Cost and clinical effectiveness of fixed-dose combination therapies in the treatment of glaucoma patients: a systematic review

Introduction Fixed-dose combinations (FDCs) have the potential in glaucoma management to improve efficacy due to the complementary mechanism of action of the drugs as well as compliance while reducing adverse effects by minimizing exposure to preservatives and the financial burden on the patients. FDC of brinzolamide/timolol has demonstrated efficacy and safety in multinational phase 3 studies in primary open-angle glaucoma (POAG) and ocular hypertension. However, efficacy and safety in the Indian population are not known. This study compared the efficacy and safety of FDC brinzolamide 1%/timolol 0.5% with FDC dorzolamide 2%/timolol 0.5% in Indian patients with POAG or ocular hypertension. Material and methods This 12-week randomized, phase 3, open-label, comparative, multicentric study was conducted on 221 subjects at nine sites in India, with assessments done at baseline and weeks 4, 8, and 12. Patients with intraocular pressure (IOP) of 24-36 mmHg of the affected eye(s), either newly diagnosed or inadequately controlled on mono-therapy of carbonic anhydrase inhibitor, beta-blocker, or any other IOP-lowering therapy, were included. Patients were randomly assigned to receive either FDC of brinzolamide 1%/timolol 0.5% (n = 111) or FDC of dorzolamide 2%/timolol 0.5% (n = 110). Primary efficacy was a noninferiority comparison of mean change in two-hour IOP and zero-hour IOP at the end of treatment compared to the respective baseline IOP. Safety was analyzed by comparing the frequency of the observed adverse events (AEs) between the two groups. Results FDC brinzolamide/timolol produced comparable and non-inferior IOP-lowering efficacy to FDC dorzolamide/timolol. The IOP reductions ranged from 6.55 to 8.36 mmHg in FDC brinzolamide/timolol group and from 5.37 to 7.55 mmHg in FDC dorzolamide/timolol group. Fewer subjects in FDC brinzolamide/timolol group experienced ocular AEs as compared with FDC dorzolamide/timolol group (9.9% vs. 26.4%), especially ocular hyperemia (2.7% vs. 22.7%). Conclusion FDC of brinzolamide 1%/timolol 0.5% affords an ocular comfort advantage with a clinically meaningful reduction in IOP that was non-inferior to FDC of dorzolamide 2%/timolol 0.5% in Indian patients with POAG and ocular hypertension.

To estimate the effect of reducing intraocular pressure (IOP) on: (i) the incidence of primary open-angle glaucoma (POAG) in patients with ocular hypertension (OH), and (ii) the progression of glaucoma. A meta-analysis of relevant randomized controlled trials was conducted. A literature search was performed to identify trials with: a randomized comparison of IOP-lowering intervention versus placebo or no treatment; visual field loss or optic disc changes as outcome; and follow-up >6 months. A pooled relative risk (RR) was calculated by a random effects model. Risk reduction of glaucoma conversion per mmHg of IOP reduction was quantified in a meta-regression model. We identified nine OH and one POAG trials. A meta-analysis of OH trials gives a pooled RR of 0.61 [95% confidence interval (CI) 0.45-0.83]. A meta-regression shows a decrease of the RR of glaucoma conversion by 14% with each mmHg extra IOP reduction (P = 0.045). No meta-analysis of POAG trials was performed because only one study has been identified. There is sufficient evidence that OH therapy reduces the risk of conversion to glaucoma. This risk reduction increases with greater IOP reduction.

BackgroundTreatment of open angle glaucoma (OAG) and/or ocular hypertension (OHT) focuses on achievement of target intraocular pressure (IOP), with the objective of slowing disease progression. However, ocular surface health is an important consideration in the optimization of treatment. We report 6 patient cases in which enhanced IOP control was achieved following appropriate management of ocular surface inflammation and a therapeutic switch to the preservative-free (PF) tafluprost (0.0015%)/timolol (0.5%) fixed-dose combination (FC).Case presentationSix patient cases, aged 48–74 years, presented with OAG or OHT. Each patient had signs and symptoms of ocular surface disease (OSD). Cases 1–3 were each receiving maximal medical therapy for OAG; regimens comprising prostaglandin analogue (PGA), β-blocker, carbonic anhydrase inhibitor (CAI) and α-2 agonist agents (including treatments containing preservative agent). Cases 1 and 2 reported IOP values ≥23 mmHg in each eye, and wide IOP fluctuations were identified when reviewing patient data concerning case 3 (11–20 mmHg). Maximal therapy was ceased and PF tafluprost/timolol FC was initiated, after which the signs and symptoms of OSD were improved and IOP was reduced (≤18 mmHg for cases 1–3) and stabilized. Cases 4 and 5 were diagnosed with OAG and case 6 had OHT. Each had symptoms and signs of OSD and were treated with a preserved PGA monotherapy (latanoprost 0.005% or bimatoprost 0.03%). At presentation, IOP was 24 mmHg in both eyes (case 4), ≥18 mmHg (case 5) and ≥ 22 mmHg (case 6). Following a switch to the PF tafluprost/timolol FC, OSD symptoms were improved and IOP was 14 mmHg (both eyes; case 4), ≤14 mmHg (case 5) and 16 mmHg (both eyes; case 6).ConclusionsIn addition to IOP-lowering efficacy, approaches to the management of OAG and OHT should consider the impact of treatment tolerability and the susceptibility of these patients to OSD. The presence of ocular surface inflammation appears to be detrimental to adherence and therefore to the effectiveness of topical medications. Addressing OSD through the use of PF FC formations, such as the PF tafluprost/timolol FC, reduces exposure to potentially toxic agents and facilitates improvements in IOP control.

In a long-term study with 3% guanethidine and 0.5% adrenaline in on eye drop (GA) the combined results of patients with primary open angle glaucoma (POAG) and glaucoma suspects showed a biphasic response in intraocular pressure (IOP). The hypertensive phase peaked 3 hrs after administration (at noon) and reached a maximum of 3.5 mm Hg (p less than 0.005) above the hypotensive phase. It is reported in the literature that during office hours untreated glaucoma patients show a peak near noon, suggesting that the initial increase in IOP may be the normal IOP pattern. When the data of untreated patients with POAG and glaucoma suspects were separated, an increase in IOP around noon in the first group and a decrease around noon in the glaucoma suspects was found. However, during GA-treatment both groups showed a hypertensive response at noon (3 hrs). In addition, the highest IOP's in day curves were timed during and without GA. It was shown that during GA there was a shift in the incidence of the highest IOP's towards noon (from 8.3% to 73.2% for patients with suspected glaucoma and from 32% to 63.6% for those with POAG). It was therefore concluded that GA induces a characteristic biphasic IOP pattern in patients with POAG as well as in glaucoma suspects. Also, glaucoma suspects may have higher peak pressures more frequently than POAG patients. Furthermore, the study showed that during office hours untreated glaucoma suspects have day curves with higher pressures in the morning while patients with POAG have higher pressures near noon.

The Glaucoma Guidelines of the Swedish Ophthalmological Society

Introduction: Glaucoma is characterised by structural damage to optic nerve head with corresponding visual field defects and often associated with increased Intraocular Pressure (IOP). It may be broadly classified as Primary Angle Closure Glaucoma (PACG) and Primary Open Angle Glaucoma (POAG). It is one of the leading causes of global blindness, and a major proportion occurs in Indian population. Aim: To study the correlation between pretreatment IOP and extent of visual field loss in PACG and POAG. Materials and Methods: A cross-sectional observational study was carried out in Regional Institute of Ophthalmology, Trivandrum, Kerala, India from April 2016 to May 2017. Newly diagnosed cases of PACG (25 patients-13 males, 12 females, mean age 58.72±10.07 years) and POAG (85 patients- 45 males, 40 females, mean age 60.28±10.42 years) underwent a detailed glaucoma evaluation which included IOP measurement with Goldmann applanation tonometer and visual field testing using Humphrey Field Analysis (HFA) 24-2 pattern. Mean Deviation (MD), Pattern Standard Deviation (PSD) and Advanced Glaucoma Intervention Score (AGIS) score was calculated from reliable visual field test result. All data were coded and entered in to statistical software, Statistical Package for Social Sciences (SPSS) version 16.0 for analysis. The correlation between pretreatment IOP and visual field loss in patients with PACG and POAG was determined by Pearson Correlation of Coefficient. Results: Amongst the total 110 patients of this study, 25 patients were of PACG while POAG were in 85 patients. A significant correlation between pre treatment IOP and the extent of visual field loss in PACG was noted. There was no significant correlation in POAG. Linear regression analysis demonstrated a significant positive correlation between IOP and AGIS score in PACG (Pearson correlation coefficient(r)=0.805, p<0.001), not in POAG (r=0.026, p=0.816). Correlation between IOP and MD is statistically significant in PACG (r=0.812, p<0.001) but not in POAG (r=0.058, p=0.597). The correlation between IOP and PSD is not statistically significant in both groups (p-value >0.450). Conclusion: A significant correlation between IOP and visual field loss in PACG indicates that extent of visual field damage can be controlled by controlling IOP alone in PACG. The correlation between the pretreatment IOP and visual field loss in POAG is not statistically significant which agrees with the current proposed pathophysiology of optic neuropathy in which multiple factors influence in addition to IOP.

Glaucoma is a clinically and genetically heterogeneous disease. First-degree relatives of primary open-angle glaucoma (POAG) patients have a disease prevalence that is between 4 and 10 times higher than that of the general population, 1–3 and there is a higher disease concordance in monozygotic twins than in dizygotic twins. 4,5 These studies indicate the significant heritability of POAG; however, a simple mode of inheritance is not likely and cannot be assumed in genetic studies designed to identify POAG susceptibility genes. POAG is also complex clinically. The relationship between intraocular pressure (IOP) elevation and retinal ganglion cell degeneration is not simple, 6 as many individuals have IOP elevation without optic nerve damage, 7 and in some individuals, optic nerve degeneration develops without elevated IOP. 8 Recent studies have shown that POAG-related clinical features, including optic nerve parameters, 9,10 central corneal thickness, 11–14 and IOP, 15 are influenced by different sets of genes. Genetic and environmental risk factors and epigenetics are thought to influence complex traits such as POAG, normal tension glaucoma (NTG) and exfoliation syndrome–related glaucoma (Fig. 1). GENETIC RISK FACTORS FOR POAG The identification and characterization of POAG susceptibility genes would elucidate the molecular pathogenesis and could suggest new methods of diagnosis and treatment. The demonstration that the function of a particular enzyme or structural protein is impaired in POAG patients may lead to the development of novel drug therapies. The identification of DNA sequence changes associated with the disease could form the basis of diagnostic tests that are useful in identifying individuals at risk. The availability of such tests would provide a mechanism for early detection and timely treatment. Those individuals at risk who are identified early in the course of the disease and who begin therapy before significant damage to the optic nerve have the best chance of maintaining useful sight. Although POAG has a significant heritability, family-based linkage studies have not revealed POAG genes with significant population effect. The lack of such findings suggests that novel POAG genes have modest effect sizes and that large data sets with well-defined phenotypes are necessary for discovery. The formation of multiple consortia and collaborations has been crucial in the success of the genome-wide association studies approach by increasing sample sizes, thereby increasing statistical power, enabling replication of findings from individual studies, and establishing common methods of analysis. Common complex diseases often require more than 10,000 cases and controls for successful identification of the predisposing genes. 16 Genome-wide association studies have recently shown promising results for POAG gene discovery. Using an Icelandic population of 1,263 cases and 34,877 population controls, two single-nucleotide polymorphisms (SNPs) in an intergenic region between the CAV1 and CAV2 genes were found to confer modest risk for POAG (odds ratio [OR] 1.3). This finding was replicated in Caucasians of European ancestry and in a Chinese

Purpose It has been implicated that vascular dysregulation plays a role in the pathogenesis of primary open angle glaucoma (POAG). In the present study the association between optic nerve head blood flow as measured with laser Doppler flowmetry and ocular perfusion pressure in patients with treated and untreated POAG, patients with ocular hypertension and healthy control subjects was compared. Methods 136 patients with treated POAG, 116 patients with untreated POAG, 138 patients with ocular hypertension and 160 control subjects were included in the study. Optic nerve head blood flow was assessed using laser Doppler flowmetry. Ocular perfusion pressure was calculated based on measurement of IOP and systemic hemodynamics. Results Optic nerve head blood flow was significantly reduced in patients with glaucoma compared to patients with ocular hypertension and healthy subjects (p<0.01). However, no difference in optic nerve head blood flow between treated and untreated glaucoma patients was detected. The highest association between ocular perfusion pressure and optic nerve head blood flow was found in untreated glaucoma patients followed by ocular hypertensives and treated glaucoma patients. Conclusion The present study confirms evidence that optic nerve head blood flow is reduced in patients with POAG and patients with ocular hypertension. Correlation coefficients in the glaucoma groups and in the ocular hypertensives indicate a vascular dysregulation in these patients compared to healthy control subjects.

Glaucoma is the leading cause of irreversible blindness globally, with the commonest subtype being primary open angle glaucoma (POAG). POAG is characterised by an increase in intraocular pressure (IOP), optic nerve damage and irreversible visual field loss. People of African descent (AD) are significantly more susceptible to POAG when compared to people of European descent (ED), and the reasons for this are complex and multifaceted. The vast level of genetic diversity in AD populations has allowed, through genome-wide association studies (GWAS), for the identification of several single nucleotide polymorphisms (SNPs) as well as differences in mitochondrial haplogroups, which could explain the pathophysiology underlying the increased susceptibility of AD populations to POAG. The altered expression of genes such as MYOC as well as the expression of inflammatory mediators influencing reactive astrocytes have also been implicated. There are also several differences in morphology between AD and ED eyes which must be considered, including differences in central corneal thickness (CCT) and corneal hysteresis (CH) as well as variation in properties of optic discs. The link between all the aforementioned factors and the increased prevalence of POAG in AD populations will be explored in this review.

Local and systemic oxidative stress in intraocular pressure (IOP) elevation and optic nerve damage may be involved in the pathogenesis of glaucoma. We reported previously that a lower level of systemic antioxidative capacity is associated with IOP elevation in open-angle glaucoma (OAG). We assessed the correlation between the visual field sensitivity value, i.e., mean deviation (MD), and systemic levels of prooxidants and antioxidants by analyzing the blood biochemistry in 202 patients with glaucoma. Serum levels of lipid peroxides, ferric-reducing activity, and thiol antioxidant activity were measured using the diacron reactive oxygen metabolite (dROM), biological antioxidant potential (BAP), and sulfhydryl (SH) tests, respectively, using a free-radical analyzer. Univariate and multivariate analyses suggested a positive correlation between MD and BAP (R = 0.005 and P = 0.0442 by a multiple regression model adjusted for seven demographic parameters), but no significant associations between the MD and the dROM (R = 0.002 and P = 0.8556) and SH tests (R = −0.001 and P = 0.8280). Use of more antiglaucoma medication and primary OAG rather than normal tension glaucoma also were associated significantly with worse visual field damage. This large and comprehensive assessment of the association between systemic redox status and visual field damage in OAG suggests that lower systemic antioxidant capacity measured by ferric-reducing activity is associated with more severe visual field damage in OAG that partly explained its roles in IOP elevation.

Increased intraocular pressure (IOP) is the leading cause and the hallmark of Glaucoma, an asymptomatic and irreversible degenerative disease that, undetected or untreated, progresses to blindness due to optic nerve atrophy. Glaucoma is the second cause of blindness and visual impairment worldwide. Peripheral visual field is first affected, often unnoticed by the patient, progressing towards the loss of the central visual field and ultimately towards blindness. Continuous monitoring of the IOP is of major importance both for a better management of Glaucoma treatment, and for a more efficient and earlier screening of Glaucoma patients amongst risk groups. Currently, the only way to get data on the dynamic behavior of the IOP is to repeat punctual measurements several times a day. No available technology can perform uninterrupted 24-hour IOP measurements during sleep or during daily activities. Consequently, the ophthalmologist does not have the tool that permits widespread, cost-effective, and precise recording of the IOP for the full 24-hour period, in the case of Glaucoma patients or for Glaucoma screening. As a result, the disease remains under-diagnosed and many Glaucoma patients are kept on insufficient or inappropriate medication. This research work was focused on the development, characterization and testing of a novel minimal invasive microsystem for the monitoring of IOP, based on a new measurement principle. The research work presented in this thesis combines microtechnology, microelectronic and biomaterials. The method of indirect continuous monitoring of IOP presented here is based on the detection of spherical deformations of the eyeball (changes in cornea curvature) due to IOP. We developed and patented a soft contact lens with a microfabricated thin film strain gage sensor embedded, which is capable of measuring cornea deformations due to IOP variations- the Contact Lens Sensor (CLS). To power the sensor and retrieve data from the contact lens wirelessly, telemetry based on absorption modulation has been investigated and integrated in the CLS. The fabrication technology is based on a well known polyimide-based technology that has been widely used to fabricate implantable microelectronics, but two critical fabrication steps have been addressed and improved: metal adhesion on polyimide and structures release from wafer after fabrication. As the application is related to the medical field, great importance has been given in the choice of biocompatibility materials. The developed fabrication technology in combination with telemetry by absorption modulation, the flip-chip-on-flex assembly technology and the silicone biocompatible encapsulation and insulation technique open up new possibilities for the development of implantable microsystems for human biometric parameters monitoring and animal long term monitoring and testing, where small wireless sensors and no battery are needed. Prototypes of the CLS have been tested on pig-enucleated eyes, under simplified physiological conditions in order to verify our novel measurement principle for the IOP monitoring. Moreover the first wired prototype has also been tested on humans to study and investigate all issues related to safety, comfort, stability and reliability of the CLS. The results presented show that the device is sufficiently sensitive to measure a signal equivalent to the human ocular pulsation (OP) and follows well the IOP variations in a reproducible way, in static and dynamic mode, validating therefore the measurement principle and theoretical calculations. Next step will be extensive clinical trials to validate the systems and its reproducibility on humans. The wireless CLS would allow for the first time minimally invasive continuous IOP monitoring over periods up to 24 hours, regardless of patient position and activities. It would permits 24-hour continuous IOP measurements performed during sleep and various independent activities without the involvement of the patient, thus opening up new diagnostic and therapeutic methods to manage Glaucoma.

Mutant human myocilin induces strain specific differences in ocular hypertension and optic nerve damage in mice

Intraocular pressure (IOP) is a elementary data in diagnosis and therapy of glaucoma. Many studies have confirmed that most tonometry, including Goldmann applanation tonometry, are influenced by central corneal thickness (CCT) and CCT varies greatly among the general population. As a result, the measurement of CCT has a great implication in management of glaucoma. Further, CCT is confirmed a risk factor for progression from ocular hypertension to primary open angle glaucoma. The idea of that CCT may bear an inverse relation with the risk for developing glaucoma damage is in debating. Many specialists bring forward that CCT measurement should be one of the regular examinations in treatment of glaucoma patients.

Primary Open-Angle Glaucoma

Mutations of the TIGR/MYOC Gene in Primary Open-Angle Glaucoma in Korea