**Purpose.**:
To present a new epidemiological method relying on randomized controlled clinical trial (RCT) data to assess whether a treatment was effective, aiding in the decision to continue or stop the treatment in clinical patients.

**Methods.**:
A cutoff point is calculated in the change of a continuous outcome for which a proportion of treated patients clearly achieved a change better than this cutoff point as a result of the treatment. This cutoff point can then be applied to individual patients during routine therapy. The method was applied to reports of the Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular AMD (MARINA) trial, which included patients with AMD treated with monthly intravitreal injections of ranibizumab, and to reports of trials involving patients with high IOP, macular edema, and convergence insufficiency.

**Results.**:
The cutoff point in the change in visual acuity (number of letters), above which a proportion of patients clearly benefited due to ranibizumab treatment, was −5.0 at 24 months follow-up. The proportion of treated patients who ended above this cutoff point due to the treatment was 60%. The cutoff point varies with time of follow-up and by subgroup.

**Conclusions.**:
Contrary to common interpretation, no change, or a limited decline, in the outcome (visual acuity) can still imply that the patients are better off with the treatment than with no treatment. Stopping the treatment above the cutoff point may not be appropriate since it was effective in at least a proportion of patients. This method applies to a broad range of scales and conditions. (ClinicalTrials.gov number, NCT00056836.)

^{ 1 }AMD is the leading cause of blindness in elderly people in developed countries.

^{ 2 }The disease plays a major role in the daily practice of many ophthalmologists. As an important measure of change in disease intensity, the level of change in visual acuity is the continuous outcome variable in AMD. In addition to this AMD example, we apply the method to other scales and conditions: IOP reduction with topical medication in elevated IOP, visual acuity in the treatment of refractory diabetic macular edema, and near point of convergence (NPC) in the treatment of convergence insufficiency.

*μ*and

_{t}*μ*, respectively) and the SD of this change (

_{r}*σ*and

_{t}*σ*, respectively) (see Tables 1, 2, 3). We converted SDs from SEMs or 95% confidence intervals in the trial reports using the guidelines in the Cochrane Handbook for Systematic Reviews of Interventions.

_{r}^{ 3 }

**Table 1.**

**Table 1.**

Follow-up (Months) | Change in ETDRS Visual Acuity, Mean (SD)* | Cutoff Point x† | A above Cutoff Point_{t} (%)‡ | TAE above Cutoff Point (%)§ | |

Ranibizumab Group ( n = 238) | Sham Group ( n = 238) | ||||

1 | 3.9 (10.2) | −0.2 (8.6) | 4.9 | 46 | 40 |

3 | 5.9 (10.5) | −3.7 (11.3) | 0.4 | 70 | 49 |

6 | 6.5 (11.8) | −6.6 (13.0) | −0.9 | 73 | 55 |

12 | 7.2 (14.6) | −10.4 (15.1) | −1.9 | 73 | 61 |

24 | 6.6 (17.2) | −14.9 (18.8) | −5.0 | 75 | 60 |

**Table 2.**

**Table 2.**

Effect Modifier | Subgroup | No. in Treated/ Reference Group | Change in Visual Acuity at 24 Months, Mean (SD)* | Cutoff Point x† | TAE (%) | |

Ranibizumab Group | Sham Group | |||||

Age, y | 50–64 | 16/11 | 6.1 (21.2) | −13.7 (23.9) | −6.2 | 48 |

65–74 | 64/67 | 7.2 (15.8) | −11.9 (19.7) | −4.8 | 54 | |

75–84 | 124/132 | 7.6 (16.4) | −16.0 (19.0) | −5.3 | 64 | |

≥85 | 36/28 | 1.9 (16.4) | −16.8 (19.3) | −9.4 | 54 | |

Initial visual acuity | 20/160 or worse | 48/51 | 10.6 (17.5) | −0.8 (13.3) | 9.1 | 57 |

20/100 to 20/125 | 59/50 | 9.3 (15.4) | −13.6 (16.1) | −2.4 | 69 | |

20/63 to 20/80 | 68/72 | 5.4 (16.2) | −20.0 (17.6) | −7.7 | 69 | |

20/50 or better | 65/65 | 1.8 (15.8) | −21.3 (19.8) | −11.4 | 61 | |

CNV lesion size, DA | ≤2 | 39/46 | 10.2 (14.2) | −13.4 (18.2) | −2.9 | 66 |

>2 to ≤4 | 86/77 | 9.7 (14.4) | −15.5 (18.7) | −4.0 | 68 | |

>4 to ≤6 | 63/60 | 3.8 (20.0) | −15.0 (18.3) | −4.3 | 57 | |

>6 | 52/55 | 2.1 (16.7) | −15.5 (20.7) | −9.8 | 49 | |

CNV lesion type | Minimally classic | 91/87 | 6.4 (20.0) | −14.7 (17.3) | −2.6 | 64 |

Occult | 149/150 | 6.2 (14.7) | −15.3 (19.5) | −6.6 | 59 |

**Table 3.**

**Table 3.**

Study | Outcome | No. in Treated/ Reference Group | Follow-up | Change in Outcome, Mean (SD) | |

Treated Group | Reference Group | ||||

Dubiner et al.^{5} | IOP reduction (%) | 21/21 | Day 29, at 12 noon | 30.1 (12.4)* | 2.1 (16.5)* |

Dehghan et al.^{6} | Visual acuity (LogMar) | 43/45 | 2 months | 0.13 (0.27)* | 0.02 (0.26)* |

CITT^{7} | NPC break reduction (cm) | 60/54 | 12 weeks | 10.4 (5.07)† | 3.9 (4.98)† |

*x*, the probability is therefore zero that this change is due to the treatment. This change in outcome can be calculated by solving for

*x*the following quadratic equation which results from equation 1: where For the first example, we derived data from the Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular AMD (MARINA) trial report.

^{1}In this trial, participants had AMD with either minimally classic or occult (with no classic lesions) choroidal neovascularization (CNV). They were treated with monthly intravitreal injections of ranibizumab or sham injections. We applied the calculations to the change in Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity. In this example (Fig. 1), at intersection

*x*, the number of patients who achieved the corresponding change in visual acuity

*x*due to the treatment with ranibizumab is zero. This change in outcome (visual acuity) is our cutoff point of interest. As illustrated in Figure 1, for a change in visual acuity above cutoff point

*x*, for example, “A” or “B,” the probability density in the treated group is greater than in the placebo group, that is, there are more treated patients with that change than there are nontreated patients with the same change.

**Figure 1.**

**Figure 1.**

*x*is the area under the distribution of the treatment group results above

*x*:

*A*, which is calculated using the error function: The proportion of nontreated patients who ended above cutoff point

_{t}*x*is the area under the distribution of the placebo group results above

*x*:

*A*, which is calculated using the error function: The treatment-attributed effect (TAE), that is, the proportion of treated patients who ended above the cutoff point due to the treatment, is calculated using

_{r}*A*and

_{t}*A*: For 1, 3, 6, 12, and 24 months of follow-up in the MARINA trial we calculated cutoff point

_{r}*x*and TAE in the change in visual acuity. Furthermore, we have applied the method to MARINA subgroup analysis results by Boyer et al.

^{4}This allowed us to assess whether the method yields different results when addressing effect modification. The subgroup analyses were based on the 24-month visual acuity results segregated by age, initial visual acuity, CNV lesion size, or CNV lesion type.

^{ 5 }We calculated cutoff point

*x*and TAE in the percentage reduction of IOP after 29 days for treatment with bimatoprost for patients with elevated IOP. The third example was based on results of a trial of triamcinolone versus placebo by Dehghan et al.

^{ 6 }We calculated cutoff point

*x*and TAE in the change in LogMar visual acuity after 2 months in the treatment of refractory diabetic macular edema. The fourth example was based on results of a trial of office-based vergence/accommodative therapy with home reinforcement versus, among others, office-based placebo therapy with home reinforcement by the Convergence Insufficiency Treatment Trial Study Group.

^{ 7 }We calculated cutoff point

*x*and TAE in the 12-week reduction in centimeters of the NPC with vergence/accommodative therapy.

*x*, this proportion is reduced to zero; in this example, the cutoff point is −5 (point

*x*in Fig. 1). At this point, the proportion of patients who achieved this change was equal in both the intervention group and the sham group. The proportion of patients in the treatment group who lost 5 letters attributable to the treatment is therefore zero. This −5 value is our cutoff point at 24 months follow-up. As illustrated with groups A and B, for every value of the change in outcome above this cutoff point (less loss or more gain), there are patients who have achieved the change as a result of the treatment. The more a change in outcome lies above the cutoff point, the larger the proportion of treated patients who achieved this change as a result of the treatment. These patients would not have achieved this outcome if the treatment had not been given.

*x*. Furthermore, it shows the proportion of treated patients who ended above this point,

*A*, as well as the proportion of treated patients who ended above this point due to the treatment, TAE. Table 2 shows cutoff point

_{t}*x*and TAE, over different levels of effect modifiers in the MARINA trial: age, initial visual acuity, lesion size, and lesion type. The means and SDs used in the calculations are specified.

**Figure 2.**

**Figure 2.**

^{ 8 }It is unclear what evidence this statement is based on. Based on meta-analysis, the published average effect of bimatoprost is ≥27% IOP reduction.

^{ 9 }If 27% IOP reduction is assumed as a cutoff point in clinical practice, instead of 16% as determined from the method example, this means that the treatment will be stopped in patients in whom bimatoprost treatment was effective in reducing IOP. However, the clinical appropriateness of the method is also influenced by the implications involved in withholding a treatment. For instance, the decision to discontinue a treatment for high IOP or hypertension can be made relatively easy since there are several other treatments to choose from.

^{ 10 }If we were to hypothetically rerandomize the MARINA trial patients at 24 months, 25% of the treated patients would be rerandomized, since the proportion of treated patients who ended above cutoff point was 75% (see Table 1).

^{ 11,12 }It is possible that a similar method has been described before, but we are unaware of such a publication. We recommend using this method in future RCTs in which a change in an outcome versus baseline is being studied, for example, visual acuity, IOP, or flare (in uveitis). We recommend presenting the calculated cutoff point as well as the proportion of treated patients ending above this cutoff point.

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