2 Minute Medicine Rewind September 23, 2019

The clinical effectiveness of sertraline in primary care and the role of depression severity and duration (PANDA): a pragmatic, double-blind, placebo-controlled randomised trial

1. Selective serotonin reuptake inhibitors (SSRIs) are not associated with significant short-term reductions in depressive symptoms in the primary care setting, but reduce short-term anxiety and improve mental health and health-related quality of life.

Evidence Rating Level: 1 (Excellent)

While most patients with depression are managed in the primary care setting, there is limited evidence regarding the effectiveness of antidepressants across different severities of illness in the outpatient setting. This is largely due to the narrow eligibility criteria used in studies conducted thus far, specifically concerning the diagnoses and severity of disease in research participants. The PANDA trial examined the effectiveness of sertraline in primary care patients with all severities of depression. Using a pragmatic, multi-centre double-blind design, 655 patients age 18 to 74 years with clinical uncertainty regarding benefit of antidepressants were randomly assigned to sertraline 50 mg daily or placebo, for a maximum of 11 weeks. Through the inclusion of patients where there was clinical uncertainty, the authors were able to generate a study sample more generalizable to the general population currently receiving antidepressant medications. The primary outcome was depressive symptoms 6 weeks after randomization, and was measured using the Patient Health Questionnaire 9-item version (PHQ-9). Researchers found no clinically meaningful difference in depressive symptoms after 6 weeks of therapy with sertraline compared to placebo, with mean PHQ-9 scores of 7.98 (SD 5.63) and 8.76 (SD 5.86) in the two groups, respectively (adjusted proportional difference 0.95, 95% CI 0.85 to 1.07, p=0.41). Sertraline was however found to reduce anxiety symptoms (adjusted proportional difference 0.79, 95% CI 0.70 to 0.89 at 6 weeks), improve mental health-related quality of life (2.41, 95% CI 1.14 to 3.96, p=0·00021), and enhance self-reported mental health improvement (adjusted OR 1.96, 95% CI 1.45 to 2.63, p<0·0001), compared to placebo. Adverse events were comparable between groups. The findings of the PANDA trial therefore suggest that while sertraline is not associated with reductions in 6-week depressive symptoms, benefits in anxiety, quality of life and self-rated mental health may support selective serotonin reuptake inhibitor use in primary care for mild to moderate symptoms of depression and/or generalized anxiety.

Patiromer versus placebo to enable spironolactone use in patients with resistant hypertension and chronic kidney disease (AMBER): a phase 2, randomised, double-blind, placebo-controlled trial

1. Potassium binder therapy with patiromer can promote longer duration of spironolactone use for resistant hypertension in the setting of chronic kidney disease.

Evidence Rating Level: 1 (Excellent).

Spironolactone is recommended in the treatment of resistant hypertension, however there is limited data regarding its use in the setting of chronic kidney disease (CKD). In CKD, where the use of spironolactone for resistant hypertension may be limited by the risk of developing hyperkalemia, there may be a role for potassium binders such as patiromer. In the AMBER trial, a phase II, multi-centre, randomized, double-blind trial, 295 participants with CKD and resistant hypertension were randomized to receive patiromer 8.4g once daily or placebo for 12 weeks to evaluate the safety and efficacy of patiromer therapy as an adjunct to spironolactone and baseline blood pressure medications in the treatment of resistant hypertension. The primary outcome was the between-group difference in proportions of patients using spironolactone at week 12. Researchers found that 86% and 66% of patiromer and placebo-group participants remained on spironolactone therapy at week 12, respectively (between-group difference 19.5%, 95% CI 10.0% to 29.0%, p<0.0001). Adverse events were minor and comparable between groups. This study therefore shows that patiromer therapy may facilitate prolonged use of spironolactone therapy in patients with CKD and resistant hypertension.

Glycaemic durability of an early combination therapy with vildagliptin and metformin versus sequential metformin monotherapy in newly diagnosed type 2 diabetes (VERIFY): a 5-year, multicentre, randomised, double-blind trial

1. Early combination therapy with vildagliptin and metformin is associated with improved glycemic durability in the setting of newly diagnosed type 2 diabetes.

Evidence Rating Level: 1 (Excellent).

Early glycemic control in type 2 diabetes is associated with glycemic durability and a reduced risk of developing related complications. The early introduction of combination therapy with two or more agents may achieve early, optimized glycemic control. Despite some support for early combination therapy for greater reduction in hemoglobin A1C (HbA1C) compared to metformin monotherapy, there is limited evidence to support the early initiation of such a strategy for maintaining glycemic control. The Vildagliptin Efficacy in combination with metfoRmIn For earlY treatment of type 2 diabetes (VERIFY) study, a randomized double-blind trial, compared early combination therapy with metformin (stable daily dose of 1000 mg, 1500 mg, or 2000 mg) and dipeptidyl peptidase-4 inhibitor vildagliptin 50 mg twice daily with metformin monotherapy and placebo. If the initial treatment did not allow for the maintenance of a HbA1C level below 7.0%, patients in the monotherapy group received vildagliptin twice daily instead of placebo as part of study period 2. The primary endpoint was time from randomization to initial treatment failure, defined as an HbA1C of at least 7.0% on two consecutive visits, 13 weeks apart. Overall, 81.3% and 78.5% of early combination therapy and metformin monotherapy patients completed the 5-year study, respectively. Researchers found that the incidence of initial treatment failure in the first study period was 43.6% and 62.1% in the combination and monotherapy groups, respectively. The median time to treatment failure was also significantly decreased in the combination group at 61.9 months (IQR 29.9 months – not reached) compared to the monotherapy group at 36.1 months (IQR 15.3 months – not reached) (HR 0.51, 95% CI 0.45 to 0.58, p<0.0001). Both treatments were well-tolerated, with minimal safety issues and no treatment-related mortality events. The findings of this study therefore suggest that early combination therapy with vildagliptin and metformin provides more substantial and long-standing glycemic control compared to current standard of care with metformin monotherapy for newly diagnosed type 2 diabetes mellitus.

Risk of rhabdomyolysis with donepezil compared with rivastigmine or galantamine: a population-based cohort study

1. Donepezil is associated with an elevated short-term risk of hospital admission for rhabdomyolysis compared to rivastigmine or galantamine for Alzheimer’s disease and dementia.

Evidence Rating Level: 2 (Good)

Regulatory agencies have issued a post-marketing surveillance warning regarding the risk of rhabdomyolysis with donepezil use, commonly used in managing symptoms of Alzheimer’s disease and dementia. The Pharmacovigilance Databases of the United States and Canada data indicated that such events occurred more frequently with donepezil than with other cholinesterase inhibitors. It is unclear whether rivastigmine and galantamine are associated with a risk of rhabdomyolysis. In this population-based retrospective cohort study from Ontario, Canada (2002-2017), researchers examined whether the initiation of donepezil is associated with a higher risk of 30-day hospital admission with rhabdomyolysis compared to rivastigmine and galantamine in patients age 66 years or older. Overall, 152,300 patients with newly dispensed prescriptions for donepezil and 68,053 patients with prescriptions for rivastigmine or galantamine were analyzed. Researchers found that donepezil was associated with a higher risk of rhabdomyolysis-associated hospital admission (88 events, 0.06%) compared to rivastigmine or galantamine (16 events, 0.02%) (weighted OR 2.21, 95% CI 1.52 to 3.22). The majority of hospital admissions following donepezil prescription were not severe. The findings of this study therefore indicate that donepezil may be associated with an elevated short-term risk of hospital admission for non-severe rhabdomyolysis compared to other commonly used agents.

Blood culture results before and after antimicrobial administration in patients with severe manifestations of sepsis: a diagnostic study

1. Early initiation of antimicrobial therapy in the setting of severe sepsis is associated with significant reduction in subsequent blood culture sensitivities.

Evidence Rating Level: 2 (Good)

Sepsis and septic shock are associated with high morbidity and mortality. Early antimicrobial administration, source control and supportive care remain the cornerstones of management for sepsis. While Surviving Sepsis Campaign guidelines recommend that blood cultures be drawn before starting antimicrobial therapy, prompt initiation of antibiotics is critical to survival, and the initiation of therapy before cultures are drawn may decrease time to treatment and improve outcomes. The diagnostic sensitivity of cultures drawn shortly after antimicrobial administration, however, is unclear. The FABLED (eFfect of Antimicrobial administration on BLood culture positivity in patients with severe manifestations of sepsis in the Emergency Department) study examined whether blood culture sensitivity is decreased after antibiotic administration in severe sepsis. Using a patient-level, single-group diagnostic study design involving Emergency Departments across Canada and the United States, blood cultures were drawn before antibiotics, and additional cultures were drawn within 120 minutes of antibiotic initiation in 325 patients with severe signs of sepsis. The primary outcome was sensitivity of blood cultures within 120 minutes after antibiotics. With a median time of 70 minutes (IQR 50 minutes to 110 minutes) for the second draw of blood cultures from initiation of antibiotics, one or more post-antimicrobial cultures were positive for 19.4%, compared to 31.4% with pre-antimicrobial culture positivity (absolute difference 12.0%, 95% CI 5.4% to 18.6%, p<0.001). The findings of this study therefore suggest that early initiation of antimicrobial therapy prior to blood cultures being drawn significantly reduces the sensitivity of blood cultures in the setting of severe sepsis.

Image: PD

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