Genome-wide association study of angioedema induced by angiotensin-converting enzyme inhibitor and angiotensin receptor blocker treatment

Angioedema in the mouth or upper airways is a feared adverse reaction to angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blocker (ARB) treatment, which is used for hypertension, heart failure and diabetes complications. This candidate gene and genome-wide association study aimed to identify genetic variants predisposing to angioedema induced by these drugs. The discovery cohort consisted of 173 cases and 4890 controls recruited in Sweden. In the candidate gene analysis, ETV6, BDKRB2, MME, and PRKCQ were nominally associated with angioedema (p < 0.05), but did not pass Bonferroni correction for multiple testing (p < 2.89 × 10−5). In the genome-wide analysis, intronic variants in the calcium-activated potassium channel subunit alpha-1 (KCNMA1) gene on chromosome 10 were significantly associated with angioedema (p < 5 × 10−8). Whilst the top KCNMA1 hit was not significant in the replication cohort (413 cases and 599 ACEi-exposed controls from the US and Northern Europe), a meta-analysis of the replication and discovery cohorts (in total 586 cases and 1944 ACEi-exposed controls) revealed that each variant allele increased the odds of experiencing angioedema 1.62 times (95% confidence interval 1.05–2.50, p = 0.030). Associated KCNMA1 variants are not known to be functional, but are in linkage disequilibrium with variants in transcription factor binding sites active in relevant tissues. In summary, our data suggest that common variation in KCNMA1 is associated with risk of angioedema induced by ACEi or ARB treatment. Future whole exome or genome sequencing studies will show whether rare variants in KCNMA1 or other genes contribute to the risk of ACEi- and ARB-induced angioedema

A double blinded randomized clinical trial of perioperative ketorolac 15 mg versus 30 mg, evaluated by visual analog score in orthopedic and ear-nose and throat patients

Objective: Ketorolac is a non-steroid anti-inflammatory drug for intravenous use, with analgesic and anti-inflammatory effects and known for its potent influence on moderate to severe postoperative pain. The literature has shown that 30mg i.v. perioperative ketorolac is efficient, well-tolerated and decreases postoperative pain scores. There is no consensus in the literature on whether or not non-steroid anti-inflammatory drugs increase postoperative bleeding. This rare but possibly severe adverse reaction justifies further research into ketorolac dose-dependant postoperative pain scores. The study aims were to evaluate the difference between 15mg and 30mg perioperative i.v. ketorolac on postoperative VAS scores and secondary analgesia consumption after orthopedic or ear, nose and throat surgery. Methods: A comparative double-blinded randomized controlled trial included 69 patients, aged 18-65 years, undergoing ear, nose and throat or orthopedic surgery. Patients were randomized to receive either 15mg or 30mg i.v. ketorolac 30 minutes prior to the end of the surgery. Postoperative pain was recorded at 0, 15, 30, 60 and 90 minutes after arriving at the post-anesthesia care unit. The total amount of supplement analgesia consumed was calculated when the patient left the postoperative care unit or after 90 minutes. Results: A two-sided t-test showed the following: VAS t0: p=0.068 (95% CI 1.564 - 2.780); VAS t15: p=0.078 (95% CI 1.641 - 2.868); VAS t30: p=0.056 (95% CI 1.751 - 3.070); VAS t60: p=0.210 (95% 1.600 - 3.119); and VAS t90: p=0.124 (95% 1.120 - 3.230). The mean postoperative oral morphine equivalent was 9.1mg [5-20 mg] in the 15 mg group and 7.9 mg [2.5-20 mg] in the 30 mg group (two- sided t-test, p=0.526 95% CI -2.21-4.25). Conclusion: Our study demonstrated that 15 mg i.v. perioperative ketorolac exerts the same postoperative pain relief as 30 mg and does not result in a higher secondary analgesia consumption. [Arch Clin Exp Surg 2017; 6(3.000): 120-125