Pharmacology Digest, July 29th, 2018



This week’s clinical pharmacology update includes​​ apomorphine​​ for Parkinson’s disease​​ and​​ conflicting​​ prehospital​​ plasma resuscitation​​ results. Antidepressants​​ are​​ associated with​​ improved​​ mortality​​ after​​ ACS, but may worsen outcomes in COPD, and​​ a two-drug HIV​​ antiretroviral​​ regimen​​ is as good as a three-drug​​ approach.

-​​ July 29nd, 2018








~  ​​ ​​​​ Pharmacology News ​​ ~

Targeting​​ Blood Pressure​​ to 120 mmHg Lowers Risk of Mild Cognitive Impairment

July 25th, AAIC Meeting: ​​​​ Intensive blood pressure control targeted at​​ a​​ systolic pressure​​ of 120 mmHg was associated with a 19% lower risk of mild cognitive impairment compared with less intensive blood pressure control (target blood pressure 140 mmHg). ​​ RCT, SPRINT MIND trial (9,361 patients).



Numerous Cases of Inflammation Associated with​​ Aflibercept​​ Injections

July 21st/July 23rd, Medscape:​​ Nearly 100 cases of eye inflammation, in some instances involving loss of visual acuity, have been attributed to aflibercept (a VEGF​​ decoy receptor) injections. ​​ Although fewer than 1/5 American​​ ophthalmologists​​ use aflibercept to treat neovascular age-related macular degeneration, 82% of​​ reported​​ adverse reactions to intravitreal drugs involved use of this medication. ​​ 



FDA Committee Recommends Against Expanding​​ Mepolizumab​​ Indications to Include COPD

July 26th, FDA: An FDA advisory committee has voted 3 to 16 not to recommend mepolizumab, an anti-IL-5 monoclonal antibody, as an add-on therapy for reducing exacerbations in patients with COPD​​ +​​ high circulating eosinophil counts. ​​ Mepolizumab is already approved for eosinophilic subtypes of asthma and granulomatosis with polyangiitis.​​ 



FDA Advisory Panel Votes Against​​ Buprenorphine​​ Sublingual-Spray for Pain Management

July 27th, FDA: A US FDA advisory panel has voted 18-to-1 against the approval of buprenorphine sublingual spray (Buvaya, by INSYS Therapeutics) for the treatment of​​ moderate-to-severe pain. ​​ The​​ committee expressed​​ concern over the safety and efficacy of the​​ formulation. ​​ 



FDA Advisory Panel Votes in Favor of Second​​ Tafenoquine​​ Antimalarial Product

July 26th, FDA:​​ A US FDA advisory committee has voted in favor of the efficacy and safety of a second tafenoquine product (Arakoda) as a once weekly malaria prophylactic. ​​ This vote comes on the heels of the approval of a​​ single-dose tafenoquine product (Krintafel) indicated for the radical cure of plasmodium vivax malaria. ​​ 



Sildenafil​​ Trial Halted Following Infant Deaths

July​​ 25th, BMJ:​​ The STRIDER trial of 183 pregnant women assigned to​​ sildenafil or placebo for the prevention of fetal growth restriction has been discontinued following a​​ high incidence of lung complications and neonatal​​ death​​ in the treatment arm. ​​ 



~  ​​ ​​​​ Clinical Trials: New Horizons  ​​ ​​​​ ~


SubQ​​ Apomorphine​​ Infusion Reduces “Off Time” in Parkinson’s Disease

July 25th, The Lancet​​ Neurology:​​ Subcutaneous infusion of apomorphine, a nonspecific dopamine agonist, in patients with Parkinson’s disease was found to reduce off time (periods where​​ antiparkinsons medications cease to adequately control symptoms) by nearly 2 hours/day. ​​ RCT (106 patients). ​​​​ 



Plasma​​ Administration During Air Transport Associated with Lower 30-Day Mortality in Trauma Patients

July 25th​​ NEJM:​​ Administration of plasma during standard traumatic resuscitation in severely injured patients receiving​​ air medical transport was associated with​​ a 10% lower 30-day mortality compared with patients treated with standard resuscitation measures alone.​​ ​​ RCT (501 patients).​​ 



Plasma​​ Administration During Ground​​ Transport Not Associated with Lower 28-Day Mortality in Trauma Patients

July 19th, The Lancet:​​ Administration of plasma during standard traumatic resuscitation in severely injured patients receiving ground medical transport was not associated with a lower​​ 28-day mortality than patients treated with saline during standard​​ resuscitation.​​ RCT (144 patients). ​​​​ 



High-Dose​​ PPI + Aspirin​​ Associated with Improved Outcomes in Barrett’s Esophagus

July 26th, The Lancet:​​ High-dose esomeprazole (40 mg PO BID)​​ +​​ 300-325 mg aspirin was associated with a 59% longer event-free period than low-dose esomeprazole (20 mg PO QD) without aspirin in patients with Barrett’s esophagus.​​ ​​ RCT, AspECT Phase III trial (2557 patients).​​ 



Novel Anti-VEGF Drug​​ Abicipar​​ Demonstrates Efficacy in Age-Related Macular Degeneration

July 19th, Allergan & Molecular Partners:​​ Abicipar, a novel anti-VEGF DARPin (an antibody mimetic), was found in two Phase III RCTs to be non-inferior to ranibizumab, a previously approved intravitreous anti-VEGF drug. ​​ Abicipar​​ required fewer injections to meet the same efficacy endpoint as rabinizumab, but was associated with higher rates of intraocular inflammation. ​​ 



Cabozantinib​​ Extends Survival in Hepatocellular Carcinoma

July 5th, NEJM:​​ Cabozantinib, a tyrosine kinase inhibitor (including​​ VEGFR1/2/3, MET, AXL) extended median overall survival by 2.2 months in patients with previously-treated​​ advanced hepatocellular carcinoma.​​ ​​ RCT, CELESTIAL trial (707 patients). ​​ 



Atezolizumab​​ Improves Survival in Metastatic Lung Cancer

June 14th, NEJM:​​ Atezolizumab, an anti-PD-L1 antibody, combined with bevacizumab, carboplatin, and paclitaxel was associated with a 1.5 month longer median​​ survival in patients with metastatic non-small cell lung cancer (NSCLC), compared with metastatic NSCLC patients receiving only bevacizumab, carboplatin, and paclitaxel. ​​ RCT, IMPower50 (356 patients).​​ 



Synthetic Cannabinoid​​ Nabilone​​ Associated with Lower Rates of Agitation in Alzheimer’s Disease

July 24th, AAIC Conference: ​​​​ Twice as many patients (47%) with Alzheimer’s Disease experienced clinically meaningful​​ improvement in agitation compared with those receiving placebo (23%). ​​ RCT (39 patients). ​​ 



Brigatinib​​ Demonstrates Superiority to First-Line Drug in Advanced Non-Small Cell Lung Cancer

July 25th, Takeda Pharmaceutical:​​ Brigatinib (Alunbrig, an anaplastic lymphoma kinase (ALK) inhibitor) has demonstrated​​ superiority to the first-line treatment crizotinib, another ALK-inhibitor, in patients with ALK-positive​​ metastatic non-small cell lung cancer (NSCLC) who are ALK-inhibitor therapy naive. ​​ Brigatinib is currently approved only as a second-line therapy, for patients who are not responsive or cannot tolerate crizotinib. ​​ RCT (275 patients).​​ 



Pembrolizumab​​ Monotherapy Improves Overall Survival in Head and Neck Squamous Cell Carcinoma

July 25th, Merck:​​ Pembrolizumab (Keytruda, an anti-PD-L1 monoclonal antibody) was effective as first-line monotherapy in patients with head and neck squamous cell carcinoma​​ (HNSCC) whose tumors express PL-L1 ligand. ​​ Patients receiving pembrolizumab experienced improved​​ overall survival compared with patients treated with the current standard-of-care​​ (cetuximab + platinum chemotherapy + 5-FU). ​​ Pembrolizumab is currently approved for HNSCC only in patients who experienced disease progression on a platinum-based chemotherapy regimen. ​​ KEYNOTE-048, Phase III RCT (~825 patients). ​​ 



~  ​​ ​​​​ Clinical Research  ​​ ​​​​ ~


Protease Inhibitors​​ Associated with Worse Outcomes in Patients with HIV + Heart Failure

July 23rd, JACC: ​​​​ Patients with HIV and heart failure treated with protease Inhibitor-based antiretroviral therapy had a two-fold higher​​ rates​​ 30-day heart-failure readmission​​ and cardiovascular mortality​​ compared with patients receiving non-protease-inhibitor antiviral regimens. ​​ Observational retrospective (394 patients).


Ondansetron​​ Associated with Slightly Increased Risk of​​ Cleft-Palate and Renal Birth Defects

July 25th, Journal Obstetrics and Gynecology:​​ Off-label use of ondansetron to treat first-trimester nausea and vomiting was associated with a slightly increased likelihood of cleft palate and renal agenesis-dysgenesis.​​ ​​ Observational retrospective (Two cohorts, 35,824 total participants).​​ 



“Enhanced” Surgery Recovery Protocol Decreases Post-Operative​​ Opioid​​ Use

July 25th, Journal Obstetrics and Gynecology: ​​​​ Implementation of a multidisciplinary perioperative care program (ERAS) involving nutritional counseling, goal-directed fluid therapy, perioperative opioid-sparing analgesia, emphasis on early ambulation, and restriction of the use of surgical​​ drains resulted in a 72% reduction in median opioid consumption​​ compared with patients receiving conventional post-operative recovery measures. ​​ Observational,​​ interventional - before/after ERAS implementation. ​​ (607 patients). ​​ 


Mediterranean Diet​​ Adherence Associated with Less Severe Psoriasis

July 26th, JAMA Dermatology:​​ In a survey-based study, patients​​ who adhered to a Mediterranean diet were nearly 30% less likely to have severe psoriasis than patients who did not adhere​​ closely​​ to a Mediterranean diet. ​​ Cross-sectional​​ observational, NutriNet-Sante Cohort (35,735 survey participants, 3557 reported having psoriasis.) ​​ 



Antidepressant​​ Use​​ Associated with Slightly Worse Outcomes in COPD

July 27th, European Respiratory Journal:​​ Recent initiation of selective serotonin reuptake inhibitor (SSRI) or serotonin/norepinephrine reuptake inhibitor (SNRI) medications in older patients with chronic obstructive pulmonary disease (COPD) was associated with a 20% higher mortality rate​​ compared to​​ propensity-matched controls who​​ had not recently started​​ SSRI/SNRI therapy. ​​ Retrospective observational (131,718 patients). ​​​​ 



Flavonoid​​ Ingestion Associated with Decreased Risk of​​ AMD

July 6th, American Journal of Clinical Nutrition:​​ A correlation has been observed between flavonoid – a type of dietary phytochemical antioxidant present in oranges and​​ some​​ other fruits and vegetables​​ - ingestion and​​ a​​ decreased​​ risk of age-related macular degeneration (AMD). ​​ Each standard-deviation increase​​ in​​ flavonoid intake was associated with a 34% lower odds ratio of developing AMD. ​​ Observational retrospective (2,856 patients). ​​​​ 



Norepinephrine​​ Associated with Lower Risk of Refractory Shock than Epinephrine Following Myocardial Infarction

July 10th, JACC:​​ Administration of norepinephrine​​ and​​ was associated with similar vascular and cardiac effects as​​ administration of​​ epinephrine in patients with cardiogenic shock following myocardial infarction. ​​ Norepinephrine was associated with a significantly lower risk of refractory shock (7% of patients) compared with epinephrine (37% of patients). ​​ RCT, OptimaCC Clinical Trial (57 patients). ​​ 



Low-Dose​​ Rivaroxaban​​ Associated with Higher Risk of Myocardial Infarction in Asians​​ with Atrial Fibrillation

July 24th, JACC: ​​​​ Compared to standard-dose rivaroxaban (Xarelto, a direct factor Xa inhibitor),​​ 10​​ mg/day​​ rivaroxaban​​ was associated with an approximately two-fold higher risk of myocardial infarction​​ in Asian patients with atrial fibrillation. ​​ Retrospective observational (6,558 patients). ​​​​ 



Dolutegravir​​ Antiretroviral Therapy Associated with Increased Risk of Neural Tube Defects

July 24th, NEJM: ​​​​ Infants born to HIV-positive women receiving dolutegravir (Tivicay, an HIV integrase inhibitor)-based antiretroviral therapy from the time of conception were found to have an 82% increased risk of neural tube defects compared with infants born to women receiving other antiretroviral therapies. ​​ Observational (88,755 births, 86 neural-tube defects). ​​​​ 



Two-Drug HIV​​ Antiretroviral​​ Regimen Non-Inferior to Three-Drug Regimen

July 25th, ViiV Healthcare:​​ A two-drug dolutegravir and lamivudine (integrase inhibitor and reverse transcriptase inhibitor, respectively) combination was found to be non-inferior compared to the standard, first-line three drug dolutegravir/tenofovir/emtricitabine (integrase inhibitor + two reverse transcriptase inhibitors) combination therapy with respect to viral load in HIV infected individuals after 48 weeks of treatment. ​​ Two RCTS, GEMINI I/II (~1,400 participants).​​ 



Escitalopram​​ Following Acute Coronary Syndrome Associated with Improved Outcomes

July 24th, JAMA: ​​​​ 24 weeks of escitalopram (Lexapro, a​​ selective serotonin reuptake inhibitor)​​ in patients experiencing depression following​​ a recent episode of​​ acute coronary syndrome was associated with an 18% decrease in​​ all-cause mortality compared with patients receiving placebo. ​​ RCT (300 patients). ​​​​ 



Rabinizumab​​ and Panretinal Photocoagulation Similarly Effective in Proliferative Diabetic Retinopathy

July 24th, JAMA Opthalmology:​​ Panretinal photocoagulation (PRP) therapy and rabinizumab were similarly effective in delaying the progression of diabetic proliferative retinopathy 5 years after initation of therapy. ​​ Patients treated with rabinizumab were 40% as likely to develop vision-impairing macular edema as those treataed with PRP. ​​ RCT, 5-year follow-up (184 participants -initial cohort size: 305).​​ 


~  ​​ ​​​​ Reviews  ​​ ​​​​ ~


Shorter Duration of​​ Antifungal​​ Therapy More Effective in HIV-Associated Cryptococcal Meningitis​​ 

July 25th, Cochrane:​​ 1 week of intravenous amphotericin B deoxycholate + oral flucytosine followed by 1 week of oral fluconazole was associated with lower 10-week mortality than guideline-recommended 2 weeks of IV amphotericin B deoxycholate + oral flucytosine. ​​ In circumstances where IV​​ amphotericin is unavailable, a two week regimen of oral flucytosine + fluconazole may be comparably effective. ​​ Systematic review and meta-analysis (13 studies, 2426 participants). ​​​​ 



Vancomycin + Pip-Tazo​​ Associated with Increased Risk of Kidney Injury​​ 

July 27th, Annals of Emergency Medicine:​​ Combination vancomycin and piperacillin-tazobactam was associated with a significantly higher risk acute kidney injury than vancomycin/piperacillin-tazobactam monotherapy,​​ vancomycin + cefepime,​​ or vancomycin +​​ carbapenem combination therapy. ​​ Systematic review and meta-analysis (15 studies, 17 abstracts – 24,799 patients).



Depression,​​ Anti-Depressant​​ Use​​ Associated with Increased Venous Thromboembolic Risk

July 12, Annals of Medicine: ​​​​ Antidepressants of several classes were associated with a 12-59% increased risk of venous thromboembolism (VTE). ​​ Analysis of a subset of studies suggested a 31% higher risk​​ of VTE in patients with depression, compared with those without depression, regardless of antidepressant use. ​​ Systematic review and meta-analysis​​ (8 observational studies, 960,113 participants.) ​​​​ 




by​​ pharmacologyreview