Fixed combination therapy in glaucoma patients

Take-home message: In this comparison study, IOP reductions were greater with BTFC than with TTFC and patients on this combination were more likely to achieve and maintain low target pressures. Combined BrTFC and DTFC may also be a more appropriate therapeutic choice for IOP lowering than TTFC and BrTFC, respectively.

By Dr Tamer A. Macky, FRCSEd

Fixed combination drops have a number of potential advantages over separate drops, including no risk of drug washout, reduced exposure to preservatives with reduced side effects, reduced cost of treatment, and ultimately better patient compliance and quality of life.

Around 50-75% of patients will need 2 or more drugs to reach their target pressure at any stage of the disease.^1,2 Since these drugs have different structures, a potential different synergy and thus efficacy could exist when these drugs are combined in a single drop. In another words, adding these drugs in fixed combinations does not mean absolute algebraic addition of each of the drug’s strengths. Hence, proper assessment of the strength of fixed combination eye drops is a critical issue as every millimeter reduction of intraocular pressure (IOP) corresponds to approximately 10% reduction in the risk of glaucoma progression.³ Direct head-to-head comparative randomised trials are essential in identifying the actual optimal strength of glaucoma medications in general, as well as in fixed combination therapy.

Bimatoprost/timolol versus travoprost/timolol fixed combination

We compared the ocular hypotensive effect of bimatoprost 0.03% plus timolol 0.5% fixed combination (BTFC) and travoprost 0.004% plus timolol 0.5% fixed combination (TTFC) in primary open-angle glaucoma (POAG) in a prospective randomised clinical study.⁴ Patients’ IOPs were evaluated for a 6 month period. Patients were also asked about adverse events and compliance. A patient was considered to be clinically successful if the investigator, after considering IOP-lowering efficacy, tolerability and any adverse events, continued the patient on his or her study drug at 6 months.

Study results

Eighty patients (80 eyes) were included with 40 patients (40 eyes) in each group. Both study medications provided statistically significant reductions of baseline IOP at all study points (P < 0.001) with no further significant reduction for each drug after the 2-week visit.

Next: Deducing the results

The BTFC showed a significant reduction in mean IOP when compared to TTFC at each study point (Table 1, Figure 1). Mean IOP reductions were 11.34 mmHg and 6.42 mmHg at 2 weeks (P = 0.000); and 11.17 mmHg and 7.89 mmHg at 6 months (P = 0.001) for BTFC and TTFC respectively. The BTFC group showed more than 40% drop of IOP throughout the 6 month period, while the TTFC showed a 26-32% drop of IOP through the same period which was statistically significant (Table 2, Figure 2). At 2 weeks, 36 eyes (90%) in the BTFC group and 22 eyes (55%) in the TTFC group reached an IOP of ≤18 mmHg, and 28 eyes (70%) in the BTFC group and 16 eyes (40%) in the TTFC group reached an IOP of ≤16 mmHg (P < 0.001). At 6 months, 38 eyes (95%) in the BTFC group and 28 eyes (70%) in the TTFC group reached an IOP of ≤18 mmHg, and 30 eyes (75%) in the bimatoprost group and 18 (45%) eyes in the travoprost group reached an IOP of ≤16 mmHg (P < 0.001).

About 95% of BTFC patients (38/40) and 70% TTFC of patients (28/40) were considered to be clinically successful (P < 0.001). We also observed that most of the BTFC patients had IOP in the lower teens, while the TTFC patients were in the upper teens. Seven eyes in the BTFC reached single digit IOP in the first month, and none of the TTFC did so throughout the study period. This power of IOP reduction of each combination drop, and the dramatic difference between them, is not affected by age, sex, diabetes, and hypertension. Similarly, Centofanti and colleagues⁵ found BTFC to be a more effective ocular hypotensive combination than TTFC.

Ocular redness was the most commonly recorded adverse event with both study medications, occurring in⁴ BTFC and⁵ TTFC patients (10% versus 12.5%, P = 0.768) with no discontinuation of any medication in either group. There is a clinically significant drop of the rate of hyperaemia when using these fixed combination drops when compared to the use of bimatoprost and travoprost alone as in our previous study⁶ (20% and 15%, respectively) and other reports.⁷

Study conclusions

In our study BTFC and TTFC provided effective IOP lowering in patients with POAG. However, the mean reductions in IOP from baseline were clinically and statistically greater and patients were more likely to achieve and maintain low target pressures with BTFC than with TTFC.

Next: Combos

Brinzolamide/timolol versus dorzolamide/timolol fixed combinations

We conducted another study to compare the ocular hypotensive effect and tolerability of brinzolamide 1% plus timolol 0.5% fixed combination (BrTFC) and Dorzolamide 2% plus timolol 0.5% fixed combination (DTFC) in primary open-angle glaucoma (POAG) (unpublished data). Patients were randomised to receive either BrTFC or DTFC twice daily and IOPs were evaluated for a 3 months period. Seventy-three eyes of 73 patients were enrolled in this study: 37 BrTFC patients (37 eyes) and 36 DTFC patients (36 eyes).

Study results

The mean IOP showed statistically significant reductions from baseline IOP at all study visits (P < 0.001). Between the 2 groups (Table 1, Figure 1), there was statistically significant lower mean IOP for DTFC at 2 weeks compared to BrTFC (P = 0.037), with a mean IOP for DTFC being non-significantly lower than BrTFC for the rest of the period. Clinical success was significantly different; BrTFC group, 86.5% (32/37), compared with 94.4% in the DTFC group, (P < 0.001).

Complete ocular comfort without any ocular adverse effects was observed in 31 patients (81.1%) in the DTFC group and 11 patients (29.7%) in the BrTFC group (P < 0.001). Ocular discomfort and ocular pain was unexpectedly higher in the BrTFC group; 9 patients (24.3%) and only in 4 patients (11.1%) in the DTFC group (P < 0.001).

Study conclusions

Both BrTFC and DTFC provided effective IOP lowering for POAG. Reductions from baseline were clinically and statistically greater and patients were more likely to achieve and maintain low target pressures with DTFC than with BrTFC. Also the tolerability of DTFC was better than BrTFC.

Next: What do these findings mean?

Summary

These findings may suggest that BrTFC and DTFC may be a more appropriate therapeutic choice for IOP lowering than TTFC and BrTFC, respectively. However, larger studies and pooled data from multiple studies in a meta-analysis are still needed to confirm this.

References

• M.A. Kass et al., Arch. Ophthalmol. 2002;120(6):701-713.

• P.R. Lichter et al., Ophthalmology. 2001;108(11):1943-1953.

• A. Heijl et al., Arch. Ophthalmol. 2002;120:1268-1279.

• T.A. Macky. J. Glaucoma. 2014;23(8):561-566.

• M. Centofanti et al., Am. J. Ophthalmol. 2010;150(4):575-580.

• T.A. Macky. J. Ocul. Pharmacol. Ther. 2010;26(6):605-610.

• A. Paranhos et al., J. Ocul. Pharmacol. Ther. 2010;26(6):611-615.

Dr Tamer A. Macky, FRCSEd

e: tamermacky@gmail.com

Dr Tamer A. Macky works at the Department of Ophthalmology, Cairo University, Cairo, Egypt.

Dr Macky has no financial or proprietary interest in any product mentioned in this article. No financial support and/or grants were provided for the original study.