Can HMG Co-A reductase inhibitors (“statins”) slow the progression of age-related macular degeneration? The Age-Related Maculopathy Statin Study (ARMSS)

Figures & data

Table 1 Inclusion and exclusion criteria

Inclusion criteria	Exclusion criteria
Male or female aged 50 years or older	Bilateral end stage AMD (CNV, central GA)
VA better than or equal to 20/60 in one eye.	Macula cannot be assessed in at least one eye
High risk drusen in both eyes: ≥1 large soft druse (≥125 microns), or >10 intermediate drusen (≥63 microns and <125 microns) OR	Medical and ophthalmic conditions which potentially affect visual function – including visually significant cataract (defined by Wilmer grading method as nuclear opacity grade 2 or greater, cortical opacity greater than grade 2, posterior subcapsular cataract ≥1 mm^2), history of diabetes and glaucoma
Late AMD (CNV, central GA) in one eye and any drusen or pigment change in the study eye
Cholesterol level within normal limits according to PBS criteria (Table 2)	Use of medications that may affect visual function, such as plaquenil, chloroquine, major tranquilizers.
	Currently on cholesterol-lowering medication.
	Use of statins is contraindicated
	Alanine aminotransferase (ALT) >2 times the upper limit of normal
	Previous severe adverse or allergic reactions to statins

Abbreviations: AMD, age-related macular degeneration; CNV, choroidal neovascularization; GA, geographic atrophy; PBS, pharmaceutical benefits schedule; VA, visual acuity.

Table 2 Pharmaceutical Benefits Schedule (PBS) qualifying criteria for subsidized statin prescriptions in Australia*

Patient conditions	Lipid level for PBS subsidy
Existing coronary heart disease	Cholesterol >4.0 mmol/L
Diabetes mellitus	Cholesterol >6.5 mmol/L
Familial hypercholesterolemia	or
Family history of coronary heart disease (1st degree relative <60 yrs of age)	Cholesterol >5.5 mmol/L and HDL <1.0 mmol/L
Hypertension
Peripheral vascular disease
HDL Cholesterol <1.0 mmol/L	Cholesterol >6.5 mmol/L
Men 35–75 yrs of age	Cholesterol >7.5 mmol/L
Postmenopausal women up to 75 yrs of age	or Triglycerides >4.0 mmol/L
If not eligible under the above	Cholesterol >9.0 mmol/L or
	Triglycerides >8.0 mmol/L

Note: Adapted from the November 2002 Schedule of Pharmaceutical Benefits.

Abbreviations: HDL, high-density lipoprotein.

Table 3 Schedule for procedures involved in the Age-related maculopathy statin study

Procedures	Screening visit	Baseline examination	Follow-up time in months
			1	6	12	18	24	30	36
Study explanation	✓	✓
Consent		✓
Randomization		✓
Blood draw for cholesterol and liver function tests	✓			✓	✓	✓	✓	✓	✓
Blood draw for DNA tests		✓
Medical history	✓	✓		✓	✓	✓	✓	✓	✓
Listing of medications	✓	✓		✓	✓	✓	✓	✓	✓
Mini-mental questionnaire		✓
Impact of Visual Impairment (IVI) survey		✓							✓
Refraction		✓		✓	✓	✓	✓	✓	✓
Visual acuity	✓	✓		✓	✓	✓	✓	✓	✓
Pupil dilation	✓	✓		✓	✓	✓	✓	✓	✓
Slit lamp examination	✓	✓		✓	✓	✓	✓	✓	✓
Macular photography		✓		✓	✓	✓	✓	✓	✓
Visual function tests		✓		✓	✓	✓	✓	✓	✓
Reporting of side effects			✓	✓	✓	✓	✓	✓	✓
Food Frequency Questionnaire		✓

Table 4 The level of detectable change (%) in visual function for three sample sizes and two statistical powers, at a significance level of 0.05 given our measured variability

	Number of subjects per group
	50 subjects		40 subjects		30 subjects
Statistical power	80%	90%	80%	90%	80%	90%
Red threshold	33	38	38	44	43	50
Blue threshold	41	47	47	53	53	61
Flicker threshold	38	44	44	53	49	57
Total static	37	43	43	49	49	56
DA – RCB	22	25	24	28	28	32

Abbreviation: DA – RCB, rod-conebreak in dark adaptation.

Table 5 References on associations between cholesterol-lowering medications and development of AMD

Reference	Details of study	Conclusion
Delcourt et al 2001	Cross-sectional study Age ≥ 60 years N = 2584	Late AMD was not significantly associated with current use of hypocholesterolemic drugs (OR 0.58, 95% CI 0.22–1.53), cardiovascular disease, known diabetes or blood pressure Obesity (BMI >30) was associated with a two fold higher risk of late AMD (OR 2.29, 95% CI 1–5.23)
McCarty et al 2001a	Cross-sectional study Age ≥ 40 years N = 4744	Past or present use of a cholesterol-lowering medication associated with an increased prevalence of early AMD (OR 1.72, 95% CI 1.18–2.49)
McCarty et al 2001b	Population-based cohort study Age ≥ 40 years N = 4744	Participants on lipid-lowering medications were almost 4 times less likely to experience AMD progression (3.6% vs 13%). Findings were not significant due to the small numbers of subjects in this group
Hall et al 2001	Cross-sectional study Age 66–75 years N = 379	AMD was more common amongst those who were not taking statins (p = 0.02). 22% of those not taking statins had AMD, whilst 4% on statins had AMD
Klein et al 2003a	Population-based cohort study Age 43–86 yrs N = 3684 for 5 years of follow up N = 2764 for 10 years of follow up	Higher serum HDL cholesterol at baseline was associated with pure geographic atrophy (RR = 1.29 per 10 mg/dl increase (1.05–1.58). Only 3.9% of the studied population were taking statins at baseline No significant association between the use of lipid-lowering medication (including nicotinic acid, fibric acid derivatives, bile acid sequestrants and statins) with early AMD incidence or progression
van Leeuwen et al 2003	Population-based cohort study Age ≥ 55 years N = 4822 452 on lipid-lowering medications Follow up at 2 and 6.5 years (26,781 person years)	No significant association between the use of lipid-lowering medication (including nicotinic acid, fibric acid derivatives, bile acid sequestrants and statins) with early AMD incidence or progression (HR 1.0, 95% CI 0.7–1.5)
McGwin et al 2003	Nested case-control study Age ≥ 50 years 550 cases of AMD and 5500 matched controls	Cases of early AMD were 70% less likely to have filled a statin prescription in comparison to those without early AMD (OR 0.30, 95% CI 0.21–0.45) Number of filled prescriptions was taken as an indication of statin use, rather than subject reported use
Wilson et al 2004	Retrospective consecutive case series Age ≥ 60 years, all subjects had AMD	Statins use was associated with an almost 50% reduction in the risk of developing CNV (HR 0.54, 95% CI 0.33–0.87) Triglyceride levels were positively correlated with the rate of CNV (HR 1.30, 95% CI 1.02–1.66)
McGwin et al 2005	Case-control study based on the population-based cohort Age 45–65yrs 871 AMD cases, 11,717 controls	Use of cholesterol-lowering medications was inversely associated with AMD 11% of those with AMD were using these medications, compared to 12.3% of controls (OR 0.89, 95% CI 0.63–0.99)
Smeeth et al 2005	Population-based case-control study Age ≥ 50 years 18,007 AMD cases and 86,169 age and gender matched controls	No significant association between the use of statins and a diagnosis of AMD (OR 0.93, 95% CI 0.81–1.07)
McGwin et al 2006	Case-control study Age ≥ 65 years 390 AMD cases, 2365 controls	Cases of AMD were more likely to be older and white than controls (p < 0.001) Nearly equal proportions of cases and controls used cholesterol-lowering medications (OR 1.06, 95% CI 0.81–1.40)
Tan et al 2007	Population-based cohort study Age ≥ 50 years N = 3654 at baseline N = 1952 at 10 years	Those on statins had a reduced risk of developing indistinct soft drusen at 10 years (HR 0.33; 95% CI 0.13–0.84) and also had a borderline nonsignificant reduced risk of any AMD
Klein et al 2007a	Randomized clinical trial of hormone replacement therapies Age 50–79 years N = 4288 women	Use of statins was inversely associated with soft drusen (OR 0.81, 95% CI 0.68–0.96), but not with early or advanced AMD
Klein et al 2007b	Population-based cohort study Age 43–86 years N = 2962 at baseline N = 2204 at 5 years	Statin use was not associated with the five year incidence of: Early AMD (OR 1.16 95% CI 0.71–1.91) Late AMD (OR 1.27 95% CI 0.60–2.69) Progression of AMD (OR 1.16 95% CI 0.75–1.78)
Friedman et al 2005	Case-control study	Those on statins had a reduced risk of AMD (RR 0.50, 95% CI: 0.23–1.09)
IOVS 46 (Suppl):199	94 cases of AMD, 54 controls

Abbreviations: AMD, age-related macular degeneration; BMI, body mass index; CI, confidence interval; HR, hazard ratio; OR, odds ratio; RR, relative risk.

Figure 1 Flow chart of the recruitment into the Age-Related Maculopathy Statin Study.

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