Comprehensive Exploration of Medications That Affect the Bleeding Risk of Oral Anticoagulant Users.

Oral anticoagulants (OACs) pose a major bleeding risk, which may be increased or decreased by concomitant medications. To explore medications that affect the bleeding risk of OACs, we conducted a nested case-control study including 554 bleeding cases (warfarin, n = 327; direct OACs [DOACs], n = 227) and 1337 non-bleeding controls (warfarin, n = 814; DOACs, n = 523), using a Japanese health insurance database from January 2005 to June 2017. Major bleeding risk associated with exposure to concomitant medications within 30 d of the event/index date was evaluated, and adjusted odds ratios (aORs) were calculated using logistic regression analysis. Several antihypertensive drugs, such as amlodipine and bisoprolol, were associated with a decreased risk of bleeding (warfarin + amlodipine [aOR, 0.64; 95% confidence interval (CI): 0.41-0.98], DOACs + bisoprolol [aOR, 0.51; 95% CI, 0.33-0.80]). As hypertension is considered a significant risk factor for intracranial bleeding in antithrombotic therapy, antihypertensive drugs may suppress intracranial bleeding. In contrast, telmisartan, a widely used antihypertensive drug, was associated with an increased risk of bleeding [DOACs + telmisartan (aOR, 4.87; 95% CI, 1.84-12.91)]. Since telmisartan is an inhibitor of P-glycoprotein (P-gp), the elimination of rivaroxaban and apixaban, which are substrates of P-gp, is hindered, resulting in increased blood levels of both drugs, thereby increasing the risk of hemorrhage. In conclusion, antihypertensive drugs may improve the safety of OACs, and the pharmacokinetic-based drug interactions of DOACs must be considered.

Interaction between Bisphosphonates and Mineral Water: Study of Oral Risedronate Absorption in Rats.

Bisphosphonates are antiosteoporotic agents prescribed for patients with osteoporosis. Drug package inserts for bisphosphonate supplements indicate that their bioavailability is reduced by high levels of metal cations (Ca(2+), Mg(2+), etc.). However, standards for these cations in water used for taking risedronate have not been defined. Here, we examined the effect of calcium and magnesium in mineral waters on the bioavailability of the third-generation bisphosphonate, risedronate, following oral administration in rats. As risedronate is unchanged and eliminated renally, risedronate absorption was estimated from the amount excreted in the urine. Risedronate was dissolved in mineral water samples and administered orally at 0.35 mg/kg. Urine samples were collected for 24 h after dosing. Risedronate was extracted from urine using ion-pair solid-phase cartridges and quantified by HPLC with UV detection (262 nm). Cumulative recovery of risedronate was calculated from the amount excreted in the urine. The 24-h recovery of risedronate from evian® (0.32±0.02% [mean±standard deviation (S.D.)], n=4) and Contrex(®) (0.22±0.05%) mineral waters was significantly lower than that from tap water (0.47±0.04%, p<0.01). Absorption of risedronate in calcium chloride and magnesium chloride aqueous solutions of the same hardness (822 mg/L) was 54% (0.27±0.04%) and 12% (0.51±0.08%) lower, respectively, compared with ultrapure water; suggesting that absorption of risedronate declines as the calcium concentration of mineral waters increases. Consumption of mineral waters containing high levels of calcium (80 mg/L or above), such as evian® and Contrex(®), is therefore not recommended when taking risedronate.

Influence of nonsteroidal anti-inflammatory drugs on the antiplatelet effects of aspirin in rats.

Low-dose aspirin acts by irreversibly acetylating internal cyclooxygenase-1 (COX-1) on platelets, thereby suppressing platelet aggregation. Because nonsteroidal anti-inflammatory drugs (NSAIDs) also inhibit COX-1, the antiplatelet effects of aspirin may be suppressed when it is co-administered with NSAIDs. In this study, the influences of ibuprofen, loxoprofen sodium and etodolac on the antiplatelet effects of aspirin were investigated in male Sprague-Dawley (SD) rats. Aspirin and/or NSAIDs were administered orally at single or multiple daily doses. Platelet aggregation (ADP and collagen were added as stimuli) and serum thromboxane B(2) (TXB(2)) concentrations were measured. The maximum inhibitions of aggregation in the aspirin before ibuprofen group were 41.0±7.8% for ADP and 38.7±5.4% for collagen at 6 h after administration; similar values were seen in the aspirin group; however, percent inhibitions in the aspirin before ibuprofen multiple administration group were lower than those in the aspirin group. Thus, the inhibitory effects of daily low-dose aspirin on platelets are competitively inhibited by the prolonged use of multiple daily doses of ibuprofen. In contrast, serum TXB(2) concentrations in all groups were lower than those in the control group (drug-free). This suggests that the relationship between the inhibition of platelet COX-1 and the suppression of platelet aggregation is nonlinear. When aspirin was administered with loxoprofen sodium, similar effects were observed; however, with etodolac, the antiplatelet effects in all groups were equal to those in the aspirin group. Accordingly, if co-administration with NSAIDs is necessary with low-dose aspirin, a selective COX-2 inhibitor, such as etodolac, should be used.

Association between Cerebral Infarction Risk and Medication Adherence in Atrial Fibrillation Patients Taking Direct Oral Anticoagulants.

Direct oral anticoagulants (DOACs) are available for nonvalvular atrial fibrillation patients. The advantage of DOACs is that regular anticoagulation monitoring is not required. However, adherence to the recommended regimen is essential. We investigated the association between medication adherence and the risk of cerebral infarction in patients taking DOACs. Patients admitted to any of the participating hospitals for cerebral infarction from September 2018 to February 2020 and prescribed DOACs before admission were defined as the case group, and patients hospitalized for diseases other than cerebral infarction, except for bleeding disorders, and prescribed DOACs before admission were defined as the control group. A nested case-control study was adapted, and 58 and 232 patients were included in the case and control groups, respectively. Medication adherence was assessed by the pharmacists through standardized interviewing. The adjusted odds ratio for the risk of cerebral infarction for low-adherence patients (<80% adherence rate) against good-adherence patients (100% adherence rate) was 9.69 (95% confidence interval, 3.86-24.3; p < 0.001). The patients' age and other background characteristics were not found to be risk factors for cerebral infarction. In conclusion, low adherence is a risk factor for cerebral infarction in patients taking DOACs. Pharmacists should focus on maintaining ≥80% adherence to DOAC therapy to prevent cerebral infarction.

Risk of hypoglycemia associated with repaglinide combined with clopidogrel, a retrospective cohort study.

BACKGROUND: Repaglinide is widely prescribed to reduce postprandial hyperglycemia and elevated glycated hemoglobin (HbA1c) levels associated with type 2 diabetes, and clopidogrel is a thienopyridine antiplatelet agent and widely used in cardiovascular and cerebrovascular diseases. It has been suggested that the concomitant use of repaglinide with clopidogrel may inhibit repaglinide metabolism, because repaglinide is a substrate of cytochrome P450 2C8 (CYP2C8) and the main metabolite of clopidogrel acyl-ß-D-glucuronide inhibits CYP2C8 activity. In this study, we retrospectively investigated the effect of clopidogrel with repaglinide on plasma glucose and the risk of hypoglycemia associated with the combination of both drugs. METHOD: Patients were taking clopidogrel (75 mg/day) and started taking glinide (1.5 mg/day repaglinide or 30 mg/day mitiglinide) for the first time from April 2012 to March 2017. We targeted subjects who were hospitalized at the start of glinide and whose preprandial plasma glucose was measured by a nurse. The glucose levels were collected for up to 5 days before and after the glinide start date. RESULTS: Average fasting plasma glucose levels (before breakfast) in the repaglinide and clopidogrel group before and after starting repaglinide were 180.1±35.5 and 136.5 ± 44.1 mg/dL, with a mean decrease of 43.6 ± 33.6 mg/dL. In contrast, there was only a moderate decrease of 11.6 ± 30.0 mg/dL in the mitiglinide and clopidogrel group. Minimum plasma glucose levels in the repaglinide and clopidogrel group before and after starting repaglinide were 145.2 ± 42.9 and 93.3 ± 36.3 mg/dL, respectively. Decrease in minimum levels after starting glinide in the repaglinide and clopidogrel group (51.9 ± 47.5 mg/dL) was more significant than those in the mitiglinide and clopidogrel group (only 2.1 ± 29.1 mg/dL), and the repaglinide group (without clopidogrel, 15.5 ± 20.0 mg/dL). Hypoglycemia was observed in 6 of 15 patients in the repaglinide and clopidogrel group, but only 1 of 15 patients in the mitiglinide and clopidogrel group, and no patients in the repaglinide group. CONCLUSION: These findings indicate that minimum plasma glucose levels were significantly decreased in patients taking repaglinide and clopidogrel. Considering the risk of hypoglycemia associated with taking repaglinide and clopidogrel, when a glinide is required in patients taking clopidogrel, mitiglinide may be a better choice.

Retrospective cohort study of the efficacy and safety of dabigatran: real-life dabigatran use including very low-dose 75 mg twice daily administration.

BACKGROUND: Dabigatran is a direct thrombin inhibitor and an anticoagulant that is prescribed to prevent ischemic stroke and systemic embolism in non-valvular atrial fibrillation. Dabigatran (150 mg twice daily) is non-inferior to warfarin for the prevention of stroke and systemic embolism. A dose reduction to 110 mg twice daily should be considered for patients with decreased renal function, elderly patients, and those with a history of gastrointestinal bleeding. A small number of patients are prescribed 75 mg twice daily; however, excessive dose reduction below that indicated on the package insert may decrease the effectiveness of dabigatran. In this study, we investigated the incidence of thromboembolic events and hemorrhagic complications in patients receiving different doses of dabigatran, including patients receiving the very low-dose of 75 mg twice daily. METHODS: Five hospitals in Meguro and Setagaya areas of Tokyo were included in this study. The subjects were patients receiving dabigatran in the hospitals from March 2011 to February 2014. Thromboembolic events (stroke, systemic embolism, and transient cerebral ischemic attack) and hemorrhagic complications occurring before December 2014 were retrospectively evaluated. RESULTS: A total of 701 subjects received dabigatran during the study period: 187 patients (26.7%) received 150 mg twice daily (normal dose), 488 patients (69.6%) received 110 mg twice daily (low-dose), and 26 patients (3.7%) received 75 mg twice daily (very low-dose). Thromboembolism occurred in 4 (2.1%), 11 (2.3%), and 3 patients (11.5%), in the normal dose, low-dose, and very low-dose groups, respectively. The odds ratio of the 75 mg dose to the 150 and 110 mg doses was 5.73 (95% CI, 1.55-21.2; p = 0.009), and the incidence with the 75 mg dose was higher than that with the other doses. Although the number of events was limited, it should be noted that 3 patients in the very low-dose group had thromboembolic events. CONCLUSIONS: The results suggest that sufficient anticoagulation efficacy may not be maintained when the dabigatran dose is excessively reduced to 75 mg twice daily.

Influence of nonsteroidal anti-inflammatory drugs on aspirin's antiplatelet effects and suggestion of the most suitable time for administration of both agents without resulting in interaction.

BACKGROUND: Low-dose aspirin irreversibly inhibits platelet cyclooxygenase-1 (COX-1) and suppresses platelet aggregation. It is effective for secondary prevention of cardiovascular events. Because nonsteroidal anti-inflammatory drugs (NSAIDs) reversibly bind with COX-1, the antiplatelet effects of aspirin may be suppressed when NSAIDs are co-administered. This interaction could be avoided by avoiding simultaneous administration; however, the minimum interval that should separate the administration of aspirin and loxoprofen is not well known. In this study, we investigated how to avoid the influence of NSAIDs on the antiplatelet effects of aspirin. An in vitro experiment was performed to investigate the influence of ibuprofen and loxoprofen at various concentrations on aspirin's antiplatelet action. METHODS: Platelet aggregation and thromboxane B2 (TXB2) levels were measured after addition of aspirin only and NSAIDs plus aspirin to platelet-rich plasma. NSAIDs were used at their maximum plasma concentrations, the assumed concentration after 6 h (for loxoprofen only), and the assumed concentration after 12 h of taking one clinical dose. Platelet aggregation threshold index (PATI), defined as the putative stimulus concentration giving 50% aggregation, was calculated as an index of aggregation activity. RESULTS: PATI decreased in ibuprofen plus aspirin group compared to that in the aspirin only group, regardless of ibuprofen concentration. Furthermore, PATI significantly decreased when aspirin was added after loxoprofen-trans-OH addition at the maximum concentration (4.1 ± 0.1 µg/mL), compared to that in aspirin only group (5.9 ± 0.1 µg/mL). PATI showed no significant difference after addition of loxoprofen at the assumed concentration after 6 h (aspirin only group, 5.0 ± 0.5 µg/mL; loxoprofen-trans-OH plus aspirin group, 4.9 ± 0.4 µg/mL).In addition, TXB2 concentration tended to decrease with increasing PATI. CONCLUSIONS: It is desirable to avoid ibuprofen co-administration with the usual once-daily low-dose aspirin therapy; however, a 6-h interval between loxoprofen and aspirin could avoid this potential interaction when loxoprofen is taken before aspirin.

Erratum to: Influence of nonsteroidal anti-inflammatory drugs on aspirin's antiplatelet effects and suggestion of the most suitable time for administration of both agents without resulting in interaction.

[This corrects the article DOI: 10.1186/s40780-017-0078-7.].

[Medical economics research on awareness of community pharmacists about raising pharmaceutical questions regarding prescriptions issued by physicians].

This study examined the impact of pharmaceutical inquiries regarding prescriptions on drug costs by surveying the actual condition of inquiries at 13 pharmacies. The study also investigated the significance of inquiries from a medical economics perspective by calculating the medical cost savings realized by preventing adverse drug reactions (ADRs). As a result, the total change in drug costs for the 13 pharmacies after pharmaceutical inquiries represented an increase of ¥9,018/month. However, upon recalculating the cost of drugs by assuming that those with an "Incomplete entry in the prescription (compared with previous prescription, etc.)" should in fact have been prescribed, and excluding them, the total drug costs for the 13 pharmacies is decreased to ¥154,743/month, translating to a cost-savings of ¥7.2/prescription. The study then undertook a comprehensive assessment based on the Diagnosis Procedure Combination (DPC) system to determine the total medical cost-savings for 5 patients in whom ADRs could have occurred if the prescriptions had not been modified as a result of pharmaceutical inquiries. The obtained figure of ¥1,188,830 suggests that pharmaceutical inquiries contribute to reduced medical costs. The findings of this study indicate that pharmaceutical inquiries regarding prescriptions by staff pharmacists not only ensure the proper delivery of drug therapy to patients, but are also effective from a medical economics perspective.

[Influence of mineral water on absorption of oral alendronate in rats].

Alendronate, an oral bisphosphonate (e.g., Fosamax(®)), is effective in the treatment of osteoporosis, and the Fosamax(®) package insert advises that the bioavailability is reduced when taken with mineral water containing high levels of metal cations (Ca(2+), Mg(2+), etc.). However, standards regarding the water used when taking alendronate are unclear. In this study, the influence of mineral water on the absorption of oral alendronate was investigated based on urinary excretion of its unchanged form in rats. Alendronate was diluted in each water sample and administered orally (0.7 mg/kg) to male Wistar rats after 24-hour fast. Urine samples were collected until 24 h after dosing. Urine samples were alkalinized, and alendronate in urine was precipitated as a calcium salt, followed by loading on an anion exchange cartridge. Eluted alendronate was derivatized with 9-fluorenylmethoxycarbonyl (Fmoc) chloride and determined by HPLC with fluorescent detection. Cumulative urinary excretion recoveries of alendronate were calculated from the amounts of urinary excretion. Alendronate was rapidly excreted in the first 6 h, and similar elimination rate constants were seen (from 0.28 to 0.45 h(-1/2)) among the water samples. Cumulative urinary excretion recoveries with tap water, evian(®) and 100% deep ocean water were 0.98±0.17%, 0.80±0.18% and 1.01±0.16% (mean±S.E., n=4). Those with Contrex(®) (0.33±0.07%) were significantly lower when compared with ultrapure water (1.56±0.35%, p<0.01). These findings suggest that the absorption of alendronate decreases based on the calcium concentration of mineral water. In conclusion, mineral water containing high levels of calcium is not recommended when alendronate is taken.