Triple Therapy in Routine Clinical Practice: Beyond Clinical Trials in COPD

ABSTRACTThe optimal antithrombotic regimen remains controversial in patients taking oral anticoagulation (OAC) undergoing coronary stenting. This study sought to compare efficacy and safety outcomes of triple therapy (OAC, aspirin, and clopidogrel) vs dual therapy (clopidogrel with aspirin or OAC) in these patients. We hypothesize OAC plus clopidogrel could be the optimal regimen for patients with indications for OAC receiving stent implantation. Medline, the Cochrane Library, and other Internet sources were searched for clinical trials comparing the efficacy and safety of triple vs dual therapy for patients taking OAC after coronary stenting. Sixteen eligible trials including 9185 patients were identified. The risks of major adverse cardiac events (odds ratio [OR]: 1.06, 95% confidence interval [CI]: 0.82‐1.39, P = 0.65), all‐cause mortality (OR: 0.98, 95% CI: 0.76‐1.27, P = 0.89), myocardial infarction (OR: 1.01, 95% CI: 0.77‐1.31, P = 0.97), and stent thrombosis (OR: 0.91, 95% CI: 0.49‐1.69, P = 0.75) were similar between triple and dual therapy. Compared with dual therapy, triple therapy was associated with a reduced risk of ischemic stroke (OR: 0.57, 95% CI: 0.35‐0.94, P = 0.03) but with higher major bleeding (OR: 1.52, 95% CI: 1.11‐2.10, P = 0.01) and minor bleeding (OR: 1.59, 95% CI: 1.05‐2.42, P = 0.03). Subgroup analysis indicated there were similar ischemic stroke and major bleeding outcomes between triple therapy and therapy with OAC plus clopidogrel. Treatment with OAC and clopidogrel was associated with similar efficacy and safety outcomes compared with triple therapy. Triple therapy could be replaced by OAC plus clopidogrel without any concern about additional risk of thrombotic events.

Using GFR, Albuminuria, and Their Changes in Clinical Trials and Clinical Care

Current commonly accepted strategies to eradicate Helicobacter pylori in children are a 10-day sequential treatment or a triple therapy for 7-14 days. To avoid further expensive and possibly risky investigations as well as induction of secondary antimicrobial resistance, a success rate of elimination strategies over 90% in a per-protocol analysis is the target goal but rates observed in clinical trials are lower. Antimicrobial resistance is a well-recognized risk factor for treatment failure; therefore, only a treatment tailored to susceptibility testing should be recommended. Adherence to therapy is also a risk factor for treatment failure but that has been poorly studied. The purpose of this study was to evaluate the influence of adherence to therapy on the elimination rates obtained with different treatment regimens. Cohort study analysis of children, aged 2-17 years, treated for Helicobacter pylori infection between October 2011 and December 2013. As a routine clinical practice, children infected with a strain susceptible to clarithromycin and to metronidazole received either a sequential regimen or a 10-day triple therapy while children infected with a strain resistant to clarithromycin or metronidazole received a 10-day triple regimen tailored to antimicrobial susceptibility. The eradication rate was assessed by a negative 13 C-urea breath test performed at least 8 weeks after the end of the treatment and adherence evaluated using a diary. One hundred forty-five children (67 girls/78 boys, median age 9.7 years) fulfilled the inclusion criteria, 118 being infected with a strain susceptible to both clarithromycin and metronidazole, 10 with a clarithromycin resistant, and 17 with a metronidazole resistant strain. A sequential regimen was prescribed in 44, a triple therapy containing clarithromycin in 84 and containing metronidazole in 17. Follow-up data were available for 130/145 and clearance of the infection observed in 105 of them. A concordance of more than 90% between the prescribed and the ingested drugs was observed in 109 children, between 50 and 90% in eight, less than 50% in 11 while these data were unknown for 2/130. A successful eradication was achieved for 89.9% of patients that received at least 90% of the prescribed drugs, whereas the eradication rate for nonadherent patients was 36.6%. Adherence above 90% was significantly higher in the absence of chronic concomitant disease, in the absence of adverse event and results in a significantly higher eradication rate. With the proposed strategy and an adherence higher than 90%, eradication was obtained in 98/109 children, the rate being only significantly superior to 90% with the sequential regimen. Adherence to therapy is a very important factor for the outcome and has to be assessed when evaluating the outcome of an H. pylori eradication regimen in order to understand the reasons of treatment failure. As we treated only after evaluation of the resistance of the H. Pylori strains, we were expecting to reach the given objective of 90% successful treatment. Children with adherence to treatment above 90% had a successful outcome of 89,9%, whereas nonadherent had a successful outcome of 36,8%. This is the first time that adherence has been assessed accurately.

Clarithromycin-resistant Helicobacter pylori has become a problem in many countries and there is considerable interest in finding new treatment regimens that can be used without culture and sensitivity testing in routine clinical practice.1 A combination of three anti-microbials with a proton pump inhibitor (PPI), commonly referred to as quadruple therapy, is a well-established therapy for H. pylori infection, and has been shown in some randomized controlled trials to be superior to triple therapy.2 A number of anti-microbials have been used in quadruple therapy and include: (i) bismuth, metronidazole and tetracycline, (ii) metronidazole, tetracycline and amoxicillin and (iii) amoxicillin, clarithromycin and metronidazole. In these studies, the combination of three anti-microbials and a PPI has been better than triple therapy (a combination of two anti-microbials and a PPI). A review has shown that increasing the degree of acid suppression with high-dose PPI therapy may improve eradication rates with triple therapy.3 Similarly, attempts to lengthen duration of triple therapy, from 7 or 10 days to 14 days, has been proposed as a way to improve the results of eradication therapy.4 The study by Molina-Infante et al. is interesting because it compares prolonged (14 days), high-dose PPI (esomeprazole 40 mg twice a day) triple therapy with clarithromycin and amoxicillin, to the same regimen with the addition of another anti-microbial (metronidazole) creating a 14-day, high-dose, prolonged PPI quadruple therapy. The study demonstrated that the eradication rate improves by 10% with the quadruple regimen and just reaches the critical threshold of 90% that an ideal treatment regimen should achieve.5 In the ultimate analysis, this and other recent studies show the poor outcomes with traditional therapies. Increasing the duration of treatment, adding another anti-microbial to triple therapy and increasing the dose of PPIs, improves the results of treatment. In the future, we need new anti-microbials to treat the growing problem of resistance in H. pylori. Declaration of personal interests: Consultant: Astra Zeneca, Baxter, Ironwood. Declaration of funding interests: None.

Radioimmunotherapy of relapsed indolent non-Hodgkin lymphoma with 131I-rituximab in routine clinical practice: 10-year single-institution experience of 142 consecutive patients

Background Guidelines recommend medical therapy optimization prior to transcatheter mitral valve repair (TMVr) in patients with heart failure (HF), left ventricular ejection fraction (LVEF) <50%, and severe secondary mitral regurgitation (SMR). Whether TMVr is being performed on the background of optimal guideline directed medical therapy (GDMT) in clinical practice is unknown. Purpose To assess pre-procedure GDMT (B-blockers, ACEI [angiotensin converting enzyme inhibitor]/ARB [angiotensin receptor blocker], ARNI [angiotensin receptor neprilysin inhibitor], MRA [mineralocorticoid receptor antagonist]) use and association with outcomes in patients with HF and LVEF <50% undergoing TMVr. Methods Patients with LVEF <50% who underwent TMVr for SMR from July 2019 – March 2022 in the Transcatheter Valve Therapy Registry were identified. Patients on inotropes or in shock pre-TMVr were excluded. Cox proportional hazards models were constructed to evaluate adjusted associations between pre-TMVr medical therapy (no, single, double, or triple therapy) and risk of the one-year composite outcome of mortality or HF hospitalization. Sensitivity analyses excluded patients with HF with mildly reduced ejection fraction (HFmrEF) (LVEF >40%) or New York Heart Association (NYHA) class I (asymptomatic) prior to TMVr. Results A total of 4,199 patients across 449 sites were identified. Prior to TMVr, B-blockers (85.1%) were prescribed most frequently, followed by ACEI/ARB (44.4%), MRA (28.6%), and ARNI (19.9%). Triple therapy was prescribed for 19.2% of patients, while 38.2% were on double therapy, 36.0% were on single therapy, and 6.5% were on no medical therapy. Triple therapy use varied from 0 - 61% across sites with an adjusted median odds ratio of 1.48 (95% confidence interval [CI] 1.25-3.88, P<0.001), suggesting a 1.5-fold variation in the likelihood that similar risk patients at 2 random US sites received triple therapy pre-TMVr (Figure 1). In patients with one-year follow-up available (n=2,014, 341 sites), the composite rate of one-year mortality or HF hospitalization was lowest in patients on triple therapy (23.1%) compared with double (24.8%), single (35.7%), and no (41.1%) therapy (P≤0.01). Associations persisted after accounting for clinically relevant covariates, with lower risk in patients on triple therapy (adjusted hazard ratio [aHR] 0.73, 95% CI 0.55-0.97) and double therapy (aHR 0.60, 95% CI 0.50-0.74) prior to TMVr compared with no/single therapy. Results were similar when only patients with symptomatic HFrEF were considered (i.e., those with HFmrEF or NYHA class I pre-TMVr were excluded) (Figure 2). Conclusions Under one-fifth of patients who underwent TMVr for SMR were prescribed comprehensive GDMT, with substantial variation across clinical sites. Compared with no or single therapy, triple and double therapy use prior to TMVr was independently associated with reduced risk of mortality or HF hospitalization one-year after intervention.Figure 1Figure 2

For patients who have an indication for anticoagulation, it is controversial whether dual therapy with an oral anticoagulant and single antiplatelet agent can be used after percutaneous coronary intervention (PCI) or acute coronary syndrome (ACS) instead of triple therapy with an oral anticoagulant and dual antiplatelet therapy. Twelve observational studies and four clinical trials were identified from three electronic databases from their inception to December, 2017. Pooled estimates were calculated using a random-effects model for meta-analysis. Compared with the triple therapy, dual therapy was associated with significantly lower risk of major bleeding [relative risk (RR), 0.63; 95% confidence interval (CI), 0.50-0.80] without statistically significant increase in major adverse cardiac events (RR, 1.04; 95% CI, 0.84-1.29), all-cause death (RR, 1.15; 95% CI, 0.77-1.71), cardiac death (RR, 1.04; 95% CI, 0.67-1.61), myocardial infarction (RR, 1.25; 95% CI, 0.98-1.59), stroke (RR, 1.27; 95% CI, 0.79-2.06), stent thrombosis (RR, 1.52; 95% CI, 0.96-2.41), and repeat revascularization (RR, 1.15; 95% CI, 0.87-1.52). Although risks of myocardial infarction and stent thrombosis were marginally higher in the dual therapy group, this trend was attenuated after excluding studies that exclusively included patients undergoing PCI for ACS, but not stable coronary artery disease. Dual therapy may be a reasonable alternative to triple therapy after PCI in patients with indication for chronic anticoagulation. However, further studies are needed to investigate efficacy of dual therapy, especially in the patients with higher ischemic risk, such as in ACS.

The FDA, bridging data, and hepatitis C

Ixazomib Plus Lenalidomide-Dexamethasone (IRd) in Relapsed/Refractory Multiple Myeloma (MM) Patients (Pts) - Effectiveness in Routine Clinical Practice Is Similar to the Efficacy in the Phase 3 Tourmaline-MM1 Trial: A Pooled Analysis from the Insight MM Observational Study and the Czech Registry of Monoclonal Gammopathies (RMG)

It is futile to have the most optimised PRO measure developed if it is going to gather dust on the shelf without any use. Whether a PRO measure can be easily integrated into clinical research or clinical practice may depend on several issues—specific to the PRO measure, factors related to the context of use and the potential users. This chapter is intended to discuss the process, key considerations and pitfalls in the application of PRO measures across the different settings – clinical trials, routine clinical practice, medicines regulatory and HTA processes. This represents Step VIII, the final step, of the roadmap presented in this book. We have included findings from some of our research, first, to illustrate integration of PROs in palliative care and chronic pain clinics, and second, perspectives of industry executives and regulators on PROs. We conclude the chapter, with some recommendations on enhancing the application of PRO assessments across different settings.

British HIV Association (BHIVA) guidelines for the treatment of HIV-infected adults with antiretroviral therapy.

Clinical Trials in COPD: Future Challenges

ObjectivesLupus anticoagulans (LACs) and aPLs, both further summarized as aPL, are frequently assessed in routine daily clinical practice in diagnostic workups for suspected autoimmune diseases or to test for underlying risk factors in patients with thrombosis or obstetric complications. The aim of this study was to determine the prevalence of aPL positivity in patients with an indication for aPL testing in routine clinical practice.MethodsIn this retrospective single-centre study, indication for aPL testing, aPL test results and clinical data were collected for patients tested between June 2015 and April 2018.ResultsDuring the study period, 16 847 single aPL tests were performed in 2139 patients. In 212 patients one or more positive aPL test was found, confirmed in 43.9% with a second positive test. Indications for aPL testing were diagnostic workup/follow-up of autoimmune diseases (33.6%), thrombosis (21.4%) and obstetric complications (28%). Seventy-four patients (3.5% of all patients) fulfilled the criteria of APS, of whom 51% were newly diagnosed. Second positive aPL titres and titres of APS patients were significantly higher compared with positive aPL titres at the first measurement (P < 0.05). Patients with indications of arterial thrombosis and diagnostic workup/follow-up of autoimmune diseases had significantly higher levels of aCL IgG and anti-β2 glycoprotein I (β2GPI) IgG compared with patients with other indications.ConclusionThe prevalence of one or more positive aPL test was 9.9% and APS was diagnosed in 3.5% of the patients. Patients with arterial thrombosis had significantly higher anti-β2GPI IgG and aCL IgG, which should be confirmed in future studies.

Digital Breast Tomosynthesis: Potential Benefits in Routine Clinical Practice.

Rush Venom Immunotherapy: Ready for Prime Time?