MedicalResearch.com Interview with:
Marco A Zarbin, MD, PhD, FACS
Alfonse Cinotti, MD/Lions Eye Research
Professor and Chair
Institute of Ophthalmology & Visual Science
Rutgers-New Jersey Medical School
Rutgers University Newark, NJ 0710
MedicalResearch.com: What is the background for this study? What are the main findings?
- Most large, randomized clinical trials are powered to assess the efficacy of drugs or interventions, but they usually do not enroll enough patients to accurately assess the frequency of uncommon, undesirable side effects.
- In order to compensate for this deficiency in trial design, investigators aggregate the results of numerous studies all of which address the same clinical question with the same (or similar) drugs/interventions to increase the power to detect uncommon side effects. These aggregate studies can be meta-analyses.
- Unfortunately, most meta-analyses do not have the ability to answer some critical questions such as the timing of an adverse event relative to the last exposure to the drug, nor can they compensate fully for differences among the aggregated studies in trial design, length of patient follow-up, or presence pre-existing risk factors for the side effects in question.
- A pooled analysis of combined clinical trials using patient level data, however, allows a more in depth analysis of side effects than study level data, which are usually used for most published meta-analyses, because patient level data allow one to incorporate the per-patient duration of exposure to treatment, adjust for imbalances in predefined baseline risk factors, and adjust for the effect of results of single studies on the overall result.
MedicalResearch.com: What should readers take away from your report?
Response: We conducted a pooled analysis of patient-level data from 6 randomized controlled clinical trials assessing the treatment of diabetic macular edema with ranibizumab. Diabetic macular edema is one of the most common causes of visual loss among working age adults in the United States.
Our goal was to assess the cardiovascular and cerebrovascular safety profile of this highly effective treatment for diabetic macular edema. Ranibizumab works by blocking the action of vascular endothelial growth factor (VEGF). A class effect of this blockade is an increased incidence of complications such as stroke with or without transient ischemic attack, myocardial infarction (MI), and vascular death.
Unfortunately, patients with diabetic macular edema have a particularly high risk of these complications even in the absence of treatment with VEGF inhibitors compared to diabetic patients without macular edema.
In this pooled analysis, which includes the largest patient-level data set on the treatment of diabetic macular edema of which we are aware, we found that intravitreal ranibizumab injection for diabetic macular edema was not associated with a significant increased risk of systemic vascular events. Uncertainty remains, however, for patients with diabetic macular edema who are at high risk for vascular disease and who have high exposure to the drug, as most of the patients at such high risk were not included in these trials. Overall, the findings are consistent with the results of previously published randomized clinical trials that demonstrated significant visual benefit with minimal systemic risk in using ranibizumab to treat patients with diabetic macular edema
MedicalResearch.com: What recommendations do you have for future research as a result of this study?
Response: Of necessity, clinical trials restrict enrollment such that the patients one encounters in clinical practice may not have qualified for enrollment in the trial. As a result, it is not always clear that the trial results will apply to a given patient in our practice. To establish the safety of anti-VEGF therapies in patient with diabetic macular edema who have a history of stroke or MI (particularly, recent stroke or MI, or multiple strokes or MIs), additional large, active controlled trials and/or “real-world” evidence (e.g., from Medicare Claims data bases) including many more such patients is needed (to increase the power of the study to accurately assess the frequency of these side effects in patients who receive the drug vs. those who do not).
MedicalResearch.com: Is there anything else you would like to add?
Response: In order to obtain patient level data, this study focused on trials that were conducted by the sponsors of these clinical trials: Genentech/Roche and Novartis Pharma AG. In addition, Dr. Zarbin is a paid consultant for the following companies: Genentech/Roche, Novartis Pharma AG, Boehringer Ingelheim, Coherus Biosciences, Frequency Therapeutics, Healios KK, Isarna Therapeutics, Makindus, Ophthotech, Percept Corp.
MedicalResearch.com: Thank you for your contribution to the MedicalResearch.com community.
Zarbin MA, Dunger-Baldauf C, Haskova Z, Koovejee P, Mousseau M, Margaron P, Snow H, Beaumont PE, Staurenghi G, Francom S. Vascular Safety of Ranibizumab in Patients With Diabetic Macular EdemaA Pooled Analysis of Patient-Level Data From Randomized Clinical Trials. JAMA Ophthalmol. Published online April 06, 2017. doi:10.1001/jamaophthalmol.2017.0455
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