Transcript document

Best-Corrected Visual Acuity Following
Treatment With Twice-Daily, PreservativeFree Ketorolac 0.45% in Patients
Undergoing Cataract Surgery
Eric Donnenfeld, MD1; Louis D. Nichamin, MD2; David R. Hardten, MD3; Michael B.
Raizman, MD4; William Trattler, MD5; Rajesh K. Rajpal, MD6; Rhett M. Schiffman, MD,
MS, MHSA7
1Ophthalmic
Consultants of Long Island, Rockville Centre, NY; 2Laurel Eye Clinic,
Brookville, PA; 3Minnesota Eye Consultants, Minneapolis, MN; 4Ophthalmic
Consultants of Boston, Boston, MA; 5Center For Excellence in Eye Care, Miami, FL;
6Cornea Consultants, McLean, VA; 7Allergan Inc., Irvine, CA
Financial Disclosures
This study was funded by Allergan, Inc., Irvine, CA.
Drs. E Donnenfeld, LD Nichamin, DR Hardten, MB Raizman, W Trattler, and RK Rajpal are
consultants to Allergan, Inc.
1
Dr. RM Schiffman is an employee of Allergan, Inc.
INTRODUCTION
• With advances in cataract surgery techniques, patients’ expectations have been
elevated to anticipate excellent vision and little or no pain during and after
surgery.1
• Nonsteroidal anti-inflammatory drugs (NSAIDs) are used to alleviate ocular
inflammation and pain after cataract surgery.2
• Ophthalmic ketorolac 0.45% solution (Acuvail®; Allergan, Inc.; Irvine, CA) is a
new formulation of ketorolac that was developed to preserve the efficacy of prior
formulations while enhancing tolerability coupled with a less frequent dosing
regimen.3
– Key formulation modifications are inclusion of carboxymethylcellulose (CMC),
exclusion of preservatives/surfactants/chelating agents, and a decrease in pH from
7.4 to 6.8.4
– The combination of CMC and lower pH results in approximately 2- to 3-fold higher
ketorolac bioavailability to ocular tissues.4
• In this study, the efficacy and safety of twice-daily, preservative-free ketorolac
0.45% for improving recovery of visual acuity and treating pain and inflammation
were evaluated in patients undergoing cataract surgery.
2
• Study design
METHODS
– Two randomized (2:1 ratio), multicenter, double-masked, vehicle-controlled trials.
– Primary eligibility criterion was uncomplicated, extracapsular phacoemulsification with
posterior-chamber IOL implantation.
– Patients received ketorolac 0.45% BID or vehicle BID starting 1 day before surgery
and continuing to 14 days after surgery.
• Outcomes
– Percentage of patients with ≥ + 3-line improvement in best-corrected visual acuity
(BCVA) from baseline
– Percentage of patients with summed ocular inflammation score (SOIS) of 0 for
anterior chamber cell and flare on day 14
– Percentage of patients with no pain 24 hours after surgery
Anterior Chamber Cell
Cell Count
Score
0
0
1-5
+0.5
6-15
+1
16-25
+2
26-50
+3
> 50
+4
3
Anterior Chamber Flare
Flare
Score
None
0
Faint
+1
Moderate
+2
Marked
+3
Intense
+4
SOIS = 0
• Outcomes were evaluated on postoperative days 1, 3, 7, and 14.
• Data from the 2 clinical trials were pooled for the purpose of this presentation,
and between-group differences were analyzed with a 2-sided Pearson
chi-square, Fisher exact test, or Wilcoxon test.
Percentage of Patients With ≥ + 3-Line
Improvement in BCVA from Baseline
RESULTS: Percentage of Patients With ≥ 3-Line
Improvement in BCVA From Baselinea
Ketorolac 0.45% (n = 301 to 315)
Vehicle (n = 116 to 155)
a Screening
60.5
50.3
54.4
c
b
day.
bP
= .003.
c P = .002.
37.1
38.1
1
41.1
3
39.1
7
Days After Cataract Surgery
44.0
14
• At baseline, the median BCVA was 20/40 in the ketorolac 0.45% group and 20/50 in the vehicle
group (P = .321).
• A significantly higher percentage of patients treated with ketorolac 0.45% than those treated with
vehicle had ≥ 3-lines of improvement from baseline at days 7 and 14.
4
• The overall incidence of corneal edema, corneal abrasion, corneal striae, corneal disorder, and
macular edema was 5.2% (17/330) in the ketorolac group and 8.6% (14/163) in the vehicle group
Note:(P
Ketorolac
0.45% is FDA-approved for control of inflammation and pain after cataract surgery. Improving visual acuity is an off-label use.
= .139)
RESULTS: Postcataract Inflammation
Percentage of Patients With SOIS = 0
SOIS = 0 During Study
aP
< .001.
= 317 for
the ketorolac
group.
Ketorolac 0.45% (n = 318)
Vehicle (n = 155)
bn
52.5
32.1
a
a
26.5
13.2
16.8
4.7
5.8
1b
11.0
3
7
Days After Cataract Surgery
14
• A significantly higher percentage of patients treated with ketorolac 0.45% than
those treated with vehicle had complete clearance of inflammation at days 7
and 14.
5
RESULTS: Postcataract Pain
Percentage of Patients With No Pain
Pain Score = 0 on Day 1
72.4a
aP
< .001.
39.7
Vehicle
(n = 156)
Ketorolac 0.45%
(n = 322)
• A significantly higher percentage of patients treated with ketorolac 0.45% than
those treated with vehicle had no pain 24 hours after surgery.
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RESULTS: Additional Efficacy Outcomes
• The median time to postoperative ocular pain resolution was significantly
shorter in patients treated with ketorolac 0.45% compared to those treated
with vehicle (1.0 day vs 2.0 days; P < .001).
• A significantly higher percentage of ketorolac patients than vehicle patients
completed the study without requiring additional medication for inflammation
or pain (81.2% vs 57.1%; P < .001).
• The rate of treatment failure was significantly higher in patients treated with
vehicle compared to those treated with ketorolac 0.45% on days 3 (29.3
versus 16.4; P = .001), 7 (29.6 vs 14.1; P < .001), and 14 (26.6 vs 12.7; P =
.001).
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RESULTS: Adverse Events With Incidence of ≥ 5%
Adverse Event
Vehicle
(n = 163)
Ketorolac 0.45%
(n = 330)
P
value
All, n (%)
79 (48.5)
116 (35.2)
.004
Increased IOP
3 (1.8)
19 (5.8)
.048
Anterior chamber cell
10 (6.1)
17 (5.2)
NS
Conjunctival hyperemia
23 (14.1)
15 (4.5)
< .001
Eye pain
25 (15.3)
14 (4.2)
< .001
Photophobia
16 (9.8)
3 (0.9)
< .001
Iritis
12 (7.4)
14 (4.2)
NS
Corneal edema
10 (6.1)
11 (3.3)
NS
Foreign-body sensation
9 (5.5)
11 (3.3)
NS
IOP = intraocular pressure; NS = not significant.
• The incidence of IOP elevation in the ketorolac group is consistent with the potential for
cataract surgery to raise IOP in the early postoperative period. 5
• The lower rate of IOP elevation in the vehicle group may reflect a higher degree of intraocular
inflammation combined with an inability to manifest a more typical increase in IOP following
cataract surgery.
• Burning/stinging was reported by 1 (0.6%) vehicle patient and 5 (1.5%) ketorolac patients. a
The between-group difference was not statistically significant.
a
8
Based on composite MedDRA terms consisting of “burning sensation in eye,” “instillation-site
burning,” or “eyes stinging.
RESULTS: Treatment-Related Adverse Events
With Incidence of ≥ 1%
Adverse Event
Vehicle
(n = 163)
Ketorolac 0.45%
(n = 330)
P
value
All, n (%)
23 (14.1)
19 (5.8)
.002
Burning and stinging
0 (0.0)
5 (1.5)
NS
Anterior chamber cell
3 (1.8)
4 (1.2)
NS
Conjunctival hyperemia
5 (3.1)
1 (0.3)
.017
AC inflammation
4 (2.5)
1 (0.3)
.043
Iritis
4 (2.5)
1 (0.3)
.043
Anterior chamber flare
3 (1.8)
0 (0.0)
.036
Uveitis
3 (1.8)
0 (0.0)
.036
Corneal edema
2 (1.2)
0 (0.0)
NS
Corneal striae
2 (1.2)
0 (0.0)
NS
AC = anterior chamber; NS = not significant.
• The incidence of treatment-related IOP elevation was 0% in the vehicle
group and 0.6% (2/330 patients) in the ketorolac 0.45% (P > .999).
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• The vast majority of all cases of IOP elevation occurred on the first
postoperative day, did not persist with continued use of ketorolac 0.45%
over the course of study, and were not considered related to treatment.
DISCUSSION
• Excellent vision is the most important outcome of cataract surgery.
• In this study, a significantly higher percentage of patients treated with
ketorolac 0.45% had clinically significant (≥ +3-line) improvement in BCVA
from baseline.
• Similarly, cataract and vitreoretinal surgery patients who were treated with
ketorolac 0.4% (Acular LS) had significantly better BCVA compared to those
treated with vehicle.6,7
• These findings suggest that perioperative use of ketorolac may help to
improve visual acuity of patients undergoing intraocular surgery.
• Twice-daily ketorolac 0.45% effectively treated both inflammation and pain
following cataract surgery.
• Adverse events were generally mild to moderate in severity, transient in
duration, and more prevalent in the vehicle group than in the ketorolac
0.45% group.
• The incidence of transient burning and stinging reported upon instillation of
ketorolac 0.45% was much lower than that reported in the package inserts for
ketorolac 0.4% or ketorolac 0.5% (Acular) (1.5% versus “20-40%” and “up to
40%”, respectively).8,9
10
• Given its effectiveness against postcataract inflammation, it appears that
ketorolac 0.45% combines the efficacy of prior ketorolac formulations with
improved tolerability and a less frequent dosing regimen.
CONCLUSIONS
• A significantly higher percentage of patients treated with ketorolac
0.45% had clinically significant improvement in visual acuity than
those treated with vehicle.
• Twice-daily ketorolac 0.45% was well tolerated and effectively
treated pain and inflammation in patients undergoing cataract
extraction.
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4.
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5.
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8.
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9.
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