Samara Rosenfeld

Recent study findings demonstrate the efficacy of dupilumab in significantly reducing severe exacerbation rates in patients with uncontrolled, persistent eosinophilic asthma.

Ian Pavord, FRCP, FMedSci, and colleagues conducted meta-analyses of dupilumab compared with standard of care on annualized severe exacerbation rates in patients with eosinophilic asthma. Dupilumab, a monoclonal antibody, blocks the shared receptor component for interleukin (IL)-4 and IL-13, drivers of type 2 inflammation in multiple diseases.

The investigators obtained data from the phase 3 QUEST and phase 2b studies to identify 3 subgroups of patients with baseline blood eosinophil count, inhaled corticosteroids dose, and number of severe exacerbations that matched the key inclusion criteria of clinical trials of anti-IL-5 biologics. The subgroups of patients had baseline characteristics similar to those of clinical trials for benralizumab (medium-/high-dose inhaled corticosteroid/long-acting β2 -agonist [LABA], eosinophils ≥300 cells/µL, ≥2 previous exacerbations, age at least 12 years old); mepolizumab (high-dose inhaled corticosteroid/LABA, eosinophils ≥150 cells/µL, ≥2 previous exacerbations, age at 12 years old); and reslizumab (medium-/high-dose inhaled corticosteroid/LABA, eosinophils ≥400 cells/µL, ≥1 previous exacerbation, age at least 18 years old).

Pavord and the team pooled the estimates of effect for dupilumab versus standard of care on annualized severe asthma exacerbation rates from the phase 3 and phase 2b studies. They calculated Number Needed to Treat to have 1 less severe exacerbation per year when using dupilumab instead of standard of care.

The team found dupilumab 200 mg and 300 mg every 2 weeks significantly reduced the annualized severe exacerbation rate in all 3 subgroups versus the standard of care. The exacerbation rate ratio for each subgroup was .26 (95% CI, .21-.33), .36 (95% CI, .29-.44), and .29 (95% CI, .23-.36), respectively, which represented a 64-74% relative exacerbation rate reduction.

The Number Needed to Treat was .91 (95% CI, .853-1.005), 1.033 (95% CI, .931-1.18), and 1.107 (95% CI, 1.034-1.228), respectively. These results indicated only 1 patient would need to be treated with dupilumab instead of standard of care to have 1 less severe asthma exacerbation per year.

Overall, the meta-analyses demonstrated dupilumab significantly reduced severe exacerbation rates in subgroups of patients with uncontrolled, persistent eosinophilic asthma.

 by the US Food and Drug Administration in 2018 as an add-on maintenance therapy for adults and adolescents at least 12 years old with an eosinophilic phenotype or with oral corticosteroid-dependent asthma.

Meta-Analyses of Dupilumab Versus Standard of Care in Patients with Uncontrolled, Persistent Asthma

,” was presented as part of the American Thoracic Society annual meeting.

Articles

Dupilumab significantly reduces exacerbation rates in patients with asthma compared to standard of care.

Dupilumab Reduces Asthma Exacerbation Rates

The use of direct oral anticoagulants in obese patients is equally efficacious with similar 

 recurrence rates compared with non-obese patients.

The findings were presented at the American Thoracic Society annual meeting.

Moustafa Younis, MBBS, and colleagues aimed to assess the rate of venous thromboembolism recurrence in obese patients diagnosed with the condition and treated with direct oral anticoagulants. The team used the Health Facts Center national data warehouse to conduct a retrospective analysis of patients with venous thromboembolism who presented at the hospital between 2010 and 2016 and were treated with direct oral anticoagulants. ICD-9-CM and ICD-10-CM codes were used to identify patients diagnosed with deep vein thrombosis or venous thromboembolism.

Younis and the investigators divided patients into 2 groups based on their weight: less than 120 kg or more than 120 kg. They recorded 6 months of venous thromboembolism recurrence rates.

Overall, the team included 18,147 patients with a mean age of 62 years old. More than half of the patients were female (52%).

Of the patients, 2419 (13%) weight more than 120 kg while the rest (15,728; 87%) weighed less than 120 kg. Significantly more female patients weighed less than 120 kg (54% vs 42%; 

 <.0001). There were no significant differences in age or tobacco use between both groups (

The investigators noted no significant difference in six months readmission rate for venous thromboembolism recurrence in patients that weighed less 120 kg (34%) compared with patients who weighed more than 120 kg (36%) (

The findings suggested the use of direct oral anticoagulants in obese patients was equally efficacious with similar venous thromboembolism recurrences rates compared with non-obese patients. Use of direct oral anticoagulants gained significant traction due to the lack of therapeutic monitoring and need for anticoagulant bridging. Data exist on the effectiveness of direct oral anticoagulants in obese patients with venous thromboembolism. In fact, preliminary subgroup and pharmacokinetic analyses demonstrated reduced efficacy in patients with a body weight of more than 120 kg or a body mass index of at least 40 kg per m2.

It is not currently recommended for such agents to be used as first line agents.

“This study paves the way for prospective multi-institutional randomized control trials to further re-enforce the safe use of such agents in this patient population,” the study authors concluded.

The Use of Direct Oral Anticoagulants in the Management of Venous Thromboembolism in Patients with Obesity

The study paves the way for prospective multi-institutional randomized control trials to further re-enforce the safe use of direct oral anticoagulants in patients with obesity.

DOACs in Obese Patients Show Similar VTE Recurrence Rates to Non-Obese Patients

Compared to placebo treatment, there was no difference in the reduction of

 and disability for those who underwent spinal manipulation or spinal mobilization.

The findings suggested spinal manipulation and spinal mobilization were both ineffective interventions for young adults with mild to moderate chronic low back pain.

James Thomas, PhD, and colleagues conducted a single-blinded, placebo-controlled randomized clinical trial to evaluate the comparative effectiveness of spinal manipulation and spinal mobilization at reducing pain and disability compared with a placebo control group.

The team randomized patients in a 1:1: ratio into 1 of 3 groups. In group 1, patients received spinal manipulation treatment 2 times per week for 3 weeks. Patients in group 2 received spinal mobilization treatment 2 times per week for 3 weeks. Those in the placebo group received sham cold laser treatment 2 times per week for 3 weeks.

For spinal manipulation treatment, participants were placed in a side-lying position facing the clinician with the more painful side facing upward. The clinician flexed the participant’s hips and knees to induce lumbar spine flexion until they felt the spinous process of the vertebrae begin to move. The participant was then rotated to their torso opposite to the side they were lying on until they felt rotation. The clinician added thrust to the shoulder and pelvis which resulted in a rotation force. Treatment was complete if an audible pop occurred. If not, the treatment was attempted again with a maximum of 2 attempts per side.

During spinal mobilization treatment, the participant was positioned the same way as during spinal manipulation. A clinician put 1 hand on the anterior should and 1 on the posterior pelvis. The participant was told to gently push the shoulder and pelvis into the clinician’s hands. The participant held the contraction for a minimum of 7 seconds with a maximum of 60 seconds. If an audible pop occurred or the clinician noticed a release in tissue tension, treatment was considered complete.

In the placebo group, a sham laser was delivered over the painful region. An insignificant amount of light energy or heat was delivered.

The investigators randomized 162 participants with a mean age of 25 years old, a majority of whom were women (57%), with chronic low back pain (mean NPRS sore, 4.3 on a scale of 1-10; higher scores indicated more pain). Of the participants, 54 were randomized into each group. The team noted no significant group differences for sex, age, BMI, duration of low back pain symptoms, depression, fear avoidance, current pain, average pain over the last 7 days, and self-reported disability.

For the primary endpoint, there was no significant difference in change in pain scores between spinal manipulation and spinal mobilization (.24; 95% CI, -.38 to .86; 

=.45), spinal manipulation and placebo (-.03; 95% CI, -.65 to .59; 

=.92), or spinal mobilization and placebo (-.26; 95% CI, -.38 to .85; 

=.39). There was also no significant difference in change in self-reported disability scores between spinal manipulation and spinal mobilization (-1; 95% CI, -2.27 to .36; 

=.14), spinal manipulation and placebo (-.7; 95% CI, -1.43 to 1.29; 

=.92), or spinal mobilization and placebo (.93; 95% CI, -.41 to 2.29; 

“We conclude that these manipulative therapy techniques do not appear to be effective for chronic low back pain, at least among relatively young individuals with mild to moderate back pain,” Thomas and the team concluded.

Effect of Spinal Manipulative and Mobilization Therapies in Young Adults With Mild to Moderate Chronic Low Back Pain

Manipulative techniques are not effective for chronic low back pain among relatively young individuals. 

Manipulative Therapy Ineffective for Chronic Low Back Pain

Findings of a recent study demonstrated patients who started dipeptidyl peptidase-4 (DPP-4) inhibitor therapy had a higher risk of 

 than those who initiated second-generation sulfonylurea therapy.

The findings suggested clinicians should be aware of the rare adverse effect in subgroups with higher risk.

Hemin Lee, MD, MPH, and colleagues characterized the incidence rate of bullous pemphigoid associated with DPP-4 inhibitor use compared with second-generation sulfonylureas. The team used data from 3 large US healthcare databases, Optum Clinformatics Data Mart, IBM MarketScan Research Database, and Medicare Parts A, B, and D. The Optum and MarketScan databases included longitudinal medical and pharmacy claims of the commercially insured population in the US.

The investigators created a new-user cohort of patients with a prescription claim for a DPP-4 inhibitor or a second-generation sulfonylurea from the date of the first approval for DPP-4 inhibitors, October 17, 2006, to the end of available data in each database. They applied a washout period of 180 days for both drugs. The date of the first prescription corresponded to the date of cohort entry.

Patients were included if they had at least 180 days of continuous enrollment in commercial insurance and fee-for-service Medicare and at least 1 diagnosis of 

. The team excluded patients younger than 40 years old because bullous pemphigoid is typically seen in older individuals.

The primary outcome was the occurrence of bullous pemphigoid, defined based on ICD-9 or ICD-10 diagnosis codes. Follow-up started 1 day after cohort entry and continued until either the occurrence of bullous pemphigoid, the end of healthcare or pharmacy eligibility, the end of the study period, the switch to a comparator drug, and discontinuation of the index drug.

Overall, the cohort consisted of 870,709 new users of DPP-4 inhibitors, a majority of whom were female (51%) with a mean age of 63.7 years old. There were more than 1.9 million new users of second-generation sulfonylureas, with more than half (51.8%) being male and a mean age of 64.8 years old.

Before matching propensity scores, sulfonylurea users were older than DPP-4 inhibitor users (mean age, 64.8 years old vs 63.7 years old) and had a higher number of antidiabetic drugs prescribed at the index date (mean, 1.26 vs 1.16). After score matching, there were 199,780 pairs of DPP-4 inhibitor or second-generation sulfonylurea users in Optum, 354,759 pairs in MarketScan, and 277,901 pairs in Medicare.

The incidence rates (IRs) per 1000 person-years of bullous pemphigoid for DPP-4 inhibitor versus sulfonylurea groups in each database were .36 vs .27 cases (HR, 1.34; 95% CI, .88-2.04) in Optum; .19 vs .19 cases (HR, 1; 95% CI, .68-1.49) in MarketScan; and .81 vs .48 cases (HR, 1.68; 95% CI, 1.3-2.17) in Medicare. The pooled number in the 3 databases was 247 cases (IR, .42 per 1000 person-years) in the DPP-4 inhibitor group and 184 cases (IR, .31 per 1000 person-years) in the sulfonylurea group. The pooled HR was 1.42 (95% CI, 1.17-1.72).

The team analyzed subgroups of patients in both groups and found there was an increased risk in those who were at least 65 years old (pooled HR, 1.62; 95% CI, 1.32-1.99) and while (pooled HR, 1.7; 95% CI, 1.3-2.24). For DPP-4 inhibitor agents, linagliptin showed the highest risk (pooled HR, 1.68; 95% CI, 1.16-2.43). The risk was less obvious in sitagliptin and saxagliptin compared with sulfonylurea use. Higher risk of bullous pemphigoid in the DPP-4 inhibitor groups was similar between men (pooled HR, 1.38; 95% CI, 1.06-1.79) and women (pooled HR, 1.34; 95% CI, 1.03-1.75).

The results of the study were consistent with other previous studies in reporting a positive association between DPP-4 inhibitors and bullous pemphigoid. Although there was an increased risk of bullous pemphigoid among DPP-4 inhibitor users compared with second-generation sulfonylurea users, the condition is rare and not all cases are associated with morbidity or mortality.

“Therefore, although clinicians should not avoid DPP-4 inhibitors entirely in patients with type 2 diabetes who may be otherwise good candidates for the therapy, they should be aware of the potential risk of bullous pemphigoid in DPP-4 inhibitor use, especially in subgroups of older and white patients and linagliptin users,” Lee and the investigators concluded.

Evaluation of Risk of Bullous Pemphigoid With Initiation of Dipeptidyl Peptidase-4 Inhibitor vs Second-generation Sulfonylurea

Older, white patients and those who use linagliptin are at a higher risk of bullous pemphigoid.

Author | Samara Rosenfeld

Articles

Dupilumab Reduces Asthma Exacerbation Rates

DOACs in Obese Patients Show Similar VTE Recurrence Rates to Non-Obese Patients

Manipulative Therapy Ineffective for Chronic Low Back Pain

DDP-4 Inhibitors Increase Risk of Bullous Pemphigoid