Is Sacubitril/Valsartan a Superior Agent in Heart Failure With Reduced Ejection Fraction? A Review of Randomized Comparative Trials.

Background: The PARADIGM HF trial showed sacubitril/valsartan (SV) to be superior to enalapril in patients with reduced ejection fraction (HFrEF). Since its publication, several other randomized trials have compared SV to either an angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) in HFrEF which showed conflicting results regarding mortality, hospitalizations, and quality of life scoring. Objective: To review randomized comparative trials of SV to either ACEI or ARB in patients with HFrEF. Methods: PubMed and Embase databases were used to identify randomized comparative trials. The text terms sacubitril, angiotensin neprilysin, and LCZ696 were used for both searches. Meta-analysis, retrospective, adhoc, and cohort studies were excluded. Results: 1476 and 3983 citations were reviewed on PubMed and Embase, respectively. Of these, 11 randomized comparative trials to either ACEI or ARB were included for analysis. The mortality/quality of life benefits of SV over enalapril in the PARADIGM HF were not corroborated in any of the other trials. The effect of hospitalizations for heart failure was inconsistent among trials. Exercise tolerance was not improved with SV versus enalapril. Conclusion: The results of the PARADIGM HF trial have largely not been confirmed in subsequent randomized comparative trials.

Sacubitril/valsartan compared to equivalent/sub-equivalent dose angiotensin receptor blocker or angiotensin-converting enzyme inhibitor in heart failure with reduced ejection fraction: a meta-analysis of randomized trials.

PURPOSE: The objective of this meta-analysis is to determine how sacubitril/valsartan (SV) compares to equivalent and sub-equivalent angiotensin receptor blockers (ARB) or angiotensin-converting enzyme inhibitors (ACEI) in patients with heart failure with reduced ejection fraction (HFrEF). METHODS: The databases of PubMed and EMBASE were used to identify those randomized controlled trials which compared SV to ARB/ACEI in patients with HFrEF. Only those trials that reported outcomes regarding total mortality, cardiovascular mortality, and worsening heart failure were considered. Meta-analysis was performed separately in those patients receiving equivalent doses of ARB/ACEI and those receiving sub-equivalent doses. Equivalent doses were SV 97/103 = valsartan 160 mg twice daily = enalapril 20 mg twice daily = ramipril 5 mg twice daily. Meta-analyses were performed using Review Manager 5.4. RESULTS: Twelve randomized trials were identified involving 17,484 patients: 11,291 in the sub-equivalent group (8 trials) and 6193 in the equivalent group (4 trials). Meta-analyses showed there were no statistical differences regarding the outcomes of total mortality, cardiovascular mortality, and worsening heart failure in the equivalent dosing group. However, SV reduced total mortality (risk ratio (RR) = 0.85, 95% confidence interval (CI) = 0.78-0.93, p < 0.001), cardiovascular mortality (RR = 0.81, 95% CI = 0.73-0.90, p ≤ 0.001) and worsening heart failure (RR = 0.77, 95% CI = 0.64-0.92, p = 0.005) in the sub-equivalent group. CONCLUSION: When compared to equivalent doses of ARB/ACEI, SV is not superior in reducing mortality and worsening heart failure. SV is superior when compared to sub-equivalent doses of ACEI.

Meta-analysis of trials comparing cefazolin to antistaphylococcal penicillins in the treatment of methicillin-sensitive Staphylococcus aureus bacteraemia.

AIMS: The objective of this study was to determine the effectiveness and safety of cefazolin vs. antistaphylococcal penicillin (ASP) in the treatment of methicillin-sensitive Staphylococcus aureus (MSSA) bacteraemia. METHODS: The databases of PubMed, Embase and Cochrane Central were used to identify comparative trials of cefazolin vs. ASP in MSSA bacteraemia. Meta-analysis of included trials was performed to assess any differences regarding mortality, clinical cure, recurrence and withdrawal from adverse effects between groups. Data were analysed using fixed effect model. Studies were weighted using Mantel-Haenszel methodology. Heterogeneity was calculated using the I2 statistic. RESULTS: Nine retrospective and one prospective trials were identified involving 4728 patients, 2954 with ASP and 1774 with cefazolin. Meta-analysis showed a lower mortality rate with cefazolin vs. ASP using fixed effect model [risk ratio (RR) 0.78, 95% confidence interval (CI) 0.69-0.88, P < 0.0001] with borderline high heterogeneity (I2  = 51%). Clinical cure was noted more often with cefazolin (RR 1.09, 95% CI 1.02-1.17, P = 0.02), although no difference was noted with relapse (RR 1.29, 95% CI 0.96-1.74 P = 0.09). Analysis also showed more withdrawals from adverse events with ASP vs. cefazolin (RR 0.27, 95% CI 0.16-0.47, P < 0.00001). A minority of patients enrolled in these trials were admitted to the intensive care unit or had endocarditis (11.4% with ASP and 9% with cefazolin). CONCLUSION: Our meta-analysis of retrospective data demonstrate that cefazolin is more effective and safer ASP in patients with MSSA bacteraemia from various causes. Low quality of trials, borderline high heterogeneity, and possible publication bias may limit the validity of our findings. Randomized trials are needed to confirm these findings.

Potentiation of Warfarin Associated with Salsalate Therapy Resulting in Bleeding.

BACKGROUND: Salsalate may offer many advantages over other non-steroidal antiinflammatory agents in patients taking warfarin, however a drug-drug interaction may occur which has not been reported in the medical literature or by the manufacturer of salsalate. OBJECTIVE: To report a case of warfarin potentiation associated with salsalate treatment, which resulted in bleeding. METHOD: Clinical review of the course of a patient, who was stable on warfarin when salsalate therapy was added for chronic pain. CASE REPORT: A patient taking stable doses of warfarin for over 1 year (with good control) was prescribed salsalate 3 g/day for pain in his knee and lower back. Approximately 1 month later he presents to the anticoagulation clinic with bruising and an International Normalized Ratio (INR) of 6.8. The patient had a good response to his salsalate therapy and wanted to continue it. The warfarin was held for 3 days and dose lowered by 50 %. His bruising then subsided and he had good control of his warfarin therapy with INRs ranging from 1.9 to 2.2 over the next 4 months. The patient was then lost to follow up. CONCLUSION: This case illustrates a strong association between starting salsalate and subsequent potentiation of warfarin, which heretofore has not been reported in the medical literature.

Does Piperacillin-Tazobactam Increase the Risk of Nephrotoxicity when Used with Vancomycin: A Meta-Analysis of Observational Trials.

BACKGROUND: Observational studies have suggested an increased risk of nephrotoxicity when piperacillin-tazobactam is added to vancomycin, although the data are confliciting. OBJECTIVE: To perform a meta-analysis of identified studies to assess if adding piperacillin-tazobactam to vancomycin increases the incidence of nephrotoxicity. METHOD: A systematic review of PubMed, EMBASE, Cochrane Central, and Google Scholar was conducted to identify studies. Studies selected for meta-analysis were full length reports, retrospective or prospective, and designed specifically to assess if the combining piperacillin-tazobactam with vancomycin increases nephrotoxicity. RESULTS: Six observational trials involving 963 patients were identified and analyzed. Five trials were retrospective and one was prospective. Vancomycin/piperacillin-tazobactam was compared to vancomycin alone in 2 trials, to vancomycin/cefepime in 3 trials, and vancomycin/cefepime or meropenem in one. Meta-analysis showed a statistical increase in the incidence of nephrotoxicity when piperacillin-tazobactam/vancomycin is compared to the control group (2.26 95% CI 1.41-3.63, p= 0.0007). No differences were noted between groups in patients requiring renal replacement. CONCLUSION: Adding piperacillin-tazobactam to vancomycin increases the risk of nephrotoxicity when compared to vancomycin alone or vancomycin with either cefepime or meropenem.

Late onset purple toe syndrome with warfarin successfully treated with fondaparinux.

Purple toe syndrome is a rarely reported adverse effect of warfarin. In all described cases, the syndrome occurred relatively quickly after initiation of warfarin with little recommendation for treatment in patients needing continued anticoagulation. We encountered a patient who developed purple toes after 1 year of warfarin therapy. The warfarin was stopped, and fondaparinux was substituted with prompt resolution of all his symptoms. This is the first case describing late onset purple toe syndrome with warfarin with successful substitution with fondaparinux.

Effect of high-dose cranberry juice on the pharmacodynamics of warfarin in patients.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Case reports suggest an association between cranberry juice and potentiation of warfarin. Studies using 240 ml of cranberry juice daily demonstrated no interaction. It is unknown if higher amounts of cranberry juice will interact with warfarin. WHAT THIS STUDY ADDS: Cranberry juice at 240 ml twice daily does not alter the pharmacodynamics of warfarin. AIM: To determine if high-dose cranberry juice (240 ml twice daily) alters the pharmacodynamic action of warfarin. METHODS: Ten male patients taking stable doses of warfarin were given cranberry juice at 240 ml twice daily for 7 days. Prothrombin times were drawn at baseline and days 2, 6 and 8 after administration of the juice. Prothrombin times were averaged for each day and mean times were compared from each study day to baseline using repeated measures ANOVA. RESULTS: There was no statistical difference between mean prothrombin time at baseline and any day tested during juice administration. CONCLUSIONS: Cranberry juice (240 ml twice daily for 1 week) did not alter the pharmacodynamics of warfarin in patients.