9)
 Myocardial infarction (3)
 Metastatic colon cancer
 Respiratory failure
 Renal failure
 Bile duct cancer
 Ovarian cancer
 Pneumonia
24

Conclusions - Efficacy
 Monthly bevacizumab was non-inferior to monthly ranibizumab in
mean VA change from baseline to Month 12
 PRN ranibizumab was non-inferior to monthly ranibizumab in mean
VA change from baseline to Month 12
 PRN bevacizumab failed to demonstrate non-inferiority versus
ranibizumab monthly and bevacizumab monthly
 A higher number of injections were required with PRN bevacizumab
(7.7) compared to PRN ranibizumab (6.9)
 Differences in retinal thickness were significantly greater at 12 months
with ranibizumab monthly treatment compared to other
treatment groups
25

Conclusions – Safety
 In CATT, despite the relatively small patient population and not being powered to
detect differences in safety events, the following safety signals were demonstrated
when comparing bevacizumab with ranibizumab:
 A higher number of deaths (15 vs 9; p=ns)
 A significantly higher incidence of gastrointestinal disorders
 A significantly higher risk of serious systemic adverse events associated with
hospitalizations
 These data are consistent with existing evidence from clinical studies1-3 including
large Medicare analyses4,5 that indicate that the risk of all-cause mortality is higher
with bevacizumab compared to ranibizumab. In addition, these Medicare analyses
have also shown an increased risk of stroke
 These findings may be related to the differences in molecular structure and
systemic exposure when injected into the eye2,3,6-10
 The use of intravitreal bevacizumab remains unlicensed for ocular conditions11
26
1.Carneiro AM et al, Ophthalmologica 2011;225:211–221. 7. Kim H et al. Mol Vis 2009;15:2803–12.
2. Matsuyama K, et al. Br J Ophthalmol published online June 10, 2010. 8. Schraermeyer U et al. Ophthalmologe 2009;106(7):619–24.
3. Barros-Pereira R et al. Presented at ARVO, May 2011. 9. Bakri SJ et al. Ophthalmology 2007;114(5):855–9.
4. Curtis LH et al. Arch Ophthalmol 2010;128:1273–9. 10.Bakri SJ et al. Ophthalmology 2007;114(12):2179–82.
5. Gower EW et al Presented at ARVO, May 2011. 11. Hoffman-La Roche Ltd. Avastin SmPC. Mar 2009.
6. Ferrara N et al. Retina 2006;26:859–70.

Conclusions
CATT not powered for safety:
 “A National Eye Institute–sponsored comparative trial of the efficacy
of ranibizumab and bevacizumab will randomly assign 1200 patients
with newly diagnosed age-related macular degeneration to 1 of 4
treatment groups (2 bevacizumab regimens and 2 ranibizumab
regimens).38 Given the baseline risks of thromboembolic events in
this population, the sample size needed to detect even a 50%
relative increase in risk (from 2.0% to 3.0%) would be at least an
order of magnitude larger than the trial protocol dictates. As
designed, the trial will not adequately assess the relative safety of
the 2 therapies.”
27
Curtis LH et al. Arch Ophthalmol 2010;128:1273–9

Serum levels of bevacizumab and ranibizumab
0.1
32
0.01
1
10
100
1000
0.1
0.01
1
10
100
Concentration,
µg/ml
Time, days
Aqueous humour Serum
Vitreous humour
Duration of bevacizumab detection in
the eye and in serum1
Duration of ranibizumab detection
in the eye2
 Following intravitreal administration in a rabbit model, peak bevacizumab
concentration in the serum was measured on Day 8
 No ranibizumab was detected in the serum following intravitreal injection
1. Bakri S et al. Ophthalmology 2007;114:855–9
2. Bakri S et al. Ophthalmology 2007;114:2179–82
0 8 16 24
No ranibizumab
detected in the serum*
0 8 16 24 32
1000
*Assay detection limit: 0.0625 ng/ml
28

Pharmacokinetics of ranibizumab and bevacizumab
differ particularly with regards to systemic exposure
 Relatively small difference in vitreous half life compared to systemic exposure
in rabbit model1,2
 The effects of bevacizumab are not confined to the injected eye3
 Bevacizumab has the potential to inhibit plasma VEGF for approximately
20 days in comparison with approximately 2 hours with ranibizumab4,5
 Bevacizumab may enter the systemic circulation more quickly when injected
into eyes with choroidal neovascularization compared to those without6
1. Bakri SJ et al. Ophthalmology 2007;114:2179–82
2. Bakri SJ et al. Ophthalmology 2007;114:855–9
3. Miki K et al. Ophthalmology 2009;116:1748–54
4. Gordon MS et al. J Clin Oncol 2001;19:843–50
Vitreous
Cmax
Vitreous
half life
Serum
Cmax
Serum
half life
Ranibizumab
Monocular intravitreal
injection of 0.5 mg
in rabbits
162 µg/mL 2.88 days 0 N/A
Bevacizumab
Monocular intravitreal
injection of 1.25 mg
in rabbits
400 µg/mL 4.32 days 3.3 µg/mL 6.86 days
5. www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Scientific_Discussion/human/000715/WC500043550.pdf.
6. Kim H et al. Mol Vision 2009; 15:2803-12
7. Genentech. Avastin prescribing information, 2004 29

Risk of hypertension with intravitreal bevacizumab
Plasma levels of VEGF before and after intravitreal bevacizumab (n = 11)
Rasier R et al. Eye 2009;23:1714–8
*Patients who had hypertension and were under medication with anti-hypertensive drugs
P-values: change in blood pressure vs. baseline
Systolic blood pressure in patients with AMD
receiving intravitreal bevacizumab
110
115
120
125
130
135
140
145
150
Hypertensive* (n = 42)
Normotensive (n = 40)
Baseline Day 1 Week 1 Week 3 Week 6
p = 0.001
p < 0.001
p < 0.003
p = 0.004
Systolic
blood
pressure,
mmHg
(mean
±
SD)
30

Inhibition of systemic VEGF with bevacizumab
 In 11 patients with diabetic retinopathy, treatment with intravitreal bevacizumab
resulted in significantly decreased VEGF plasma levels1
• A single injection of 1.25 mg significantly reduced plasma VEGF levels from
1 day up to at least 30 days (114 pg/ml before treatment to 25 pg/ml at 30 days)
• This reduction in plasma VEGF is comparable to that seen with intravenous
bevacizumab in cancer patients (157 pg/ml to 45 pg/ml at 14 days)2
1. Matsuyama K, et al. Br J Ophthalmol published online June 10, 2010
2. Loupakis et al. J Clin Oncol 2007;25:1816–8
0
100
200
300
Concentrations
of
immunoreactive
VEGF
(pg/mL)
Before 1 day 1 week 1 month
Individual VEGF
concentration
Mean VEGF
concentration
p < 0.001
Plasma levels of VEGF before and after intravitreal bevacizumab (n = 11)
31

Carneiro et al:
Arterial Thromboembolic Events in Patients with Exudative Age-Related Macula
Degeneration Treated with Intravitreal Bevacizumab or Ranibizumab
Study objectives
 To determine and compare the incidence of ATEs in patients with wet AMD treated with
intravitreal injections of bevacizumab or ranibizumab)
 To evaluate whether bevacizumab administration constitutes a higher risk for ATE as
compared to ranibizumab administration
Study design:
 Retrospective, non randomized, comparative, interventional study
 Single- centre:Department of Ophthalmology, Hospital São João, Portugal
 Treatment regimen: as-needed strategy (PRN) of treatment and follow up visits in 4 weekly
intervals
Wet AMD
378 patients*
Ranibizumab group
219 patients
*Patients that received both drugs for the treatments (n=56/15%) were excluded for the study, as well as patients
that died due to cancer (n=4) and patients with congestive heart failure (n=2)
Bevacizumab group
97 patients
Carneiro AM et al, Ophthalmologica 2011;225:211–221 32

Primary analysis – ATE incidence rate
10.16 increased risk of ATEs with bevacizumab over ranibizumab
 Statistically significant difference of ATE incidence rate between bevacizumab
and ranibizumab treatment group
* Fisher’s exact test p < 0.0001. OR = 10.16; 95% CI = 2.80–36.93.
Bevacizumab
(n=97)
Ranibizumab
(n=219)
P value
Total nr of ATEs 12 (12.4%) 3 (1.4%) p < 0.0001*
MI 2 (2.1%) 1 (0.5%)
Stroke 4 (4.1%) 2 (0.9%)
Lethal stroke 2 (2.1%) 0 (0%)
Sudden death 1 (1.0%) 0 (0%)
Peripheral ATE 1 (1.0%) 0 (0%)
TIA 1 (1.0%) 0 (0%)
Unstable angina 1 (1.0%) 0 (0%)

Conclusions
 The findings could suggest that the occurrence of new
ATEs is more frequent in the patients treated with
bevacizumab than in those treated with ranibizumab
 The present study has several limitations (mainly due to its
retrospective nature, the relatively small number of patients
as well as the lack of randomization).
 Prospective randomised trials with large sample sizes to
reduce CIs will have to further investigate the findings.

Curtis et al. Arch Ophthalmol 2010 methodology:
Primary comparative analysis between groups
Pegaptanib
group
36,942 patients
Bevacizumab
group
38,718 patients
Participants
Photodynamic
control group
52,256 patients
Ranibizumab
group
19,026 patients
 Research-identifiable claim files and associated denominator files from
the Centers for Medicare & Medicaid Services for all Medicare
beneficiaries from January 1, 2004, through December 31, 2007
 Beneficiaries aged 65 years or older who were living in the United States
and who had any claim with a diagnosis of AMD
 4 adverse events were examined: all-cause mortality, incident
myocardial infarction, bleeding, and incident stroke
35
Wet AMD
146,942 patients

Methodology:
The groups were relatively homogeneous, with a slight trend in the
ranibizumab groups for less healthy patients
Baseline characteristics
and concomitant diseases
Photodynamic
therapy
Pegaptanib Bevacizumab Ranibizumab
N 52,256 36,942 38,718 19,026
Age (median) 81.0 81.0 81.0 82.0
Male (%) 36.1 35.5 36.4 35.5
Co-morbid conditions (%)
Cancer 15.9 16.2 15.6 16.9
Cerebrovascular disease 17.5 17.8 17.7 18.8
COPD 26.1 26.0 25.1 25.2
Congestive heart failure 15.3 15.5 15.3 14.9
Coronary heart disease 34.2 34.6 33.3 34.5
Dementia 2.9 2.9 2.9 3.2
Diabetes mellitus 24.5 25.1 26.8 25.1
Hypertension 74.0 74.8 74.8 76.1
Peptic ulcer disease 2.2 2.1 2.0 2.1
Peripheral arterial disease 7.1 7.5 7.5 8.0
Peripheral vascular disease 19.4 19.8 20.2 20.7
Renal disease 5.0 5.6 7.1 7.0 36

Adjusted results – adverse events at 1 Year
Significantly lower hazard of mortality and MIs with ranibizumab
 Significantly lower hazard of mortality with ranibizumab vs PDT or pegaptanib
 Significantly lower hazard of myocardial infarction with ranibizumab vs PDT
 No significant differences between bevacizumab vs other treatments
Number of ATEs % (n)
HR (99% CI)
Pegaptanib Bevacizumab Ranibizumab P
Mortality <0.001
Photodynamic therapy 1.01 (0.91–1.12) 0.94 (0.86–1.04) 0.85 (0.75–0.95)
Pegaptanib 0.93 (0.84–1.04) 0.84 (0.74–0.95)
Bevacizumab 0.90 (0.79–1.02)
Myocardial infarction 0.005
Pegaptanib 0.95 (0.78–1.16) 0.80 (0.62–1.02)
Bevacizumab 0.84 (0.66–1.06)
Bleeding 0.14
Photodynamic therapy 1.01 (0.92–1.10) 0.94 (0.86–1.02) 0.97 (0.88–1.07
Pegaptanib 0.93 (0.85–1.02) 0.96 (0.86–1.07)
Bevacizumab 1.03 (0.93–1.15)
Stroke 0.02
Pegaptanib 1.07 (0.91–1.25) 0.87 (0.72–1.05)
Bevacizumab 0.81 (0.68–0.98)
37

Methodology:
Secondary comparative analysis between bevacizumab
and ranibizumab
Bevacizumab
group
21,815 patients
Participants
Ranibizumab
group
19,026 patients
 Objective of secondary analysis: to compare hazard ratio of ranibizumab versus
bevacizumab
 Study population limited to newly-treated patients who received bevacizumab
or ranibizumab from July through December 2006
38
Wet AMD
40,841 patients

Secondary Medicare analysis shows significant
differences in risk of death and stroke
 Secondary analysis from retrospective Medicare claims analysis shows
significantly increased risk of stroke (28%) and all-cause mortality
(16%) with bevacizumab compared with ranibizumab1
Adverse event No. of events/ No.
(%) of patients
who received
ranibizumab
No. of events/ no.
(%) of patients
who received
bevacizumab
Unadjusted HR
(95% CI)
Adjusted HR
(95% CI)
July-December 2006
Death 647/19026 (4.1) 833/21815 (4.7) 0.87 (0.76–0.99) 0.86 (0.75–0.98)
Myocardial
infarction
170/19026 (1.1) 227/21815 (1.3) 0.84 (0.64–1.08) 0.83 (0.64–1.08)
Stroke 289/19026 (1.8) 405/21815 (2.2) 0.80 (0.65–0.97) 0.78 (0.64–0.96)
“After adjustment for patient characteristics, we observed
significantly lower hazards of all-cause mortality… and stroke
with ranibizumab compared with bevacizumab.”
1. Curtis LH et al. Arch Ophthalmol 2010;128:1273–9
39

Results – Secondary analysis hazard ratios at 1 Year
Hazard ratio of mortality and stroke significantly lower with ranibizumab
than with bevacizumab
 The hazard ratios of 0.78 and 0.86 seen with ranibizumab versus bevacizumab correspond to
a 22% (0.78 - 1) and 14% (0.86 - 1) reduction of risk with ranibizumab versus bevacizumab
 These data can also be expressed in terms of increased risk with bevacizumab,
corresponding to a 28% statistically significant increased risk of stroke for bevacizumab
(1/0.78 - 1) and a 16% increased risk of mortality (1/0.86 - 1)
Risk of death, myocardial infarction, bleeding and stroke
with bevacizumab versus ranibizumab
40
Increased risks of death, myocardial infarction
and stroke with Avastin® versus Lucentis®
Adjusted outcomes at 1 year for the comparison of Lucentis® and Avastin®
0.86 (0.75–0.98)
0.83 (0.64–1.08)
1.03 (0.92–1.16)
0.78 (0.64–0.96)
Fewer events with ranibizumab More events with ranibizumab
*Adjusted outcomes at 1 year for the comparison of ranibizumab and bevacizumab

Gower (JHU) et al, ARVO 2011:
Adverse Event Rates Following Intravitreal Injection of Avastin or Lucentis for
Treating Age-Related Macular Degeneration
Background:
 Intravitreal injections (IVT) of Bevacizumab (off-label) and Ranibizumab are
used to treat neovascular age-related macular degeneration (AMD).
However, the safety of Bevacizumab used for IVT has not been fully
established.
 Current clinical trials of Bevacizumab versus Ranibizumab for AMD are not
powered to evaluate some infrequent but important safety outcomes.
Study Objective:
 This Medicare claims database analysis compares the relative safety of
Ranibizumab and Bevacizumab for treating neovascular AMD.
Gower EW, Cassard C, Chu L, Varma R, Klein R.
Presented at the Association for Research in Vision and Ophthalmology (ARVO) Annual Meeting, May 2011
41

Methods
 Medicare claims data were obtained for all beneficiaries with 1+ neovascular
AMD claim between 2005-2009. Bevacizumab & Ranibizumab treatment were
defined based on their respective drug codes paired with an IVT.
 Beneficiaries receiving more than one treatment type were excluded.
 To allow for equal follow up time, the primary analysis was limited to
beneficiaries initiating treatment in 2008-9.
 The primary analysis cohort includes 77,886 beneficiaries (46%Ran).
 Propensity scores were used to help balance the groups on baseline
characteristics.
 Systemic and ocular event rates were calculated.
 Hazard ratios (HR) comparing Bevacizumab with Ranibizumab were calculated
using Cox proportional hazard models.
 HRs adjusted for baseline comorbidities, demographics and socio-economic
status proxies
42

The results from the primary statistical analysis after adjustment
for baseline demographics, comorbid conditions and socio-
economic status are the following:
 The risk of mortality was 11% higher with Avastin than with Lucentis
(HR: 1.11; 99% CI: 1.01–1.23)
 The risk of hemorrhagic stroke was 57% higher with Avastin than with Lucentis
(HR: 1.57; 99% CI: 1.04–2.37)
 The risk of ocular inflammation was 80% higher with Avastin than with Lucentis
(HR: 1.8; 99% CI: 1.2–2.8)
 There were no statistically significant differences in risk of myocardial infarction or
ischemic stroke between the two treatments
 Patients treated with Avastin were 11% more likely to have cataract surgery following
AMD treatment (HR: 1.11; 99% CI: 1.01–1.23)
 Patients treated with Avastin were 19% less likely to have newly diagnosed ocular
hypertension/glaucoma (HR 0.81; 99% CI: 0.71–0.93)
 Differences in overall mortality and hemorrhagic stroke were attenuated in secondary
analyses that included use of Avastin or Lucentis based on unclassified drug codes and
data back to 2006.
43

Gower et al Medicare Analysis conclusions
 Data suggest differences in the safety profile of Lucentis and Avastin
 However, this study is limited by incomplete information on some
important confounding factors, e.g., smoking, lipid and blood pressure
levels, which would further clarify the relative safety of these treatments
in wet AMD
44

Bevacizumab is intended for intravenous administration and
is not required to meet standards for ophthalmic solutions
 Manufacturing standards for intravenous drug formulations permit a
higher concentration of particulate matter than ophthalmic formulations
Particulate matter may cause irritation and inflammation if injected into
the eye
 Requirements for particle counts in ophthalmic solutions are clearly
defined in US Pharmacopoeia
• USP chapter 789 limits for ophthalmic products: maximum of 50
particles of ≥10 μm permitted in a volume of 1 mL1
• USP chapter 788 limits for intravenous medications: maximum of
3000 particles of ≥10 μm per container (up to 100 mL)2
1. USP 28/NF 23, Chapter <788> "Particulate Matter in Injections". United States Pharmacopeial Convention, Inc. Rockville, MD 2005.
2. USP 28/NF 23, Chapter <789> "Particulate Matter in Ophthalmic Solutions". United States Pharmacopeial Convention, Inc. Rockville, MD 2005.
45

American Society of Hospital Pharmacists
Guidelines1
 ‘The sterility of [ophthalmic] products, as well as accuracy in the
calculation and preparation of doses, is of great importance’
 ‘In practice, serious errors in technique have occurred in the
preparation of intravitreal solutions’
 ‘To ensure adequate stability, uniformity and sterility, ophthalmic
products from licensed manufacturers should be used whenever
possible’
1. ASHP. Am J Hosp Pharm 1993;50:1462–3
46

UK Royal College of Ophthalmologists guidance1
 ‘The College does not recommend the routine use of intravitreal
bevacizumab for choroidal neovascularisation over anti-VEGFs
already licensed for that indication’
 ‘It is now obvious that large randomized control trials are required to
determine the safety, efficacy and optimal dosing of intravitreal
bevacizumab’
 ‘Ranibizumab is currently considered the gold standard in the
treatment of CNV secondary to wet AMD’
1. The Royal College of Ophthalmologists. The use of bevacizumab (Avastin) in AMD. 2009
47

1. General Medical Council. Good Practice in Prescribing Medicines. http://www.gmc-uk.org/guidance/current/library/prescriptions_
faqs.asp#5d. (accessed Oct 2009)
General Medical Council guidelines1
 When prescribing a medicine for use outside the terms of its
license, physicians must be satisfied that:
 It would better serve the patient's needs than an appropriately
licensed alternative
 There is a sufficient evidence base and/or experience of using
the medicine to demonstrate its safety and efficacy
 Patients receive sufficient information about the proposed
treatment, including any known serious or common side-effects
or adverse reactions
48

Diagnostic and Treatment Dilemmas
in RAP -6YR FOLLOW UP
Dr. Ajay Dudani

Definition
 Yannuzzi et al. coined the term retinal angiomatous
proliferation (RAP) to describe a variant of neovascular
age-related macular degeneration (NV-AMD) with a
presumed retinal origin1
 Retinal angiomatous proliferation (RAP) is a distinct
form of choroidal neovascularization which may
complicate a wet age related macular degeneration
(AMD)2
1. Retina 2001;21:416e34; 2. Curr Drug Targets. 2011 Feb;12(2):199

RAP Features
RAP is associated with
 Proliferation of retinal capillaries
 Intraretinal neovascularisation (IRN)
 Surrounding telangiectatic response
Clinical manifestations include
 Pre- and intraretinal haemorrhages
 Exudates
 Intraretinal oedema
 serous detachment of the pigment epithelium
Br J Ophthalmol. 2010;94:672-67

Clinical Classification of RAP
 Stage I - Intraretinal neovascularization (IRN):
describes the capillary proliferation within the retina that
originates from the deep capillary plexus in the
paramacular region. This stage is often accompanied by
intraretinal hemorrhages and edema.

Retinal angiomatous proliferation (RAP) Stage I:
intraretinal neovascularization

Some More Images
A,
Fluorescein angiogram of an
RAP stage I lesion. Note that
intraretinal
neovascularization
(IRN) is bordered by
telangiectatic vessels.
B,
Magnified image of the RAP
lesion.
C,
Indocyanine green
angiogram
showing a “hot spot.”
D,
Ophthalmic coherence
tomogram of the same case
shows reflectance and
shadowing by the IRN.
Retina. 2008 Mar;28(3):375-84

Stage II
 Stage II consists of sub retinal neovascularization
(SRN) that occurs when the IRN extends posteriorly,
beyond the photoreceptor layer of the retina into the
subretinal space. A localized, neurosensory retinal
detachment develops with increasing intraretinal
edema, intraretinal and preretinal hemorrhages, as well
as an associated serous pigment epithelial detachment
(serous-PED)

RAP Stage II: subretinal neovascularization
with a retinal-retinal anastomosis.

Some More Images
A: Fluorescein angiogram
of type 3 neovascularization
stage II with serous pigment
epithelial detachment
(PED). Hyper-fluorescence
of the PED (arrows)
corresponds to the RAP
lesion.
B: Indocyanine green
angiogram demonstrates
the “hot spot,” whereas the
serous PED is
hypofluorescent and
optically clear.
C: Ophthalmic coherence tomogram (OCT) shows cystic change in the
retina,
the intraretinal RAP lesion (arrow), and the serous PED.
D: Fluorescein angiogram of type 3 neovascularization stage II with
serous PED.
E: OCT reveals the intraretinal neovascularization and a possible
Retina. 2008 Mar;28(3):375-84

Stage III
 Stage III describes choroidal neovascularization seen
clinically and angiographically, sometimes in
association with a vascularized pigment epithelial
detachment (vascularized-PED) . During the evolution
of this vascularized process, an axonal communication
between the retinal and choroidal circulation forms a
retinal-choroidal anastomosis (RCA)

RAP Stage III: Choroidal neovascularization with a
vascularized pigment epithelial detachment and a
retinal-retinal anastomosis.

Some More Images
A: Indocyanine green angiogram shows communication among
intraretinal, subretinal, and choroidal neovascularization (retinal–
choroidal anastomosis [RCA]).
B: Optical coherence tomography shows the cascading
neovascularization
process with an RCA. Retina. 2008 Mar;28(3):375-84

History
 81year old male
 Strong family history of AMD
 LE – Diagnosed with AMD 8 years ago, Underwent 2
TTT’s, 3 PDT’s with IVTA, now has macular scar with
Vn of HM
 RE – Has had 1 PDT (Nov 2005) for extra foveal RAP
lesion and 25 injections of Lucentis in the past 7 years.

Fundus Photos before injections
(sep 2005)

PDT (sep 05)
 Underwent PDT for RAP lesion
 2 months later OCT (nov 05)

Monthly OCT’s
 Underwent
monthly OCT’s
and had fluid in
OCT after 6
months. (may 06)

ICG (early) at this time (may 06)

ICG (mid) at this time (may 06)

ICG (late) at this time (may 06)

Lucentis started (may 06)
 Underwent 3
injections of lucentis
at 2 monthly
intervals
 Then had monthly
OCT’s with no fluid
and maintaining
vision of 6/9 N5 for
the next 8 months
POST INJECTION OCT

OCT 8 months after 3 consecutive lucentis
injections (may 2007)

Lucentis
 Undergoing monthly OCT’s since 3 years now
 Since May 2007, fluid appears on OCT every 3 months.
FFA every year. There is no change in vision / or
metamorphopsia.
 Has received Lucentis every 3 months since May 2007.

Lucentis Protocol followed
 Initially 3 injections at 2 month intervals
 Monitored with monthly OCTs – Fluid was noted 8
months later – Injection given.
 Underwent cataract surgery under cover of Lucentis
injection – 1 week before and 2 more injections,
monthly, after surgery.
 Further monitored on monthly basis and has developed
fluid consistently every 3 months warranting an
injection.

RECENT OCTs
(2008- till date)
 OCT (Sep 08) : Fluid
with thickening always in same
area- infero – nasal extra foveal
region.
 Vision 6/9
 No metamorphopsia Lucentis
given

OCT (Oct 08):
 Post injection-
no fluid / no thickening

OCT (Dec 08)
 3 months post
injection-
Infero-nasal extra foveal
thickening.
No fluid.
FFA done.
Vision 6/9
No metamorphopsia
LUCENTIS GIVEN

OCT – Jan 09
 No fluid
No Thickening
Vision 6/9
 Needed injection again in
march 09

March 09 to
May 09
 Injection lucentis
every 3 months
 There is infero-
nasal thickening in
para foveal region
just prior to fluid
appearing

On May 09
 Vision: RE 6/9, N5
LE HM
reduced contrast vision
 Bilateral pseudophakia
 RE: Confluent drusen with RPE atrophy
 LE: Extensive macular scar with serous elevation.
 We now inject 2 weeks prior to 3 months and then
extend so that we inject just before the fluid
appears

Lucentis Protocol followed (RE)
 Initially 3 injections at 2 month intervals
 Monitored with monthly OCTs – Fluid was noted 8
months later – Injection given.
 Underwent cataract surgery under cover of Lucentis
injection – 1 week before and 2 more injections,
monthly, after surgery.
 Further monitored on monthly basis and has developed
fluid consistently every 3 months warranting an
injection.
 Treat and extend

Fundus Photos before injections (sep
2005)

Serial angiography
Sep
2005
(FFA)
May 2006
(ICG)
Oct
2008
(FFA)

Serial OCTs
Sep 05 – PDT
done
May 06 – post lucentis
– 3 injections at 2
monthly intervals
May 06 – fluid 6
months later –
Lucentis started

Serial OCTs
May 07 – Fluid 8 months
after last injection –
needed injection every 3
months since..
Jan 09 – eg of OCT post
injection
March 09 – fluid in
3 months –
Thickening of
same parafoveal
area every 3
months

Serial SLO photos
Aug 2010
Mar 2009
Sep 2008
May 2011

Discussion
 RPE atrophy progressed in last 4 years
 Reduced contrast vision
 Protocol:
 Judicial use of Lucentis
 Extend the interval between injections based on fluid
on OCT.

Yannuzzi’s Opinion
 Complimented on accurate diagnosis
 The Retinal Angiomatous Proliferation which was on the
nasal side of the fovea in the left eye soon became
associated with pigment epithelial detachment.
 Macula is flat, but there is regressed and consolidated
neovascularization
 Only a few intraretinal cystic changes are present

 The primary concern is well known and manifested in the
paramacular region with globular atrophy.
 For some reason, this particular variant of
neovascular age-related macular degeneration becomes
associated with a virulent type of progressive atrophy.
 Cause of the above is not known clearly
 According to Dr. K. Bailey Freund and me (Yannuzzi)
atrophic progression can be beyond insidious in nature
 I do not believe that is associated with the
injections, but certainly we don’t have absolute information
regarding that.

 With an acuity of 20/25+, medication interval at 3
months should be used on experiencing recurrent
exudation for a shorter period.
 Maintenance of your systemic blood pressure,
avoidance of chronic exposure to the sun and smoking,
and supplemental anti-oxidant medications would be
supportive measures within the group.
 There is no evidence regarding the Lutein, but Omega 3
and of course the standard anti-oxidants are rational
supplemental medications.

CATT Trial Compares AMD Drugs Bevacizumab and Ranibizumab

CATT Trial Compares AMD Drugs Bevacizumab and Ranibizumab

Recommended

Recommended

More Related Content

What's hot

What's hot (20)

Similar to CATT Trial Compares AMD Drugs Bevacizumab and Ranibizumab

Similar to CATT Trial Compares AMD Drugs Bevacizumab and Ranibizumab (20)

More from AjayDudani1

More from AjayDudani1 (20)

Recently uploaded

Recently uploaded (20)

CATT Trial Compares AMD Drugs Bevacizumab and Ranibizumab