Efficacy and safety analysis of new P2Y12 inhibitors versus clopidogrel in patients with percutaneous coronary intervention: a meta-analysis

Objective:

New P2Y₁₂ inhibitors, classified as oral (prasugrel and ticagrelor) and intravenous (cangrelor and elinogrel) drugs, have shown improved antithrombotic effects compared with clopidogrel in patients with acute coronary syndrome (ACS) or patients undergoing percutaneous coronary intervention (PCI) in landmark trials. The purpose of this study was to perform a meta-analysis of randomized trials that compared new P2Y₁₂ inhibitors with clopidogrel to determine their efficacy and safety in patients undergoing PCI.

Methods:

Randomized controlled trials of at least 4 weeks, comparing new P2Y₁₂ inhibitors with clopidogrel in PCI, were identified using the electronic databases Cochrane Central Register of Controlled Trials, Medline, PubMed, Web of Science, and Google Scholar from January 1, 1980, to July 31, 2014.

Main outcome measures:

The primary efficacy endpoints were all-cause death and major adverse cardiovascular events (MACEs). The primary safety endpoint was thrombolysis in myocardial infarction (TIMI) major bleeding.

Results:

Twelve studies including 71,097 patients met the inclusion criteria. New P2Y₁₂ inhibitors significantly reduced all-cause death (odds ratio [OR]: 0.81; 95% confidence interval [CI] 0.73–0.90, p?p?p?p?=?0.03) and cardiovascular death (OR 0.82; 95% CI 0.73–0.92, p?=?0.001) compared with clopidogrel. There were no significant differences between stroke (OR 0.87; 95% CI 0.72–1.05, p?=?0.14) and major bleeding events (OR 1.22; 95% CI 0.99–1.52, p?=?0.06) between the new P2Y₁₂ inhibitor and clopidogrel groups.

Conclusion:

New P2Y₁₂ inhibitors decreased death in patients undergoing PCI compared with clopidogrel with a considerable safety and tolerability profile; however, the risk/benefit ratio of ischemic and bleeding events should be further investigated.     

A pharmacokinetic interaction study of ticagrelor and digoxin in healthy volunteers

Purpose

Ticagrelor is a reversibly binding P2Y₁₂ receptor antagonist for the prevention of atherothrombotic events in patients with acute coronary syndrome. Previous in vitro studies showed that ticagrelor is a substrate and inhibitor of P-glycoprotein (ABCB1). Therefore, we examined the potential interaction between digoxin, a P-glycoprotein substrate, and ticagrelor by evaluating the pharmacokinetics, safety, and tolerability.

Methods

This was a randomized, double-blind, two-period crossover study in healthy volunteers (n?=?20). Pharmacokinetic parameters of digoxin and ticagrelor were evaluated following co-administration of ticagrelor 400 mg qd or placebo on days 1–16, and digoxin (0.25 mg bid on day 6 and 0.25 mg qd on days 7–14).

Results

Co-administration of ticagrelor increased the digoxin maximum plasma concentration by 75 %, from 1.8 ng/ml to 3.0 ng/ml (Gmean ratio [GMR] 1.75 [95 % CI, 1.52–2.01]); minimum plasma concentration by 31 %, from 0.5 ng/ml to 0.7 ng/ml (GMR 1.31, 1.13–1.52); and mean area under the curve by 28 %, from 16.8 ng?·?h/ml to 21.0 ng?·?h/ml (GMR 1.28, 1.12–1.46), compared with placebo. Renal clearance of digoxin was unaffected by the presence of ticagrelor. Digoxin had no effect on the pharmacokinetics of ticagrelor or its active metabolite, AR-C124910XX. Co-administration of ticagrelor and digoxin was well tolerated.

Conclusions

Collectively, these results indicate that ticagrelor is a weak inhibitor of the P-glycoprotein transporter. Based on these findings, it is recommended that serum concentrations of drugs like digoxin (P-glycoprotein transporter substrates with a narrow therapeutic range) are monitored when initiating or changing ticagrelor therapy.     

Effects of prasugrel on membrane potential and contractile activity of rat ventricular myocytes

Background

Though prasugrel is one of the important P2Y₁₂ inhibitors currently in use for antiplatelet therapy, its potential effects on contractility and electrical activity of ventricular myocytes have not yet been investigated. Hence this study was designed to study the impact of prasugrel on contractile function and membrane potential of isolated ventricular myocytes.

The pharmacokinetics and pharmacodynamics of prasugrel in healthy Chinese, Japanese, and Korean subjects compared with healthy Caucasian subjects

Purpose

Prasugrel is a novel thienopyridine prodrug metabolised to an active metabolite that binds irreversibly to the platelet P2Y₁₂ receptor and inhibits adenosine diphosphate (ADP)-induced platelet aggregation. We compared prasugrel pharmacokinetics, pharmacodynamics, and tolerability in healthy Chinese, Japanese, Korean and Caucasian subjects.

Methods

In an open-label, single-centre, parallel-design study, 89 healthy subjects (25 Chinese, 20 Japanese, 22 Korean and 22 Caucasian) aged 20–65 years were given a prasugrel 60-mg loading dose (LD) followed by daily 10-mg maintenance doses (MD) for 7 days and then 5-mg MD for 10 days. Plasma concentrations of prasugrel’s active metabolite and inhibition of ADP-induced platelet aggregation (IPA) were determined.

Results

Mean exposure to prasugrel’s active metabolite in all treatment regimens was higher in each of the Asian groups than in the Caucasian group, although there was considerable overlap between individual exposure estimates in Asians and Caucasians. The mean IPA was also higher in Asians than in Caucasians following a prasugrel 60-mg LD, although the difference did not consistently achieve statistical significance. Prasugrel 10-mg or 5-mg MD produced statistically significantly higher IPA in each Asian group compared with that in the Caucasians. Prasugrel was well tolerated during the LD and MD regimens by all groups.

Conclusions

Mean exposure to the prasugrel active metabolite following prasugrel 60-mg LD and during daily 10-mg or 5-mg MD was higher in each of the Asian groups than in the Caucasian group, which resulted in greater platelet inhibition.     

Emerging antiplatelet therapy for coronary artery disease and acute coronary syndrome

Antiplatelet therapy is used widely with proven benefit for the prevention of further ischemic cardiac complications in patients with known coronary artery disease (CAD) and a history of acute coronary syndrome (ACS). The limitations of conventional antiplatelet therapy with aspirin, clopidogrel, or prasugrel, as well as the fact that rates of recurrent ischemic events still remain high with use of these agents, underscore the need to investigate alternate agents that may further reduce event rates while limiting bleeding risk. The selection of antiplatelet therapy is further influenced by the following: ticagrelor was approved in July 2011 by the United States Food and Drug Administration (FDA), and clopidogrel is slated to become available as a generic productin 2012. We provide an overview of emerging agents for the treatment of CAD and ACS, including the reversible P2Y(12) antagonists ticagrelor, cangrelor, and elinogrel, and a new class of oral protease-activated receptor-1 (PAR-1) inhibitors, vorapaxar and atopaxar.The recently approved P2Y(12) antagonists prasugrel and ticagrelor demonstrate enhanced ability to prevent adverse cardiac outcomes. However, this comes at a cost of a potential increased risk of bleeding. New adverse effects have also emerged, including dyspnea for all of the reversible P2Y(12) antagonists (ticagrelor, cangrelor, and elinogrel) and ventricular pauses for ticagrelor. In addition, the newer P2Y(12) antagonists have a faster onset and offset. Two of these agents, cangrelor and elinogrel, are available as intravenous formulations, which may provide additional benefits in patients who undergo coronary artery bypass graft (CABG) surgery. Trials with the PAR-1 inhibitors have also shown trends toward reductions in cardiac events, but not without the possibility of increased bleeding. More than ever, as the arsenal of antiplatelet therapy expands, health care providers need to understand the pharmacologic and pharmacodynamic differences between conventional and emerging antiplatelet therapies for patients with ACS and CAD. Health care providers must also carefully assess patient-specific factors such as risk of thrombosis, concomitant disease states, age, drug adherence, and aspirin dose, and plan for those patients who will be undergoing CABG when selecting antiplatelet therapy in order to optimally balance bleeding and thrombosis risk.     

Risk of hypertension with regorafenib in cancer patients: a systematic review and meta-analysis

Background

Regorafenib is a novel multikinase inhibitor approved for use in metastatic colorectal cancer (mCRC) and locally advanced gastrointestinal stromal tumors (GISTs). Hypertension is one of the major adverse events of this agent, but to date the incidence and risk of hypertension with regorafenib have not been systematically investigated. We have conducted a systematic review and meta-analysis of published clinical trials to determine its overall incidence and risk.

Methods

PubMed, Web of Science and abstracts presented at the American Society of Clinical Oncology annual meetings were searched to identify relevant studies published up to September 9, 2013. Eligible studies were prospective phase II or III clinical trials using regorafenib in cancer patients with data on hypertension available. The incidence and relative risk (RR) of hypertension were calculated using a random-effects model.

Results

Data from a total of 1,069 patients (regorafenib n?=?750; controls n?=?319) from five clinical trials were included for analysis. The overall incidence of all-grade and high-grade hypertension were 44.4 % [95 % confidence interval (CI) 30.8–59.0 %) and 12.5 % (95 % CI 5.2–27.1 %), respectively. The use of regorafenib in cancer patients was associated with a significantly increased risk of all-grade (RR 3.76, 95 % CI 2.35–5.99) and high-grade (RR, 8.39, 95 % CI 3.10–22.71) hypertension. The risk might vary with tumor types (P?=?0.000).

Conclusions

Patients with cancer receiving regorafenib have a significantly higher risk of developing hypertension. Close monitoring and appropriate management of this hypertension are strongly recommended.     

Pharmacokinetic interaction studies of co-administration of ticagrelor and atorvastatin or simvastatin in healthy volunteers

Purpose

Interactions between ticagrelor and atorvastatin or simvastatin were investigated in two-way crossover studies.

Methods

Both studies were open-label for statin; the atorvastatin study was placebo-controlled for ticagrelor. For atorvastatin, volunteers (n?=?24) received ticagrelor (loading dose 270 mg; 90 mg twice daily, 7 days) or placebo, plus atorvastatin calcium (80 mg; day 5). For simvastatin, volunteers (n?=?24) received simvastatin 80 mg, or ticagrelor (loading dose 270 mg; 180 mg twice daily, 7 days) plus simvastatin (80 mg; day 5). In each study, volunteers received the alternate treatment after washout (≥7 days).

Results

Ticagrelor increased mean atorvastatin maximum plasma concentration (C_max) and area under the plasma concentration-time curve from zero to infinity (AUC) by 23 % and 36 %, respectively. Simvastatin C_max and AUC were increased by 81 % and 56 % with ticagrelor. Ticagrelor also increased C_max and AUC of analysed atorvastatin metabolites by 13–55 % and 32–67 %, respectively, and simvastatin acid by 64 % and 52 %, respectively. Co-administration of ticagrelor with each statin was well tolerated.

Conclusions

Exposure to ticagrelor and its active metabolite, AR-C124910XX, was generally unchanged by a single dose of either statin, except for a minor increase in ticagrelor C_max in the presence of simvastatin. Effects of ticagrelor on atorvastatin pharmacokinetics were modest and unlikely clinically relevant, while with simvastatin, changes were slightly larger, and simvastatin doses >40 mg with ticagrelor should be avoided.     

Chemotherapy plus multitargeted antiangiogenic tyrosine kinase inhibitors or chemotherapy alone in advanced NSCLC: a meta-analysis of randomized controlled trials

Background

Most patients with advanced non-small-cell lung cancer (NSCLC) require systemic chemotherapy. Chemotherapy plus multitargeted antiangiogenic tyrosine kinase inhibitors (TKI; e.g., sorafenib, sunitinib, cediranib, vandetanib, BIBF 1120, pazopanib, axitinib) has recently been evaluated in patients with NSCLC. However, the advantage of this therapy over chemotherapy alone in patients with advanced NSCLC remains largely unknown.

Methods

A meta-analysis of randomized controlled trials (RCTs) was performed to compare the efficacy and toxicity of chemotherapy plus multitargeted antiangiogenic TKI with chemotherapy alone in patients with advanced NSCLC. PubMed, the ASCO and ESMO databases, and the Cochrane Library were searched for references to published articles. Two reviewers independently assessed the quality of the trials. Data were extracted, and overall response rate (ORR), pooled progression-free survival (PFS), overall survival (OS) with 95 % confidence intervals (CI), and major toxicities/adverse effects were analyzed.

Results

Six RCTs involving 3,337 patients with advanced NSCLC were ultimately analyzed. Compared to chemotherapy alone, chemotherapy plus multitargeted antiangiogenic TKI significantly increased the ORR [relative risk (RR)?1.71, 95 % CI??1.43–2.05] and PFS [hazard ratio (HR) ?0.83, 95 % CI?0.76–0.90], but not OS (HR 0.93, 95 % CI?0.83–1.03). Patients who received chemotherapy plus multitargeted antiangiogenic TKI exhibited more rash, diarrhea and hypertension (OR?2.78, 95 % CI? 2.37–3.26; OR?1.92, 95 % CI?1.65–2.24; OR ?2.90, 95 % CI?2.19–3.84, respectively) and less nausea and vomiting (OR?0.71, 95 % CI?0.60–0.83; OR?0.75, 95 % CI?0.61–0.92, respectively). The incidence of hemorrhage, fatigue, cough, constipation, anorexia, and alopecia were comparable between the two groups.

Conclusions

Therapy consisting of chemotherapy plus multitargeted antiangiogenic TKI was found to have specific advantages over chemotherapy alone in terms of PFS and ORR. The toxicity was comparable between the two therapies. Therefore, chemotherapy plus multitargeted antiangiogenic TKI may be a safe and valid therapeutic option for patients with advanced NSCLC.     

Prasugrel but not high dose clopidogrel overcomes the lansoprazole neutralizing effect of P2Y12 inhibition: Results of the randomized DOSAPI study

Aims

The potential negative metabolic interaction between proton pump inhibitors and clopidogrel is an unsolved issue. We hypothesized that doubling the clopidogrel maintenance dose (150 mg) would be less effective than switching to prasugrel 10 mg maintenance dose (MD) to overcome this negative interaction.

Method and results

In a randomized study with a factorial design, 82 stable coronary artery disease patients treated with 75 mg clopidogrel MD and aspirin were assigned to receive in a double blind fashion lansoprazole (30 mg/day) or placebo and to receive in an open fashion 150 mg clopidogrel MD or 10 mg prasugrel MD. The primary endpoint was the relative change in residual platelet reactivity over the 14-day study period [(RPA_14day-RPA_baseline)/RPA_baseline]. The effect of doubling the clopidogrel MD on relative change in RPA was neutralized by lansoprazole (?53.6±48.4 % versus +0.8±53.7 % without and with lansoprazole, respectively, p?=?0.02) whereas 10 mg of prasugrel MD dramatically reduced RPA irrespective of lansoprazole co-administration (?81.8 %±24.8 % vs. ?72.9 %±32.9 % without and with lansoprazole, respectively, p?=?NS). Lansoprazole exposure was the only parameter with a significant interaction with RPA among subgroups.

Conclusion

The higher platelet inhibitory effect obtained by doubling the clopidogrel MD was totally neutralized by the co-administration of lansoprazole. This drug interaction was not observed with prasugrel 10 mg.     

Safety of fluconazole in paediatrics: a systematic review

Purpose

To determine the safety of fluconazole in neonates and other paediatric age groups by identifying adverse events (AEs) and drug interactions associated with treatment.

Methods

A search of EMBASE (1950–January 2012), MEDLINE (1946–January 2012), the Cochrane database for systematic reviews and the Cumulative Index to Nursing and Allied Health Literature (1982–2012) for any clinical study about fluconazole use that involved at least one paediatric patient (≤17 years) was performed. Only articles with sufficient quality of safety reporting after patients’ exposure to fluconazole were included.

Results

We identified 90 articles, reporting on 4,209 patients, which met our inclusion criteria. In total, 794 AEs from 35 studies were recorded, with hepatotoxicity accounting for 378 (47.6 %) of all AEs. When fluconazole was compared with placebo and other antifungals, the relative risk (RR) of hepatotoxicity was not statistically different [RR 1.36, 95 % confidence interval (CI) 0.87–2.14, P?=?0.175 and RR 1.43, 95 % CI 0.67–3.03, P?=?0.352, respectively]. Complete resolution of hepatoxicity was achieved by 84 % of patients with follow-up available. There was no statistical difference in the risk of gastrointestinal events of fluconazole compared with placebo and other antifungals (RR 0.81, 95 % CI 0.12–5.60, P =?0.831 and RR 1.23, 95 %CI 0.87–1.71, P?=?0.235, respectively). There were 41 drug withdrawals, 17 (42 %) of which were due to elevated liver enzymes. Five reports of drug interactions occurred in children.

Conclusion

Fluconazole is relatively safe for paediatric patients. Hepatotoxicity and gastrointestinal toxicity are the most common adverse events. It is important to be aware that drug interactions with fluconazole can result in significant toxicity.     

Efficacy and safety of canagliflozin in subjects with type 2 diabetes: systematic review and meta-analysis

Purpose

To assess the efficacy and safety of the novel sodium glucose co-transporter 2 (SGLT2) inhibitor—canagliflozin for type 2 diabetes (T2DM).

Methods

A search of Medline (1946–January 2014), Embase (1950–January 2014), and The Cochrane Library for randomized controlled trials of canagliflozin compared to placebo or active comparator in T2DM was performed. Clinical Trials website and unpublished U.S. Food and Drug Administration data were also searched.

Results

Ten trials including 6,701 patients were analyzed. Compared with placebo, canagliflozin produced absolute reductions in glycated hemoglobin A_1c levels when used as monotherapy (weighted mean difference (WMD) ?1.08 %, 95 % confidence interval (CI) [?1.25 to ?0.90], p?p?HbA1c by ?0.21 % (WMD, 95 %CI [?0.33 to ?0.08], p?=?0.001). Canagliflozin led to greater body weight loss (vs. placebo, WMD ?2.81 kg, 95 %CI [?3.26 to ?2.37]; vs. active comparators, WMD ?3.49 kg, 95 %CI [?4.86 to ?2.12]). Hypoglycemia with canagliflozin was similar to placebo or sitagliptin, and was lower than glimepiride (risk ratio (RR) 0.15, 95 %CI [0.10 to 0.22]). Genital tract infections were more common with canagliflozin (vs. placebo, RR 3.76, 95 %CI [2.23 to 6.35]; vs. active comparators, RR 4.95, 95 %CI [3.25 to 7.52]). Similar incidences of urinary tract infections were noted with canagliflozin compared with control groups.

Conclusion

Canagliflozin led to improvements in reducing glycated hemoglobin A_1c levels and body weight with low risk of hypoglycemia in patients with T2DM. Common adverse effects including genital tract infections and osmotic diuresis-related AEs were identified and reviewed. Risks of cardiovascular events are even less certain, and more data on long-term effects are needed.     

Prostanoid therapy for pulmonary arterial hypertension: a meta-analysis of survival outcomes

Background

Prostanoids have played an important role in the treatment of pulmonary arterial hypertension (PAH). However, whether prostanoid therapy provides a survival advantage is still not clear. The aim of this meta-analysis was to evaluate the efficacy and safety of prostanoids in PAH, focusing on the improvement in overall survival.

Methods

Trials were identified from the Cochrane Library, EMBASE, and PUBMED databases. We calculated risk ratios (RR) for dichotomous data and weighted mean differences with 95 % confidence intervals (CI) for continuous data.

Results

Fourteen trials with a total of 2,244 adult patients (1,189 patients in the prostanoid treatment group and 1,055 patients in the placebo group) were included in the meta-analysis. All-cause mortality rate in the control group was 4.17 %. In a 13.4-week follow-up, prostanoid treatment was associated with a 44 % reduction in mortality (RR 0.56; 95 % CI 0.35–0.88; P = 0.01).Subgroup analysis suggested that only treatment with intravenous prostanoids provided a survival benefit. Compared with placebo, prostanoids significantly reduced clinical worsening (RR 0.60; 95 % CI 0.46–0.80; P = 0.0003), increased the 6-min walk distance by 27.95 m, reduced mean pulmonary arterial pressure and pulmonary vascular resistance, and increased the cardiac index and mixed venous oxygen saturation. However, patients receiving prostanoid treatment showed a much higher incidence (RR 3.25; 95 % CI 2.07–5.10; P?<?0.00001) of withdrawal due to its adverse effects.

Conclusion

The results of this meta-analysis suggest that treatment with prostanoids improves the survival of patients with PAH.     

Benzodiazepine therapy in psychiatric outpatients is associated with deliberate self-poisoning events at emergency departments—a population-based nested case–control study

Rationale

Deliberate self-poisoning (DSP), the most common form of deliberate self-harm, is closely associated with suicide. Identifying risk factors of DSP is necessary for implementing prevention strategies.

Objectives

This study aimed to evaluate the relationship between benzodiazepine (BZD) treatment in psychiatric outpatients and DSP cases at emergency departments (EDs).

Methods

We performed a retrospective nested case–control study of psychiatric patients receiving BZD therapy to evaluate the relationship between BZD use and the diagnosis of DSP at EDs using data from the nationwide Taiwan National Health Insurance Research Database.

Results

Regression analysis yielded an odds ratio (OR) and 95 % confidence interval (95 % CI) indicating that the use of BZDs in psychiatric outpatients was significantly associated with DSP cases at EDs (OR?=?4.46, 95 % CI?=?3.59–5.53). Having a history of DSP, sleep disorders, anxiety disorders, schizophrenia, depression, or bipolar disorder was associated with a DSP diagnosis at EDs (OR?=?13.27, 95 % CI?=?8.28–21.29; OR?=?5.04, 95 % CI?=?4.25–5.98; OR?=?3.95, 95 % CI?=?3.32–4.70; OR?=?7.80, 95 % CI?=?5.28–11.52; OR?=?15.20, 95 % CI?=?12.22–18.91; and OR?=?18.48, 95 % CI?=?10.13–33.7, respectively). After adjusting for potential confounders, BZD use remained significantly associated with a subsequent DSP diagnosis (adjusted OR?=?2.47, 95 % CI?=?1.93–3.17). Patients taking higher average cumulative BZD doses were at greater risk of DSP.

Conclusion

Vigilant evaluation of the psychiatric status of patients prescribed with BZD therapy is critical for the prevention of DSP events at EDs.     

Bevacizumab increases the risk of gastrointestinal perforation in cancer patients: a meta-analysis with a focus on different subgroups

Background

The aim of this meta-analysis was to gather current data and evaluate not only the risk of gastrointestinal (GI) perforation with bevacizumab, but also the potential risk factors for this adverse event.

Materials and methods

We carried out a literature search in PubMed for randomized controlled trials (RCTs) reported from January 2000 to December 2013. Summary incidence, relative risks (RRs) and 95 % confidence intervals (CIs) were calculated using random-effects or fixed-effects models based on the heterogeneity of the included studies.

Results

A total of 26,833 patients from 33 RCTs were included in the meta-analysis. Bevacizumab-containing therapy significantly increased the risk of developing all-grade (RR 3.35, 95 % CI 2.35–4.79, P?<?0.001) and fatal GI perforation (RR 3.08, 95%CI: 1.04–9.08, P?=?0.042). On subgroup analysis, no significant risk differences were found based on bevacizumab dosage, treatment duration, treatment line, type of clinical trial and median age. When stratified by tumor types, a significantly increased risk of GI perforation with bevacizumab was observed in colorectal cancer (RR 2.84, 95% CI 1.43–5.61, P?=?0.003), gynecologic cancer (RR 3.37, 95% CI 1.71–6.62, P?<?0.001) and prostate cancer (RR 6.01, 95% CI 1.78–20.28, P?=?0.004). Additionally, the use of bevacizumab significantly increased the risk of GI perforation when used in conjunction with taxanes (RR 3.09, 95% CI 1.92–4.96, P?<?0.001) or oxaliplatin (RR 2.85, 95% CI 1.07–7.57, P?=?0.036).

Conclusions

Bevacizumab treatment is associated with a significantly increased risk of developing GI perforation, and clinicians should be aware of the risks of GI perforation with the administration of this drug in cancer patients.     

Association between spironolactone added to beta-blockers and ACE inhibition and survival in heart failure patients with reduced ejection fraction: a propensity score-matched cohort study

Purpose

Heart failure (CHF) guidelines recommend mineralocorticoid receptor antagonists for all symptomatic patients treated with a combination of ACE inhibitors/angiotensin receptor blockers (ARBs) and beta-blockers. As opposed to both eplerenone trials, patients in RALES (spironolactone) received almost no beta-blockers. Since pharmacological properties differ between eplerenone and spironolactone, the prognostic benefit of spironolactone added to this baseline combination therapy needs clarification.

Methods

We included 4,832 CHF patients with chronic systolic dysfunction from the Norwegian Heart Failure Registry and the heart failure outpatients’ clinic of the University of Heidelberg. Propensity scores for spironolactone receipt were calculated for each patient and used for matching to patients without spironolactone.

Results

During a total follow-up of 17,869 patient-years, 881 patients (27.0 %) died in the non-spironolactone group and 445 (28.4 %) in the spironolactone group. Spironolactone was not associated with improved survival, neither in the complete sample (HR 0.82; 95 % CI 0.64–1.07; HR 1.03; 95 % CI 0.88–1.20; multivariate and propensity score adjusted respectively), nor in the propensity-matched cohort (HR 0.98; 95 % CI 0.82–1.18).

Conclusion

In CHF outpatients we were unable to observe an association between the use of spironolactone and improved survival when administered in addition to a combination of ACE/ARB and beta-blockers.     

Effect of ticagrelor on pulmonary function in healthy elderly volunteers and asthma or chronic obstructive pulmonary disease patients

Abstract

Background:

Ticagrelor is a direct-acting, reversibly binding, oral P2Y₁₂ platelet inhibitor that reduces thrombotic cardiovascular events in patients with acute coronary syndrome. Dyspnea is one of the most commonly reported adverse events associated with ticagrelor.     

Effect of a single-dose rifampin on the pharmacokinetics of pitavastatin in healthy volunteers

Purpose

As an inhibitor of HMG-CoA reductase that catalyses the first step of cholesterol synthesis, pitavastatin undergoes little hepatic metabolism; however, it is a substrate of uptake and efflux transporters. Since pitavastatin is potentially co-administered with agents that affect transporter activities, the pharmacokinetics of pitavastatin was investigated on the effects of a single-dose rifampin in healthy volunteers.

Methods

Twelve Chinese healthy male volunteers took 4 mg pitavastatin orally with 150 ml water or with a single dose of 600 mg rifampin on separate occasions and the plasma concentrations of pitavastatin were measured over 48 h by HPLC-MS/MS.

Results

A single dose of rifampin significantly increased the mean area under the plasma concentration-time curve(AUC)_(0-48h) and C_max of pitavastatin by 573.5 %(95%CI, 373.3–773.7 %, p?<?0.001) and 819.2 %(95 % CI, 515.4–1123.0 %, p?<?0.001) respectively, while significantly decreased the t_1/2 and CL/F of pitavastatin by 38.8 % (95 % CI, 18.2–59.4 %, p?<?0.001) and 81.4 % (95 % CI, 75.0–87.7 %, p?<?0.001) respectively.

Conclusions

Co-administration of pitavastatin with a single dose of rifampin resulted in a significant increase in plasma levels of pitavastatin in Chinese healthy subjects.     

Thienopyridines and Other ADP-Receptor Antagonists

Platelet P2Y12 receptor inhibition plays a pivotal role in preventing thrombotic vascular events in patients with ACS and in patients undergoing percutaneous coronary intervention (PCI). Among the P2Y12 receptor inhibitors, the group of thienopyridines include ticlopidine, clopidogrel and prasugrel, all of which are orally administered prodrugs leading to irreversible P2Y12 receptor inhibition. Non-thienopyridine derivatives including ticagrelor, cangrelor and elinogrel do not require metabolic activation and lead to a reversible P2Y12 receptor inhibition in contrast to thienopyridines. The extend of platelet inhibition is subject to the administered antiplatelet agent and influenced by individual genetic and clinical factors. Insufficient platelet inhibition, termed high platelet reactivity (HPR) is associated with an increased risk for ischemic events after PCI whereas exceeding platelet inhibition results in an increased bleeding risk. Pharmacologic properties and clinical outcome data differ substantially between the existing P2Y12 receptor inhibitors. Whether individualized antiplatelet treatment incorporating different P2Y12 receptor inhibitors improves patients' clinical outcomes warrants further investigation.