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APhA Staff

Daprodustat offers an alternative for treatment of anemia in incident dialysis patients 

Hemodialysis has become a safe and well-tolerated therapy for patients with chronic kidney disease, but patients starting dialysis, known as incident dialysis patients, are at risk from abrupt physiological changes, including anemia. Injectable erythropoiesis stimulating agents (ESAs) such as darbepoetin alfa and epoetin alfa are routinely used to treat anemia in these patients, but a global group of researchers led by Ajay K. Singh, MBBS, at Brigham and Women’s Hospital (Boston) have suggested that oral daprodustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, could be used as an alternative treatment.

The researchers conducted a randomized open-label clinical trial of 312 incident dialysis patients in 90 centers across 14 countries. Patients with advanced CKD were eligible if they planned to start dialysis within 6 weeks from screening or had started and received hemodialysis or peritoneal dialysis within 90 days before randomization, had a screening hemoglobin (Hb) concentration of 8.0 to 10.5 g/dL and a randomization Hb of 8.0 to 11.0 g/dL, were ESA-naive or had received limited ESA treatment, and were iron-replete. Patients were randomized 1:1 to receive oral daprodustat or injectable darbepoetin alfa.

Results of the study, published on April 4, 2022, in JAMA Internal Medicine, showed that the mean Hb concentration during the evaluation period was 10.5 g/dL for the daprodustat and 10.6 g/dL for the darbepoetin alfa group, indicating noninferiority. Adverse event rates were 76% for daprodustat versus 72% for darbepoetin alfa. The authors concluded that hypoxia-inducible factor prolyl hydroxylase inhibitors such as daprodustat may represent a potential oral alternative to a conventional ESA for incident dialysis patients. ■

SGLT-2 inhibitors before metformin?

Both SGLT-2 inhibitors and metformin are used to lower blood glucose in patients with diabetes, but which medication should be used first for newly diagnosed patients? A recent cohort study by Shin and colleagues at Brigham and Women’s Hospital and Harvard Medical School (Boston) assessed cardiovascular outcomes among adults with type 2 diabetes who were treated with either first-line SGLT-2 inhibitors or metformin.

The study, published on May 24, 2022, in the Annals of Internal Medicine, used claims data from two large U.S. commercial and Medicare databases from April 2013 to March 2020. Patients with type 2 diabetes aged 18 years and older initiating treatment with SGLT-2 inhibitors (canagliflozin, empagliflozin, or dapagliflozin) or metformin during April 2013 to March 2020, with no use of diabetes medications before cohort entry, were identified. Treatment selection was not randomized.

Among 8,613 patients receiving first-line SGLT-2 inhibitors matched to 17,226 patients receiving metformin, those receiving SGLT-2 inhibitors as a first treatment had a similar risk for myocardial infarction, stroke, and all-cause mortality, and a lower risk for heart failure than those who received metformin during a mean follow-up of 12 months. The two groups showed a similar safety profile except for a significantly higher risk for genital infections (5.4% vs. 2.4% annually) for those receiving SGLT-2 inhibitors compared with those receiving metformin. ■

Trials evaluate tenecteplase for treatment of ischemic stroke

Two recent studies, one in Norway and the other in Australia, compared the efficacy of tenecteplase with that of alteplase, the global standard for treatment of ischemic stroke. Both studies were published in the June 2022 issues of The Lancet Neurology.

The first study, a phase 3, randomized, open-label, blinded-endpoint NOR-TEST trial conducted by Kvistad and colleagues at 11 Norwegian hospitals with stroke units, investigated the efficacy and safety profile of 0.4 mg/kg of tenecteplase and 0.9 mg/kg of altephase in patients with moderate or severe ischemic stroke.

More than 200 patients with suspected acute ischemic stroke who were eligible for thrombolysis and admitted within 4 to 5 hours of symptom onset between October 28, 2019, and September 26, 2021, were included in the study. The primary outcome was favorable functional outcome defined as a modified Rankin Scale score of 0–1 at 3 months. The trial was stopped early for safety reasons and is designated part A for analysis. Part B is ongoing with a lower dose of tenecteplase (0.5 mg/kg).

Findings of the study indicated that a favorable functional outcome was reported in 32% of patients who received tenecteplase compared with 51% of patients who received al-teplase. Intracranial hemorrhage and mortality at 3 months were also more frequent in those treated with tenecteplase than those treated with alteplase. The researchers concluded that future trials should assess a lower dose of tenecteplase versus alteplase.

The second study, a phase 2, randomized, open-label trial at the Melbourne mobile stroke unit (MSU) and 5 tertiary hospitals in Melbourne, Australia (TASTE-A) tested the hy-pothesis that tenecteplase administered in an MSU would result in superior reperfusion at hospital arrival when compared with treatment with alteplase.

Adult patients with ischemic stroke who were eligible for thrombolytic treatment were randomly assigned to receive, within 4 to 5 hours of symptom onset, either standard-of-care alteplase (0.9 mg/kg with a maximum of 90 mg) administered intravenously with 10% as a bolus over one minute and 90% as an infusion over one hour or tenecteplase (0.5 mg/kg with a maximum of 25 mg) administered as an intravenous bolus over 10 seconds before being transported to the hospital for ongoing care.

The primary outcome was the volume of the perfusion lesion on arrival at the hospital, assessed by CT-perfusion imaging. Secondary safety outcomes were a modified Rankin Scale score of 5 or 6 at 90 days, symptomatic intracerebral hemorrhage within 36 hours, and death at 90 days.

Between June 20, 2019, and November 16, 2021, 104 patients were enrolled in the study. On arrival at the hospital, the perfusion lesion volume was significantly smaller after treatment with tenecteplase than with alteplase. At 90 days, a modified Rankin Scale of 5 or 6 was reported in 15% of patients who received tenecteplase and 20% of patients who received alteplase. Mortality from any cause at 90 days was similar for the two groups. No cases of symptomatic intracerebral hemorrhage were reported within 36 hours with either treatment.

Through day 90, 13 serious adverse events were noted: five (5%) in patients treated with tenecteplase and eight (8%) in patients treated with alteplase. The authors concluded that treatment with tenecteplase in the MSU resulted in a superior rate of early reperfusion compared with treatment with alteplase, supporting the use of tenecteplase and MSUs in stroke care.

The divergent results of these two studies indicate that further study of tenecteplase, particularly a noninferiority study using the lower 0.5 mg/kg dose, would be valuable in assessing first-line treatment of ischemic stroke. ■