Impact of Antihypertensive Drug Class on Outcomes in SPRINT.

BACKGROUND: The primary objective of this analysis is to assess if greater exposure to any major antihypertensive drug class was associated with reduced primary composite outcome events in SPRINT (Systolic Blood Pressure Intervention Trial). METHODS: This is a secondary analysis of the SPRINT trial evaluating whether longitudinal, time varying exposure to any major antihypertensive drug class had any impact on primary outcome events, after adjusting for effects of randomization arm, time varying achieved systolic blood pressure, other drug class exposure, and baseline characteristics. RESULTS: Nine thousand two hundred fifty-two participants were included. After adjustments, exposure of one year or greater to thiazide-type diuretics or renin-angiotensin system blockers was associated with significantly fewer primary events than exposure of less than one year (hazard ratio, 0.78 [95% CI, 0.64-0.94]). There was no significant difference with longer versus shorter exposure to calcium channel blockers. Greater exposure to beta-blockers was associated with an increase in primary events compared with exposure of <1 year (hazard ratio, 1.35 [95% CI, 1.13-1.62]). Furthermore, thiazide-type diuretics were associated with a reduction in heart failure events and renin-angiotensin system blockers with reduced myocardial infarction. Both were associated with less cardiovascular deaths. CONCLUSIONS: The SPRINT trial demonstrated a lower target blood pressure led to reductions in adverse cardiovascular events. This analysis suggests greater exposure to thiazide-type diuretics and renin-angiotensin system blockers also contributed to reduced adverse cardiovascular events. Greater exposure to beta-blockers was associated with increased cardiovascular events.

Decreased warfarin sensitivity among patients treated with elbasvir and grazoprevir for hepatitis C infection.

PURPOSE: We previously reported an interaction with warfarin anticoagulation when initiating treatment with direct-acting antiviral agents for hepatitis C infection. A decreased warfarin sensitivity led to subtherapeutic anticoagulation. To study this interaction further, we expanded our research to include patients treated with the combination of elbasvir and grazoprevir concurrent with warfarin anticoagulation and investigated changes in warfarin sensitivity during and after treatment. METHODS: Using electronic health records of the Veterans Health Administration, patients starting treatment with elbasvir-grazoprevir for hepatitis C infection concurrent with warfarin anticoagulation were identified. Inclusion required stable warfarin anticoagulation prior to 12 weeks of treatment with elbasvir-grazoprevir. A warfarin sensitivity index (WSI) was calculated at the start of treatment, after 12 weeks after treatment, and at the end of treatment. The primary endpoint was the difference in WSI from pre- to end-treatment. The secondary endpoint was the WSI difference from before treatment to Changes in International Normalized Ratio, warfarin doses, and time in therapeutic range were measured. RESULTS: In the final sample of 43 patients, the mean WSI decreased during treatment from 0.53 to 0.40, or 25.2%. After treatment, the mean WSI rose to 0.51. Although the mean weekly warfarin dose increased from 40.3 to 44.6 mg during treatment, the mean International Normalized Ratio decreased from 2.40 to 1.96, recovering to 2.59 after treatment. The time spent in therapeutic range decreased from 74.1% before treatment to 39.8% during treatment and back to 64.9% 12 weeks posttreatment. CONCLUSION: When elbasvir-grazoprevir was added to stable warfarin anticoagulation, warfarin sensitivity decreased significantly during treatment and returned to baseline after treatment.

Evaluation of a Potential Interaction Between New Regimens to Treat Hepatitis C and Warfarin.

OBJECTIVE: New regimens to treat hepatitis C virus infection have expanded the eligible patient population to include more patients receiving concurrent warfarin. The primary objective of this study was to assess whether a drug interaction occurs when these regimens are added to warfarin therapy. METHODS: This was a retrospective cohort design using a nationwide database of the Veterans Affairs Health System. Patients on warfarin therapy treated with sofosbuvir or ombitasvir, paritaprevir-ritonavir, and dasabuvir (OBV-PTV/r-DSV) from March 2014 through October 2015 were identified. The warfarin dose response was calculated using a warfarin sensitivity index (WSI) defined as the steady-state INR divided by the mean daily warfarin dose. The primary outcome was the change in WSI from hepatitis C treatment initiation to completion. RESULTS: The final sample consisted of 271 patients. The WSI decreased 23% from a mean baseline value of 0.53 to 0.39 (decrease of 0.14; 95% CI = 0.11 to 0.16; P < 0.001). OBV-PTV/r-DSV produced a significantly greater decrease than any sofosbuvir regimen. Concurrent ribavirin accounted for an additional decrease in warfarin sensitivity of -0.09 (95% CI = -0.06 to -0.12; P < 0.001). The percentage of subtherapeutic INR results increased from 26% prior to hepatitis C treatment to 58% during treatment. CONCLUSIONS: Results indicate a clinically significant reduction in warfarin dose-response when hepatitis C treatment regimens were added to warfarin. They were most profound with OBV-PTV/r-DSV. Ribavirin was associated with an additive effect. Clinicians should be aware of this potential drug interaction to closely monitor and minimize subtherapeutic levels of anticoagulation.

Comparative dose response using the intravenous versus enteral route of administration for potassium replenishment.

OBJECTIVE: To compare the change in potassium concentration (dose-response) using the intravenous versus enteral route for potassium replenishment. RESEARCH METHODOLOGY/DESIGN: Cross-sectional analysis of individual potassium chloride doses with resulting changes in plasma potassium concentrations in intensive care patients. Potassium chloride was administered according to potassium replenishment protocols. For inclusion, doses were required to have pre- and post-dose plasma potassium concentrations obtained within 8hours of administration. SETTING: Medical and surgical intensive care units of a United States Veterans Affairs Medical Center. MAIN OUTCOME MEASURES: The primary outcome was the dose-response slope for intravenous versus enteral potassium administration as estimated by linear regression analysis. Multivariable linear regression was employed to adjust for potential confounders. RESULTS: The sample had 278 potassium chloride doses administered to 142 patients. The potassium concentration change per 20mmol of potassium chloride was similar for intravenous and enteral routes, 0.25mmol/L (95% confidence interval 0.16-0.33) versus 0.27mmol/L (0.15-0.39) respectively (p=0.73). Multivariable linear regression did not alter results. The success of achieving a minimum potassium concentration defined by the specific protocol was similar for intravenous (61%) and enteral (59%) administration. Overall, 77% of potassium chloride doses were administered at a time when patients were eligible to receive an enteral dosage form. CONCLUSION: The enteral route was as effective as the intravenous route in increasing the plasma potassium concentration. The enteral route was widely available for potassium replenishment. Despite enteral route availability and the well-known reliability of potassium chloride absorption, the majority of doses were administered intravenously.

Comparison of equations with estimate renal function to predict serum vancomycin concentration in patients with spinal cord injury--does the use of cystatin C improve accuracy?

BACKGROUND: Vancomycin dose selection is challenging in the spinal cord injury (SCI) population because of the difficulty in accurately estimating the renal function. Creatinine-based equations have been shown to be unreliable in this patient population. Adjusted equations designed for patients with SCI have not been well studied. Cystatin C is an alternative marker of renal function that is less affected by muscle mass and may offer improvement in estimating renal function leading to improved initial dose selection. OBJECTIVE: To compare the accuracy of serum creatinine- and serum cystatin C-based equations used in a pharmacokinetic (PK) model to predict steady-state serum vancomycin concentration in an SCI population. The rationale for this study is the need for an improved predictive model to guide initial vancomycin dose design before the availability of a measured steady-state serum concentration. METHODS: Patients with SCI receiving vancomycin with measured serum creatinine, cystatin C, and steady-state serum vancomycin concentration were identified. Serum creatinine- and cystatin C-based equations to estimate renal function were substituted into a population-based PK model to predict steady state-serum vancomycin concentration. Predictions using each equation in the model were compared with the measured steady-state serum vancomycin concentration. Predictive performances using each equation in the PK model were compared. RESULTS: The final study population included 37 patients with SCI. The Chronic Kidney Disease Epidemiology Collaboration cystatin C equation provided significantly less bias, greater precision, and superior accuracy when used in the PK model. CONCLUSIONS: In the SCI population, the use of Chronic Kidney Disease Epidemiology Collaboration cystatin C equation may improve initial vancomycin dosing. Further study into this potential is encouraged.

Unnecessary antimicrobial use in patients with current or recent Clostridium difficile infection.

OBJECTIVE: To determine the fraction of unnecessary antimicrobial use among patients with current and/or recent Clostridium difficile infection (CDI). DESIGN: Retrospective review from January 2004 through December 2006. SETTING: Minneapolis Veterans Affairs Medical Center (MVAMC). PARTICIPANTS: Patients with new-onset CDI diagnosed at the MVAMC without another CDI diagnosis in the prior 30 days. METHODS: Pharmacy and medical records were reviewed to identify incident CDI cases, non-CDI antimicrobial use during and up to 30 days after completion of CDI treatment, and patient characteristics. Two infectious disease physicians independently assessed non-CDI antimicrobial use, which was classified as unnecessary if not fully indicated. Factors associated with only unnecessary use were identified through univariable and multivariable analysis. RESULTS: Of 246 patients with new-onset CDI, 141 (57%) received non-CDI antimicrobials during and/or after their CDI treatment, totaling 2,147 antimicrobial days and 445 antimicrobial courses. The two reviewers agreed regarding the necessity of antimicrobials in more than 99% of antimicrobial courses (85% initially, 14% after discussion). Seventy-seven percent of patients received at least 1 unnecessary antimicrobial dose, 26% of patients received only unnecessary antimicrobials, and 45% of total non-CDI antimicrobial days included unnecessary antimicrobials. The leading indications for unnecessary antimicrobial use were putative urinary tract infection and pneumonia. Drug classes frequently used unnecessarily were fluoroquinolones and ß-lactams. CONCLUSIONS: Twenty-six percent of patients with recent CDI received only unnecessary (and therefore potentially avoidable) antimicrobials. Heightened awareness and caution are needed when antimicrobial therapy is contemplated for patients with recent CDI.

Enoxaparin outcomes in patients with moderate renal impairment.

BACKGROUND: Enoxaparin sodium has predictable pharmacokinetics that allow for simplified dosing without laboratory monitoring. Reliance on renal function for excretion may lead to accumulation of enoxaparin in patients with moderate renal impairment. However, there is no dose adjustment recommended for these patients. We conducted a review to compare bleeding events in patients with moderate renal impairment compared with those with normal renal function. METHODS: Patients received enoxaparin sodium, 1 mg/kg, every 12 hours or 1.5 mg/kg once daily between June 1 and November 30, 2009. Moderate renal impairment was defined as creatinine clearance (CrCl) of 30 to 50 mL/min. Normal renal function was defined as CrCl greater than 80 mL/min. The primary outcome was major bleeding, defined as any bleeding resulting in death, hospital admission, lengthened hospital stay, or an emergency department visit. The secondary outcome was thromboembolism. RESULTS: A total of 164 patients met the inclusion criteria: 105 with normal renal function and 59 with moderate renal impairment. The primary outcome occurred in 6 of 105 patients (5.7%) with normal renal function vs 13 of 59 patients (22.0%) with moderate renal impairment, representing an unadjusted odds ratio of 4.7 (95% CI, 1.7-13.0; P = .002). The odds ratio using multivariable logistic regression adjusting for differences in risk was 3.9 (95% CI, 0.97-15.6; P = .055). There was no recurrent thromboembolism in either group. CONCLUSIONS: Our results suggest an increased risk of major bleeding in patients with moderate renal impairment who receive enoxaparin. Because enoxaparin is frequently used and outcomes can be life saving or life threatening, we encourage further study of the appropriate dose in patients with moderate renal impairment.

Antimicrobial use and risk for recurrent Clostridium difficile infection.

BACKGROUND: Although antimicrobial use during and immediately after Clostridium difficile infection (CDI) is discouraged, the frequency and consequences of such use are poorly defined. We sought to determine the frequency of non-CDI antimicrobial therapy during and after treatment for CDI, and the association of such therapy with recurrent disease. METHODS: Retrospective review of all CDI cases at a Veterans Affairs medical center from 2004-2006. Outcomes were non-CDI antimicrobial use during and within 30 days after completing CDI treatment, and recurrent CDI. RESULTS: From 2004 to 2006, new-onset CDI occurred in 249 unique patients. No follow-up information was available for 3 patients, leaving 246 as study subjects. Of these, 141 (57%) received non-CDI antimicrobials, including 61 (25%) who received non-CDI antimicrobials during CDI treatment, and 80 (33%) who received non-CDI antimicrobial therapy after CDI treatment. With adjustment for age, disease severity, duration of CDI treatment, and recent hospital or intensive-care unit stay, receipt of non-CDI antimicrobials after CDI treatment was significantly associated with recurrent CDI (odds ratio [OR] 3.02; 95% confidence interval [CI], 1.66-5.52), compared with no antimicrobial use. Antimicrobial use during CDI treatment was not associated with recurrent CDI (OR 0.79; 95% CI, 0.40-1.52). Neither number of antimicrobial courses nor antimicrobial days was associated with recurrence. CONCLUSIONS: Non-CDI antimicrobial therapy after an episode of CDI is common and is associated with a 3-fold increase in the odds of recurrent disease. The added risk associated with antimicrobial exposure (regardless of duration) should be considered if such therapy is contemplated.

Treatment of non-life-threatening methicillin-resistant Staphylococcus aureus infections with alternative antimicrobial agents: a 2-year retrospective review.

The emergence of methicillin-resistant Staphylococcus aureus (MRSA) infections has created a need for additional antimicrobial options. Patients at the Minneapolis Veterans Affairs Medical Center, Minneapolis, MN, who received alternative (nonvancomycin, nonlinezolid) therapy for MRSA infections from January 2004 to December 2005 were identified retrospectively, with sulfamethoxazole/trimethoprim, clindamycin, tetracyclines, and fluoroquinolones assessed as alternative agents. Medical records were reviewed to determine therapeutic outcome and drug tolerance. During 2004 to 2005, 87 subjects received alternative therapy for MRSA infections. Infections included skin/musculoskeletal (n=74 [85%]) and urinary tract infections (n=13 [15%]). Thirty-five (40%) subjects received vancomycin initially, and then an alternative agent, whereas 52 (60%) received only alternative therapy. Treatment succeeded clinically in 77 (89%; 95% confidence interval, 78-96%) subjects. Adverse events were uncommon (6 subjects) and minor, necessitating a change of therapy in only 4 subjects. Alternative agents can be used successfully to treat non-life-threatening MRSA infections in appropriate patients. Randomized comparative trials are needed.

Symptom-driven lorazepam protocol for treatment of severe alcohol withdrawal delirium in the intensive care unit.

STUDY OBJECTIVE: To compare outcomes of treating alcohol withdrawal delirium (AWD) with a symptom-driven benzodiazepine protocol versus nonprotocol benzodiazepine infusions in the intensive care unit (ICU). DESIGN: Retrospective observational study of a quality improvement project. SETTING: Medical intensive care unit at a Veterans Affairs medical center. PATIENTS: Thirty-six patients who had 40 ICU admissions for AWD between January 1, 1994, and May 31, 2003. Sixteen episodes (15 patients [historical controls]) occurred before implementation of the symptom-driven protocol in 1998, and 24 episodes (21 patients) occurred after implementation. MEASUREMENTS AND MAIN RESULTS: Outcomes evaluated were time to reach symptom control, total dose of benzodiazepine, amount of time receiving continuous benzodiazepine infusion, length of ICU and hospital stay, polypharmacy (use of multiple benzodiazepines), and complications of treatment. The historical control group was treated according to physician preference, which consisted of continuous-infusion midazolam without a protocol. The symptom-driven protocol used lorazepam administered initially as intermittent intravenous doses, progressing to a continuous intravenous infusion according to a locally developed symptom scale. The mean +/- SD values for the outcomes in the historical control group versus the protocol group were as follows: time to control symptoms 19.4 +/- 9.7 versus 7.7 +/- 4.9 hours (p=0.002), cumulative benzodiazepine dose in lorazepam equivalents 1677 +/- 937 versus 1044 +/- 534 mg (p=0.014), time receiving benzodiazepine continuous infusion 122.1 +/- 64.4 versus 52.0 +/- 35.1 hours (p=0.001), length of stay in the ICU 7.7 +/- 6.3 versus 5.6 +/- 1.7 days (p=0.21), and length of hospital stay 15.3 +/- 8.9 versus 11.2 +/- 3.4 days (p=0.43). CONCLUSIONS: Use of a symptom-driven protocol was associated with significantly decreased time to symptom control, amount of sedative required, and time spent receiving benzodiazepine infusion compared with historical controls. The use of the protocol is effective but requires close monitoring to ensure protocol compliance and to avoid potential propylene glycol toxicity.

Comparison of plasma concentrations for two amiodarone products.

BACKGROUND: A generic formulation of amiodarone was recently approved by the Food and Drug Administration based on single-dose equivalence data. Because amiodarone has complex pharmacokinetic properties, a narrow therapeutic range, and a significant adverse effect profile, concern about equivalency persists. OBJECTIVE: To compare steady-state plasma concentrations of the brand-name reference product Cordarone with the AB-rated generic formulation, Pacerone, in patients exposed to both products. METHODS: A retrospective analysis was performed at the Minneapolis Veterans Affairs Medical Center on 138 patients who were taking a stable dose of amiodarone before and after an amiodarone generic product substitution. RESULTS: Seventy-seven patients had steady-state plasma concentrations documented for each product at the same dose. The mean steady-state plasma concentrations of amiodarone were not significantly different for Cordarone compared with Pacerone (1.07 +/- 0.48 vs. 1.19 +/- 0.66 micro g/mL, respectively); similarly, the concentrations of the active metabolite (desethylamiodarone) did not differ (0.95 +/- 0.30 vs. 0.96 +/- 0.49 micro g/mL, respectively). However, the variability in plasma drug concentrations between products was increased as compared to variability within each product. CONCLUSIONS: This study indicates that comparable steady-state concentrations can be achieved with a change in formulation from Cordarone to Pacerone. However, individual responses vary, suggesting that monitoring of plasma concentrations is prudent 1-3 months after any change from one product to another.