With medicine advancing at such a rapid pace, it is crucial for physicians to keep up with the medical literature. This can quickly become an overwhelming endeavor given the sheer quantity and breadth of literature released on a daily basis. Primecuts helps you stay current by taking a shallow dive into recently released articles that should be on your radar. Our goal is for you to slow down and take a few small sips from the medical literature firehose.
Using data from two randomized, open-label, controlled trials, this article compared the efficacy and safety of vadadustat, an oral hypoxia-inducible factor (HIF), to an erythropoiesis-stimulating agent (ESA) named darbepoetin alfa, the standard of care in treatment of maintenance anemia in non-dialysis-dependent chronic kidney disease (NDD-CKD).
The two phase 3 studies enrolled 3476 participants with NDD-CKD not previously treated with an ESA with a hemoglobin concentration of <10 g/dL and NDD-CKD patients previously treated with an ESA with a hemoglobin concentration of 8-10 g/dL in the United States or 9-12 g/dL in other countries. Participants were randomized in a 1:1 ratio to receive either oral vadadustat or subcutaneous or intravenous darbepoetin alfa. The primary efficacy outcome was mean change in hemoglobin concentration from baseline during weeks 24 – 36 (primary evaluation period) as well as during weeks 40 – 52 (secondary evaluation period) with a noninferiority margin of -0.75 g/dL. The primary safety end point was the first major cardiovascular event (MACE) defined as death from any cause, nonfatal myocardial infarction, or nonfatal stroke, assessed in a time-to-event analysis with a noninferiority margin of 1.25.
The mean change in hemoglobin concentration in ESA-treated patients during the primary evaluation period was -0.01 g/dL (95% confidence interval, -0.09 to 0.07) and in the ESA-untreated patients was 0.05 g/dL (95% confidence interval, -0.04 to 0.15). Further, the mean change during the secondary evaluation period for corresponding values was 0.00 g/dL (95% confidence interval, -0.10 to 0.09) and 0.04 g/dL (95% confidence interval, -0.06 to 0.14). Hence, vadadustat was shown to be noninferior to darbepoetin alfa in hematologic efficacy. However, the noninferiority criteria was not met with the primary safety endpoint, a first MACE. In the pooled analysis across the two trials, a first MACE occurred in 22% of the vadadustat group and in 19.9% in the darbepoetin alfa group, a hazard ratio of 1.17 (95% confidence interval, 1.01 to 1.36).
The reason for the percentage of patients with a first MACE being higher in the vadadustat group remains unclear. The authors propose that higher hemoglobin concentration targets in non-U.S. countries may have contributed as the findings seemed to be driven by non-U.S. participants. However, the U.S. and non-U.S. participants achieved similar mean hemoglobin concentrations. Furthermore, as described below, the results published by Eckardt et al.  in the same issue of The New England Journal of Medicine demonstrate that in similar trials among dialysis-dependent CKD (DD-CKD) patients vadadustat was noninferior with respect to a first MACE. It is known that the safety profile of medications can differ in NDD-CKD compared to DD-CKD patients, but more studies are needed to determine why vadadustat did not meet the noninferiority margin and whether the benefits outweigh the risks of vadadustat in CKD patients.
This article, similar to the one above by Chertow et al.  which was published in the same issue of The New England Journal of Medicine, compared the hematologic efficacy and cardiovascular safety of vadadustat to darbepoetin alfa using data from two randomized, open-label, controlled trials among dialysis-dependent chronic kidney disease (DD-CKD) patients, rather than non-dialysis-dependent CKD patients as above.
The two phase 3 studies enrolled 3923 participants with anemia and incident DD-CKD (initiated dialysis within 16 weeks before screening and had limited exposure to ESAs) with a hemoglobin concentration between 8 – 11 g/dL or prevalent DD-CKD (undergoing maintenance dialysis for at least 12 weeks before screening and were receiving treatment with an ESA) with a hemoglobin concentration between 8 – 11 g/dL in the United States or 9 – 12 g/dL in other countries. Participants were randomized in a 1:1 ratio to receive either vadadustat or darbepoetin alfa. The primary efficacy outcome was mean change in hemoglobin concentration from baseline during weeks 24 – 36 (primary evaluation period) as well as during weeks 40 – 52 (secondary evaluation period) with a noninferiority margin of -0.75 g/dL. The primary safety end point was the first major cardiovascular event (MACE) defined as death from any cause, nonfatal myocardial infarction, or nonfatal stroke, assessed in a time-to-event analysis with a noninferiority margin of 1.25. The secondary safety end point was first occurrence of “expanded MACE” (a MACE plus hospitalization for either heart failure or a thromboembolic event, excluding vascular access failure).
The mean change in hemoglobin concentration between groups during the primary evaluation period in the incident DD-CKD trial was -0.31 g/dL (95% confidence interval, -0.53 to -0.10) and in the prevalent DD-CKD trial was -0.17 g/dL (95% confidence interval, -0.23 to -0.10). Further, the mean change during the secondary evaluation period for corresponding values was -0.07 g/dL (95% confidence interval, -0.34 to 0.19) and -0.18 g/dL (95% confidence interval, -0.25 to -0.12). Thus, vadadustat was shown to be noninferior to darbepoetin alfa in hematologic efficacy. Contrary to the study above, the noninferiority criteria was met with the primary and secondary safety endpoints. In the pooled analysis across the two trials, a first MACE occurred in 18.2% of the vadadustat group and in 19.3% in the darbepoetin alfa group, a hazard ratio of 0.96 (95% confidence interval, 0.83 to 1.11).
The results of this study and those published by Chertow et al.  demonstrate the noninferiority of oral vadadustat compared to darbepoetin alfa in the maintenance treatment of anemia in both dialysis-dependent and non-dialysis-dependent CKD patients. However, there are limitations of the noninferiority design and additional studies need to be conducted, as questions still remain as to whether vadadustat offers any additional efficacy or reduction of adverse effects. Further, no assessment can be made regarding potential improvements in cost or convenience, the latter which might be an indication to choose vadadustat over darbepoetin alfa.
Promising studies have shown that there are possibly treatment options of shorter duration for tuberculosis. This randomized controlled trial sought to evaluate whether rifapentine with or without moxifloxacin for 4 months could effectively treat tuberculosis compared to the standard 6-month regimen, as well as assessing its safety profile.
The phase 3 study enrolled 2343 participants across 4 continents with newly diagnosed culture-positive tuberculosis that was not resistant to rifampin, isoniazid, or fluroquinolones and randomized in a 1:1:1 ratio to a 6-month control regimen with rifampin, isoniazid, pyrazinamide, and ethambutol, a 4-month regimen in which rifapentine at a daily dose of 1200mg replaced rifampin, or a 4-month regimen in which rifapentine replaced rifampin and moxifloxacin at a daily dose of 400mg replaced ethambutol. The primary efficacy outcome was survival free of tuberculosis at 12 months with a noninferiority margin of 6.6 percentage points. The primary safety outcome was an adverse event of grade 3 or higher during the time in which the trial medications were administered up to 14 days later. There were 2 analysis populations, namely the microbiologically eligible population (patients with culture-positive drug-susceptible tuberculosis) and the assessable population (patients in the microbiologically eligible population whose outcome was not assessable).
The absence of tuberculosis disease-free survival at 12 months after randomization in the microbiologically eligible population was 15.5% in the rifapentine-moxifloxacin group vs. 14.6% in the control group (95% confidence interval, -2.6 to 4.5), and corresponding values in the assessable population were 11.6% vs. 9.6% (95% confidence interval, -1.1 to 5.1). Thus, the 4-month rifapentine-moxifloxacin regimen was shown to be noninferior to the standard 6-month regimen in efficacy. The rifapentine group was not shown to be noninferior to the control group in either analysis population. Additionally, there was no significant difference in adverse events of grade 3 or higher in the rifapentine-moxifloxacin group compared to the control group.
While the results of this study are convincing, there are several limitations of this study. Most notably, neither the participants nor the staff were blinded. Further, there are several issues to address before implementing the regimen change. This necessitates use of rapid molecular drug susceptibility testing to fluoroquinolones and isoniazid which is only currently in clinical testing. Further, the drug cost of changing the standard regimen might be higher in the short term. In summary, this study provided evidence for efficacy and safety of a shorter duration treatment of tuberculosis; however, more studies are needed to determine the feasibility of changing national tuberculosis programs.
In this randomized, head-to-head, placebo controlled trial obese, non-diabetic adults (BMI 32 – 43) followed a low calorie diet (800 kcal per day) for 8 weeks and participants that lost at least 5% of their body weight (in total 166) were randomized to 4 treatment strategies for 1 year: exercise plus liraglutide, exercise plus placebo, liraglutide plus usual activity, or placebo plus usual activity. The study found that the combination of liraglutide and a moderate-to-vigorous-intensity exercise program was more effective in maintaining weight loss than either exercise or liraglutide alone. While the exclusion criteria limits generalizability to patients with diabetes, older age (>65 years old), and greater obesity (BMI > 43), this study suggests liraglutide can be useful in select patients with adherence to exercise programs.
Effect of Half-Dose vs. Stable-Dose Conventional Synthetic Disease-Modifying Antirheumatic Drugs on Disease Flare in Patients with Rheumatoid Arthritis in Remission: The ARTIC REWIND Randomized Clinical Trial 
This randomized, parallel, open-label noninferiority study in which 155 rheumatoid arthritis (RA) patients in remission for 12 months were randomized to half-dose synthetic disease-modifying antirheumatic drugs (csDMARDs) or stable-dose csDMARDs found that there were significantly fewer flares over 12 months in the stable-dose group (flares occurred in 25% in half-dose group compared with 6% in stable-dose group [risk difference 18%, p=0.003]). The results of this study argue against treatment of RA patients in remission with half-dose therapy. However, further studies are needed to determine if any level of tapering can be tolerated and to further study other csDMARDs as methotrexate monotherapy was used by most patients.
Effect of Therapeutic Drug Monitoring vs Standard Therapy During Infliximab Induction on Disease Remission in Patients With Chronic Immune-Mediated Inflammatory Diseases: A Randomized Clinical Trial 
In this randomized, parallel-group, open-label clinical trial 411 patients with rheumatoid arthritis, ulcerative colitis, Crohn disease, spondyloarthritis, psoriatic arthritis, or psoriasis initiating infliximab therapy were randomized to therapeutic drug monitoring (at each infusion, trough levels and antidrug antibodies were measured and the recommended dose and interval was calculated) or standard therapy without drug and antibody monitoring Clinical remission over 30 weeks was achieved in 50.5% in the therapeutic drug monitoring and 53% of standard therapy groups (adjusted difference 1.5%, p=0.78). Therefore, there was no significant difference in clinical remission rates, thus proactive monitoring during infliximab induction is not recommended. It is known that the lack of response to TNF inhibitors can be associated with the formation of antidrug antibodies as result of the immune response, and the authors propose two interesting theories as to why the monitoring of antibodies did not improve remission rates [7,8]. First, perhaps only a subset of patients develop antidrug antibodies and this study did not include sufficient number of patients, and secondly it is possible that the formation of antidrug antibodies is irreversible. However more studies are needed to examine this.
Dr. Kyra Hansson Floyd is a first-year resident at NYU Langone Health
Peer reviewed by Pamela Boodram, MD, chief resident, NYU Langone Internal Medicine Residency
Image courtesy Pixabay
- Pergola PE, Farag Youssef MK, Rajiv A, et al. Vadadustat in Patients with Anemia and Non–Dialysis-Dependent CKD. N Engl J Med. 2021;384(17):1589-1600. https://www.nejm.org/doi/full/10.1056/NEJMoa2035938
- Rajiv A, Aswad A, Awad A, et al. Safety and Efficacy of Vadadustat for Anemia in Patients Undergoing Dialysis. N Engl J Med. 2021;384(17):1601-1612. https://www.nejm.org/doi/full/10.1056/NEJMoa2025956
- Dorman SE, Kurbatova EV, Phillips Patrick PJ, et al. Four-Month Rifapentine Regimens with or without Moxifloxacin for Tuberculosis. N Engl J Med. 2021;384(18):1705-1718. https://www.nejm.org/doi/full/10.1056/NEJMoa2033400
- Lundgren JR, Janus C, Jensen Simon BK, et al. Healthy Weight Loss Maintenance with Exercise, Liraglutide, or Both Combined. N Engl J Med. 2021;384(18):1719-1730. https://www.nejm.org/doi/full/10.1056/NEJMoa2028198
- Lillegraven S, Paulshus Sundlisæter N, Aga A, et al. Effect of Half-Dose vs Stable-Dose Conventional Synthetic Disease-Modifying Antirheumatic Drugs on Disease Flares in Patients With Rheumatoid Arthritis in Remission: The ARCTIC REWIND Randomized Clinical Trial. 2021;325(17):1755–1764. https://jamanetwork.com/journals/jama/article-abstract/2779548
- Syversen SW, Goll GL, Jørgensen KK, et al. Effect of Therapeutic Drug Monitoring vs Standard Therapy During Infliximab Induction on Disease Remission in Patients With Chronic Immune-Mediated Inflammatory Diseases: A Randomized Clinical Trial. 2021;325(17):1744–1754. https://jamanetwork.com/journals/jama/article-abstract/2779549
- Thomas SS, Borazan N, Barroso N, et al. Comparative immunogenicity of TNF inhibitors: impact on clinical efficacy and tolerability in the management of autoimmune diseases. a systemic review and meta-analysis. BioDrugs. 2015;29(4):241-258. https://link.springer.com/article/10.1007%2Fs40259-015-0134-5
- Nencini F, Vultaggio A, Pratesi S, et al. The kinetics of antidrug antibodies, drug levels, and clinical outcomes in infliximab-exposed patients with immune-mediated disorders. J Allergy Clin Immunol Pract. 2018;6(6):2065-2072. https://www.sciencedirect.com/science/article/abs/pii/S2213219818302782