This study has shown a trend toward more frequent side effects and increased DLI from the minocycline treatment, although the difference between minocycline and doxycycline did not reach statistical significance in this small pilot study. There were no trends showing an increase of adverse events compared to other tetracycline clinical trials [9
The percentage of side effects observed in this study (50%) was similar to, or even slightly lower than, previously reported clinical trials in other cardiovascular or neurological diseases. For instance, 61% of the subjects reported side effects in a multi-center study with six months of doxycycline at the same dosage in AAA patients [9
]. The use of broad spectrum antibiotics for extended periods (1–2 yrs) to influence cardiovascular disease, e.g., through treatment of a potential chlamydial infection, has not revealed a significant issue with side effects regarding safety or compliance [16
]. In recent trials examining the role of minocycline in neurodegenerative diseases, a futility trial in Parkinson’s disease revealed 77% tolerability and reported upper respiratory symptoms, joint pain and nausea as the most common side effects [15
While the range of adverse events was similar in both drugs, side effects were less frequent in the doxycycline group. In our study population, the rate of gastrointestinal (GI) side effects was very low in both groups, in contrast to others showing that doxycycline was associated with a much higher risk of upper gastrointestinal disorders [17
]. Vertigo, consistent with previous reports, occurred only in the minocycline group in our study. In contrast to reported hypersensitivity reactions to minocycline [18
], we had only one case in the doxycycline group, and none in the minocycline group. Our monitoring of laboratory values did not reveal signs of thrombocytopenia, hepatal or renal dysfunction, although they have been documented as side effects by others [19
]. None of our patients reported musculoskeletal toxicity, a common side effect in broad-band MMP-inhibitors [20
] or lupus-like syndrome, to minocycline [21
]. Although gender difference related to drug tolerability has not been reported in tetracyclines, our results suggested female gender as a possible predictor for increased intolerance. On the other hand, age did not seem to have an effect on DLI.
The two occurrences of hemorrhage in our study were not unexpected considering prior natural history studies. Increased age, initial hemorrhagic presentation, deep brain location, and exclusive deep venous drainage have been found as independent predictors of AVM hemorrhage in the untreated course after diagnosis [23
]. Thus, the 82 year old AVM patient with ICH in our study, who was at an advanced age and had a hemorrhagic presentation, could be at elevated risk. The ISUIA study found that aneurysm size and location are predictors of bleeding, with a first year rupture risk of 17% for giant aneurysms, reaching 50% at 5 years for posterior circulation lesions [25
]. The aneurysm hemorrhage in our study occurred in a patient harboring a giant basilar tip aneurysm. Our point estimates of the observed hemorrhage rate were 5.6%/yr for AVMs and 5.8%/yr for aneurysms, both of which were well within those reported in previous studies.
We feel that this is an appropriate time to report the overall tolerability and feasibility of the study, since most of the side effect-related withdrawals experienced by the patients occurred within 18 months of the study. To date, the majority of our patients have been enrolled for more than 18 months, making this the longest reported follow-up of tetracycline treatment in neurological and vascular diseases compared to previous trials [7
]. The retention of patients in this long-term study has been encouraging, as 69% have remained in the two-year treatment course. Other shorter-term tetracycline clinical trials have reported higher retention rates, including 92% in the six-month doxycycline treatment of AAAs [9
], and 89% in 12-month minocycline administration with Parkinson’s disease. The length of the study appears to be a key factor, given 12 months as the mean time for all withdrawal events in our study. Allowing patients to take the highest tolerated dose, instead of fixed doses, may have reduced withdrawal rates.
This pilot study suggests that long-term tolerability of minocycline and doxycycline in patients with brain vascular malformations is sufficient to support a larger Phase II or III trial to examine efficacy endpoints.