International Bulletin of Pharmaceutical Sciences 2012, 1 (1-2): 17–29 International Bulletin of Pharmaceutical Sciences Article Type: Minireview Use of Metabolomics for Monitoring Metabolic Responses Caused by Drug Administration 2. Application of Metabolomics in the Study of Metabolic Changes Induced by Drugs
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Www1.uwindsor.caDrugs Aging (2013) 30:687–699 Optimizing the Use of Anticoagulants (Heparins and OralAnticoagulants) in the Elderly Virginie Siguret • Isabelle Gouin-Thibault •Pascale Gaussem • Eric Pautas Published online: 25 July 2013 Springer International Publishing Switzerland 2013 As longevity constantly increases, the number use. Emergence of new oral anticoagulants (dabigatran, of elderly patients (75 years and older) who require anti- rivaroxaban, apixaban), which appear to be much more coagulation likewise rises steadily. Managing elderly convenient, is promising. Even though some elderly patients receiving anticoagulants is challenging because patients were included in pivotal clinical trials evaluating those patients are at high risk of both thrombosis and these new anticoagulants, the safety of these drugs remains bleeding. Moreover, older patients are commonly frail: uncertain in real life.
including renal impairment and frequent acute illnesses andare often polymedicated. There remains a clear need to optimize the use of anticoagulant drugs in these patients,especially at full anticoagulant dose. In the last decade, The risk of thromboembolic disease increases with efforts have been made to better understand the inter- advancing age: annual incidence of venous thromboem- individual variability in the response of elderly patients to bolism (VTE) reaches 1 % in patients aged 75 years and traditional anticoagulants including heparin derivatives above; prevalence of atrial fibrillation (AF) exceeds 10 % (unfractionated heparin, low molecular weight heparins in octogenarians [–]. In addition, advanced age is asso- and fondaparinux) and vitamin K antagonists. Moreover, ciated with a high risk of acute coronary syndromes (ACS) their safety profile has been evaluated in different settings As populations age, the number of elderly patients in the elderly, assisting in minimizing risks related to their (75 years and older) who require anticoagulation risessteadily. Managing elderly patients receiving anticoagu-lants is challenging because those patients are at high risk V. Siguret (&) I. Gouin-Thibault P. Gaussem E. Pautas of both thrombosis and bleeding and anticoagulants Universite´ Paris Descartes, Sorbonne Paris Cite´, Paris, France have a narrow therapeutic index. Moreover, older patients are commonly frail: they have substantial chronic co- V. Siguret I. Gouin-Thibault P. Gaussem E. Pautas morbid conditions, frequent acute illnesses and, conse- INSERM UMR-S765, 4 avenue de l'Observatoire, Paris, France quently, take numerous medications. Among co-morbidconditions, renal insufficiency is highly prevalent, affecting V. Siguret P. GaussemService d'He´matologie biologique, Assistance Publique more than 75 % of patients [75 years, potentially leading Hoˆpitaux de Paris, Hoˆpital Europe´en Georges Pompidou, to accumulation and overdosage of renally cleared anti- coagulant drugs Cognitive impairment is also commonamongst elderly patients, hampering their participation in I. Gouin-ThibaultService d'He´matologie biologique, Assistance Publique clinical studies. Because of those impairments and for Hoˆpitaux de Paris, GH Cochin-Hoˆtel-Dieu, Paris, France many other reasons, frail elderly patients have been largelyexcluded from clinical trials when in fact they are the very population most likely to benefit from these drugs. In Unite´ de ge´riatrie aigue¨, Assistance Publique Hoˆpitaux de Paris,GH Pitie´-Salpeˆtrie re-Charles Foix, Ivry-sur-Seine, France epidemiological surveys, anticoagulant drugs still appear as V. Siguret et al.
the first cause of drug-related adverse events and advanced More recently, CG CrCl below 30 mL/min has also been age consistently emerges as one of the main determinants an exclusion criterion of most randomized clinical trials of bleeding complications Thus, there is a clear need to evaluating NOA in AF, and CG CrCl was used for dose optimize the use of anticoagulant drugs in the frail elderly, adjustment of dabigatran, rivaroxaban and apixaban in and prescribers must be aware of this special concern. In elderly patients with impaired renal function . One the present paper, we will focus on anticoagulant drugs must keep in mind that patients with severe renal impair- used at therapeutic dose since bleeding complications are ment defined by a CG CrCl below 30 mL/min may rep- more frequent and severe than those observed at prophy- resent up to 20–30 % of elderly hospitalized subjects, and lactic dose. Besides traditional anticoagulants including those with moderate renal impairment two-thirds of elderly unfractionated heparin (UFH), low molecular weight hep- outpatients In addition, when using the arins (LMWH), fondaparinux and vitamin K antagonists MDRD (Modification of Diet in Renal Disease) Study (VKA), new oral anticoagulants (NOA) have been recently equation or Chronic Kidney Disease Epidemiology Col- marketed for the prophylaxis and management of throm- laboration (CKD-EPI) creatinine-based equation rather boembolic disease in many countries . Even though than the CG formula to calculate CrCl, prescribers should many elderly patients were included in pivotal clinical be aware that CrCl results differ widely in patients over trials, the safety of these new drugs remains uncertain in 80 years , ]: CrCl results are consistently the real life.
higher with MDRD or CKD-EPI as demonstrated in more A search was conducted on MEDLINE between 1998 than 3,000 patients aged over 80 years included in the and 2012 for articles containing the keywords ‘elderly', EPICA study . Finally, CG CrCl has been shown to be ‘aging', ‘heparin', ‘LMWH', ‘vitamin K antagonist' and a good reflection of frailty in the elderly, taking into ‘oral anticoagulant'. Studies published in English that account age, serum creatinine and weight ]. For all these included patients [75 years of age or analysed a subset of reasons, the CG formula should be preferred to MDRD or patients [75 years of age were selected.
CKD-EPI for the prescription of anticoagulants in theelderly.
2 Estimation of Renal Function in the Elderly Receiving Anticoagulant Drugs 3 Heparin Derivatives The estimation of renal function is of major importance in Numerous clinical trials and meta-analyses have confirmed the elderly before making decisions on an anticoagulant that LMWH and fondaparinux are at least as effective and treatment option, especially including a heparin derivative safe as UFH for initial treatment of acute VTE and in the or an NOA. Moreover, re-evaluating renal function in management of ACS . Thus, in many clinical sit- special situations and at least once a year should be con- uations, LMWH have progressively replaced UFH due to a sidered since renal function may worsen throughout acute better predictable effect, a longer half-life and as they are illnesses and improve when the acute episode is over. In easier to use as there is no routine need to monitor the addition, many concomitant medications have the potential anticoagulant effect. However, one limitation of LMWH to be nephrotoxic. Taking into account serum creatinine use is that they are mainly cleared by the kidneys. There is level alone is unreliable in estimating renal function in the therefore a risk of overdosing and/or accumulation in elderly and therefore creatinine clearance (CrCl) is pre- elderly patients with severe to moderate renal impairment ferred . Different equations assessing estimated glo- ], given that unlike heparin no routine monitoring of merular filtration rate have been developed in the last anticoagulant effect is necessary. The risk is especially decade. However, none of the commonly used formulas increased when treatment is prolonged, increasing the risk have been validated in patients over 75 years [– of bleeding [For the synthetic pentasaccharide fonda- Thus, an important issue is to decide which formula could parinux, excretion is completely renal. So, concerns have be the most appropriate for CrCl calculation when initiat- been raised about the safety of LMWH and fondaparinux in ing anticoagulant drugs in the frail elderly.
elderly patients, especially in those with moderate to severe The Cockcroft–Gault formula (CG CrCl) ] has been renal impairment.
consistently used in clinical trials evaluating LMWH orNOA. Patients with severe renal impairment were excluded 3.1 Pharmacokinetic/Pharmacodynamic Studies from clinical trials with LMWH/fondaparinux at thera- peutic dose, leading health authorities of some countries tocontraindicate the use of LMWH/fondaparinux at thera- While LMWH were developed in the 1980s, the first peutic dose below the CG CrCl threshold of 30 mL/min.
Optimizing the Use of Anticoagulants specifically devoted to the elderly were only conducted in When the risk of accumulation is a concern, two the late 1990s. Studies based on anti-Xa activity mea- approaches are considered to optimize the use of LMWH in surement contributed to show that the PD response, espe- the elderly: anti-Xa monitoring or empiric LMWH dose cially the risk of accumulation effect, may differ among reduction. In dose-finding studies and in cohort observa- LMWH preparations: therefore, LMWH cannot be con- tional studies in ACS patients, it has been demonstrated sidered interchangeable (Tables ) , ]. Indeed, that very high peak or residual enoxaparin anti-Xa activity high molecular weight (MW) chains are cleared mostly levels were associated with an increased risk of bleeding through the reticulo-endothelial system, whereas low MW , –However, it is still debated whether there is a chains are preferentially cleared by the kidney [ clear benefit in anti-Xa monitoring regarding LMWH (Table ). Thus, the higher proportion of long chains in efficacy and safety outcomes, especially in patients with some LMWH preparations, such as tinzaparin or daltepa- renal impairment [In order to detect overdosage at rin, compared with enoxaparin, bemiparin or nadroparin an early stage, some health authorities suggest that LMWH may account for a lower contribution of the kidney in the anti-Xa activity monitoring be performed in patients who elimination process of these compounds, leading to dif- are at risk of accumulation. Similar recommendations have ferent PK/PD profiles in the elderly/renally impaired been also proposed by the Ninth Conference of the (Tables , ). Since fondaparinux is exclusively cleared by American College of Chest Physicians (ACCP) in patients the kidney, a bioaccumulation of anti-Xa activity has been with severe renal insufficiency ]. Of note, if monitoring observed in patients with renal impairment even at low is considered, appropriate upper thresholds for peak anti- Xa activity levels should be used, unique to each LMWHand on the dose regimen, taking into account the PD profile 3.2 Clinical Use of Heparin Derivatives at Therapeutic of each compound ]. One limitation is that thresholds have not always been validated in terms of clinical out-comes [Alternatively, empirically reducing the dose to Numerous clinical observations and observational cohort 50 % of the recommended dose has also been proposed studies have highlighted factors associated with an with a low grade of recommendation for enoxaparin in increased risk of bleeding in the elderly treated with hep- patients with ACS or VTE with severe renal impairment arin derivatives in different settings , – ]. However, Montalescot et al. [showed that the advanced age, degree of renal failure, concomitant use of empirical reduction of the initial enoxaparin dose without antiplatelet drugs (aspirin, thienopyridines, non-steroidal systematic monitoring could lead to an anti-Xa peak level anti-inflammatory drugs) or drugs interacting with platelets below 0.5 IU/mL, leading to an increase of the thrombotic such as serotonin reuptake inhibitors, very low body weight risk. No specific recommendations have been made for ( 45 kg) and a misuse (dosing errors, absence of recent other LMWH preparations given the lack of sufficient data body weight to calculate the body weight adjusted dose, etc.). Educational interventions to reduce misuse or the In patients with renal insufficiency, the use of UFH is concomitant use of interacting drugs may contribute to suggested as UFH elimination is less dependent on renal minimize the bleeding risk of heparin derivatives in the function. However, UFH use is challenging, especially in the elderly. Compared with younger patients, lower UFH Table 1 The chemical and pharmacological characteristics of heparin derivatives Controlled nitrous Controlled nitrous Controlled alkaline IIa activityratio MW molecular weight, PS polysaccharide, UFH unfractionated heparin, ? infinitya Heparin is extracted from porcine intestine mucosa V. Siguret et al.
Optimizing the Use of Anticoagulants doses are required to maintain therapeutic levels of anti-Xa No specific data have been published in the very elderly activity or activated partial thromboplastin time (APTT) receiving fondaparinux at curative dose [ [Large intra- and inter-individual variability of theresponse is observed in elderly patients as a result ofbinding to acute phase plasma proteins and cellular com- 4 Vitamin K Antagonists ponents. Therefore, at least daily monitoring is mandatorywith iterative blood samplings, and frequent dose adjust- In patients older than 75 years, the two main indications for VKA therapy are the treatment of VTE and the prevention of systemic embolism in patients with non-valvular AF: in Given the numerous drawbacks, LMWH have often both indications, a target international normalized ratio been preferred to UFH in the elderly in real life. In the (INR) of 2.5 (range 2.0–3.0) is recommended. Although Global Registry of Acute Coronary Events (GRACE) VKA are beneficial in thromboembolic disorders, e.g. with including 6,203 patients aged 75 years and older, a lower a 68 % relative risk reduction for stroke for patients with utilization of intravenous UFH versus LMWH has been AF, they are still underused especially in patients older observed in older patients compared with younger patients than 75 years , There are two main reasons for this . The physicians' choice has been guided by less fre- underuse in this group of age: (1) the management of VKA quent monitoring when using LMWH , ]. In the therapy is complex for both physicians and patients; and SYNERGY trial, the age subgroup analysis found similar (2) major bleeding is a feared adverse effect, especially in comparative efficacy and safety of enoxaparin and UFH in frail patients.
the oldest subgroup (n = 2,540 with age C75 years) In elderly patients included in the FAST-MI registry (mean 4.1 Factors Influencing the Variability of the Response age 82 years), the use of LMWH was found to be associ- to Vitamin K Antagonists in the Elderly ated with less major bleeding and a significantly highersurvival compared with the use of UFH ].
VKA are characterized by a marked inter- and intra-patient In patients with VTE, the safety profiles of LMWH in variability and many non-genetic and genetic factors have the elderly are less well known , The IRIS now been identified as influencing the response to VKA, (‘Innohep in Renal Insufficiency Study') was the first especially assessed by the maintenance dose. First of all, multicentre, randomized controlled trial specifically con- advanced age is associated with a low warfarin mainte- ducted in elderly patients with moderate-to-severe renal nance dose, independently of the presence of co-morbid impairment for the initial treatment of acute deep vein conditions or co-medications. The decrease in the required thrombosis (DVT) The primary objective was to maintenance dose has been estimated at about 10 % per compare the safety profile of the full, unadjusted dose of decade , Indeed, the mean warfarin maintenance tinzaparin with APTT-adjusted UFH. Based on an imbal- dose is around 6 mg in 30-year-old patients versus around ance in overall mortality favouring the UFH group in the 4 mg in 70-year-old patients and &3 mg in octogenarians 350 patients in the interim analysis and a futility consid- ]. Secondly, it has been demonstrated that patients with eration, the Data Monitoring Committee recommended that low body weight, patients with stable co-morbid conditions the study should be stopped. The study was closed early, such as congestive heart failure, liver disease or severe with 539 patients (mean age 83 years) randomized and renal failure require lower doses. Furthermore, acute ill- followed for 90 days as predefined. In summary, there were nesses such as fever, diarrhoea or prolonged fasting may be no differences between the two groups either in the rate of accompanied by a decrease in the maintenance dose [ clinically relevant bleedings (11.9 vs. 11.9 %) or in the rate ]. Thirdly, many medications used in geriatric practice of recurrent VTE (2.6 vs. 1.1 %; p = 0.34). There was a potentiate the VKA dose response: amiodarone, azole higher rate of deaths in the tinzaparin arm (11.5 vs. 6.3 %; antibiotics and antifungal agents, macrolides, quinolones, p = 0.035). When the results were adjusted for patient other antithrombotic agents, non-steroidal anti-inflamma- baseline characteristics, mortality was not significantly tory drugs, including selective cyclo-oxygenase-2 inhibi- correlated to treatment group. However, because of the tors, selective serotonin reuptake inhibitors, omeprazole, premature termination of the study, the IRIS study remains and lipid-lowering agents [In surveys conducted in inconclusive in terms of clinical outcomes ]. A sub- hospitalized patients with a mean age of 85 years, antibi- study showed no accumulation of anti-Xa activity of tin- otics, azole antifungal agents and amiodarone were the zaparin at peak level, suggesting no need for systematic most often recorded drugs that likely led to the over-anti- anti-Xa monitoring in these patients ]. The high pro- coagulation , Thus, polypharmacy contributes to portion of high MW moieties in tinzaparin may account for the low VKA maintenance dose in these patients and fre- its reduced dependence on renal elimination (see Sect. quent changes in medications make INR results more V. Siguret et al.
Table 3 Unfractionated heparin initial regimen in the elderly and laboratory monitoring UFH anti-Xa activity administration route 400–600 IU/kg/24 h 4 h after the start of infusion 1.5 to 3.5–4 according to APTT reagent Half-course between 2 injections 1.5 to 3.5–4 according to APTT reagent 2 or 3 SC injections/24 ha APTT activated partial thromboplastin time, IV intravenous, SC subcutaneous, UFH unfractionated heparina An initial bolus of 50 IU/kg allows reaching more rapidly efficacious anticoagulation unstable than those observed in younger middle-aged patients on an age-adjusted regimen had high out-of-range patients ]. Moreover, when acute illnesses and deterio- INRs, compared with standard dosing [In a pro- ration in chronic co-morbidities or changes in medication spective multicentre study, we developed and validated a use occur, INR monitoring should be intensified because of simple low-dose regimen for starting warfarin therapy in the narrow therapeutic index of VKA. The increased sen- elderly inpatients with a daily dose of 4 mg for the first sitivity of older patients to VKA remains poorly under- 3 days , (Table ). The daily maintenance dosage stood, not only related to co-morbid conditions or was predicted from the INR measured the day after the concomitant medications: it could be explained on the basis third daily intake of 4-mg warfarin (day 3). The physician of age-related PK changes, such as modifications in hepatic adjusted the daily dose as needed from day 4 onward based drug metabolism, especially due to lower blood flow on INR values obtained at least every 2–3 days until (which is difficult to evaluate). Changes in body compo- determination of the actual maintenance dose. The pre- sition with advancing age (relative lipid content increases dicted daily maintenance warfarin dose was closely cor- and total body water and lean body mass decreases) can related with the actual maintenance dose (R2 = 0.84). The also affect drug PK parameters ].
mean time needed to achieve a therapeutic INR was Even though numerous acquired factors contribute to 6.7 ± 3.3 days (median 6.0 days). Only a few patients had lower the maintenance dose in the elderly, variant alleles of an INR above 4.0 during this period even among the subset both genes encoding vitamin K epoxide reductase C1 requiring very low ‘maintenance doses' (0.5–2 mg) [ (VKORC1) VKA pharmacological target and genes ]. One question is whether VKORC1 and CYP2C9 encoding cytochrome P450 2C9 (CYP2C9) metabolism genotype information would guide initiation dosing. Before enzyme of VKA also contribute to the dose response var- starting warfarin therapy, VKORC1 genotype is the best iability , In a cohort of Caucasian inpatients mean predictor of the maintenance dose. Once treatment is aged 87 ± 6 years, we found that in addition to age, started using induction doses tailored for elderly patients, genetic variants of VKORC1, CYP2C9 and CYP4F2 were the contribution of VKORC1 and CYP2C9 genotypes in found to be significant predictor variables for the mainte- dose refinement is negligible compared with two INR nance dose of warfarin, explaining about one-quarter of the values measured during the first week of treatment [ dose inter-individual variability ].
Response to a standard dosing algorithm can accuratelypredict maintenance dose without genotyping. In order to 4.2 Optimizing Vitamin K Antagonist Initiation simplify and improve the management of VKA in elderly patients, safe and accurate VKA induction regimens forelderly patients should be introduced into computer-based The induction phase of VKA treatment is challenging and dosage programmes [ this period is associated with the highest risk of bleeding[Various algorithms for the initiation of warfarin 4.3 Optimizing Long-Term Vitamin K Antagonist have been published in order to minimize the time required Treatment in the Elderly to achieve the therapeutic range (TTR) without causingexcessive anticoagulation. Many VKA dose regimens were In long-term treatment, the indication and the safety should associated with unacceptable dangerous over-anticoagula- be carefully re-evaluated, at least annually, balancing the tion during treatment induction in older patients ]. It is risk to benefit ratio for each individual patient. For now clear that a single dosing algorithm is unlikely to be instance, a fall is a frequent event in an elderly patient.
effective for all patients. In the elderly, lower initiation Patients at high risk for falls are presumed to be at doses more approximating the average maintenance dose increased risk for intracranial haemorrhage (ICH), and high may be more appropriate Significantly fewer risk for falls is cited as a contraindication to antithrombotic Optimizing the Use of Anticoagulants Table 4 Warfarin induction dosing algorithm based on theinternational normalized ratio measured on day 3 and day 6[, Measure INR daily and omit doses until INR 2.5, then give 1 mg Increase by 1 mg/day Maintain the dosage INR international normalized If warfarin dosage C2 mg Reduce by 1 mg/day If warfarin dosage =1 mg Maintain the dosage a This algorithm does not apply Hold warfarin and determine INR daily until to patients who have a pre- INR value B3. Restart at lower dose treatment INR [1.3 therapy. Yet Man-Son-Hing et al. [calculated that AF proportion of patients with mean INR close to 2.5 was patients taking warfarin would need to fall about 295 times strongly associated with a higher percentage of time in the in 1 year for warfarin to not be the optimal choice of TTR than those with mean INR close to the lower or upper therapy. Thus, the fall-related bleeding risk is probably limit of the TTR (2.0 or 3.0) as shown in the VARIA over-estimated and over-utilized in not giving eligible (Veterans AffaiRs study to Improve Anticoagulation) study patients anticoagulants despite the benefit of VKA treat- ment. As with the risk of falls, other risk factors depending In addition, Waterman et al. ] demonstrated that on patient characteristics should be regularly re-evaluated being older than 80 years was predictive of out-of-range in order to better detect patients at high risk of bleeding.
INRs due to non-adherence. Adherence can be improved Another challenge is to avoid over-anticoagulation among older patients by providing pill containers or home during long-term treatment with VKA. Indeed, when INR health visits, repeating adherence education, and recruiting is greater than 4.0, the risk of bleeding increases sharply.
a family member to oversee medication use. Self-moni- Of note, the risk for ICH increases linearly with an increase toring or self-management in older adults with education in INR; the risk for a subdural haematoma increases has also been shown to be beneficial. In this setting, studies markedly for INRs greater than 4.0 . Over-anticoagu- in anticoagulated patients aged 65 years or over reported lation is frequent in geriatric practice. Over a 1-year period, that the percentage time within the TTR was higher in the at least one INR value C5.0 was found in 25.6 % of 524 self-monitoring patients than in those with usual care [ patients aged 80–89 years versus 15 % of 333 patients It is noteworthy that patient education alone improves the aged 60 years or below (p = 0.003) [These patients quality of anticoagulation in the elderly [Interest- need to be monitored carefully as recommended by the ingly, in 323 patients aged 80 years or above treated with Ninth ACCP Conference on Antithrombotic Therapy warfarin, Kagansky et al. ] showed that socioeconomic, Of note, when changes in concomitant drugs occur, and cognitive variables and functional impairments were not especially when drugs known to potentiate the effect of associated with an increased rate of bleeding; the poor VKA are added, oral anticoagulation should be closely quality of patient education about warfarin was the most monitored to allow early detection of excess anticoagula- significant risk factor for the ineffectiveness of anticoagu- tion and thus to minimize potential bleeding complications lation and for bleeding complications. A comprehensive [Even though managing older outpatients or inpatients geriatric assessment focused on the risk and/or the cause of on VKA is challenging, those who are monitored by anti- falling, the level of cognitive performance, the level of coagulation clinics show a good quality of anticoagulation autonomy and anticipated problems with compliance [, The median time in the TTR exceeded 60 % should be systematically conducted in older patients, in 4,093 outpatients over 80 years followed by Italian especially in those discharged from hospital to the com- munity. At home, educated caregivers (family or health V. Siguret et al.
professionals) and general practitioners need to manage Table 5 New oral anticoagulants: pharmacological data oral anticoagulant therapy in a coordinated fashion in order to detect adverse effects to VKA early or to make dosing decisions during the treatment course. Risk factors ordeterminants for bleeding depending on treatment charac- teristics may be minimized with patient or caregiver edu- cation, and an organized system of follow-up.
Bioavailability (%) 5 New Oral Anticoagulants The drawbacks with the use of traditional anticoagulantshave encouraged the finding of NOA agents that ideally CYP 3A4–CYP 2J2 would be safer and easier to use. Two classes of directly Renal elimination 33 (active form), 33 (inactive form) active NOA have been developed, selectively targetingeither thrombin (dabigatran) or activated coagulation factor CYP cytochrome P450, P-gp P-glycoprotein, Tmax time of maximumdrug concentration X (rivaroxaban, apixaban, edoxaban…) (Table Their properties are attractive: rapid onset of action, pre- Dabigatran etexilate is converted into dabigatran by rapid esterase- catalysed hydrolysis dictable response allowing fixed doses and no regular b The half-life is prolonged in older patients Several randomized trials have shown that NOA are non-inferior to heparins and VKA for preventing and those above 75 years of age (5.10 vs. 4.37 %; p = 0.07).
treating VTE disease, or preventing embolism in AF.
There was no interaction with age for ICH: the rates of ICH Published data in the frail elderly are scarce and no trial has were 0.61, 0.14 and 0.26 % for warfarin, 110- and 150-mg specifically focused on older patients (Table ). However, dabigatran, respectively, in patients under 75 years of age, some data are available in subgroup analysis of trials, versus 1.00, 0.37 and 0.41 % in patients above 75 years especially comparing VKA and NOA in AF. Dabigatran, (p values for interaction 0.28 and 0.29, respectively) [ an oral direct thrombin inhibitor, was approved in 2010 by An extension of the RELY study, the RELY-ABLE study, the US FDA for the prevention of stroke and systemic is currently ongoing to evaluate the long-term safety of embolism in patients with AF [The RELY study compared dabigatran with dose-adjusted warfarin (target Rivaroxaban, an oral direct factor Xa inhibitor, was INR 2.0–3.0) in patients with AF in a multicentre, ran- approved in 2011 by the FDA in patients with non-valvular domized, open-label study ]. Results of this study AF. The ROCKET trial was a randomized, double-blind, showed that both doses of dabigatran were non-inferior to double-dummy trial, comparing rivaroxaban with warfarin warfarin in preventing systemic embolism or stroke. With in the prevention of stroke and systemic embolism in 150 mg twice daily (bid), the prevention of thromboem- patients with AF and a history of stroke, TIA, systemic bolism was greater than that conferred by warfarin, while embolism or at least two risk factors for stroke ]. In this with 110 mg bid, fewer major bleeding accidents occurred.
trial, 14,264 patients were randomized to take either riva- Overall, there was a lower risk of bleeding (major, life- roxaban (20 mg/day, or 15 mg in patients with CrCl of threatening, intracranial, and major or minor bleeding) but 30–49 mL/min) or dose-adjusted warfarin (target INR a higher incidence of dyspepsia and gastrointestinal 2.0–3.0) (Table The rate of primary events (stroke or bleeding compared with warfarin , ]. The RELY systemic embolism) was 2.1 %/year in the rivaroxaban trial included 7,528 patients aged 75 years and older group and 2.4 %/year in the warfarin group [hazard ratio (Table ). A significant interaction between age and (HR) 0.88; 95 % CI 0.74–1.03; p 0.001 for non inferi- treatment assignment was observed in terms of major ority; p = 0.12 for superiority). The incidence of major bleeding complications. In patients aged 75 years, da- and clinically relevant non-major bleeding was not signif- bigatran 110 mg bid was associated with a lower risk of icantly different in the two groups, but ICH (HR 0.67; major bleeding (1.89 vs. 3.04 %; p 0.001), whilst the 95 % CI 0.47–0.93) and fatal bleeding were less common risk was similar in patients aged 75 years and older (4.43 with rivaroxaban, whereas major bleedings from a gastro- vs. 4.37 %; p = 0.89), and dabigatran 150 mg bid was also intestinal site were more common with rivaroxaban. In the associated with a lower risk of major bleeding in patients ROCKET trial, 18 % of the included patients were aged 80 younger than 75 years (2.12 vs. 3.04 %; p 0.001) versus years and older, and the efficacy as well as the safety of a trend towards more major bleeding complications in rivaroxaban appears to be consistent irrespective of age, Optimizing the Use of Anticoagulants Table 6 Trials evaluating new oral anticoagulants for the prevention of stroke in patients with atrial fibrillation ROCKET AF (rivaroxaban) ARISTOTLE (apixaban) Drug dosage vs.
20 mg (15 mg if moderate renal 5 mg 9 2 (2.5 mg 9 2 if [80 years, weight impairment) vs. warfarin 60 kg, or creatinine 133 lmol/L) vs. warfarin Elderly patients (%) Patients with previous AF atrial fibrillation, CHADS2 Congestive heart failure, Hypertension, Age 75 years or above, and Diabetes mellitus, and 2 points for priorStroke/transient ischaemic attack although more detailed analyses on the elderly have not yet account for almost 90 % of deaths from VKA-associated been published.
bleeding and the majority of disability in survivors [ Apixaban, another oral direct factor Xa inhibitor, was However, the suitability of the NOA has not been exten- compared with warfarin in the prevention of stroke and sively studied in geriatric patients with multiple morbidi- systemic embolism in patients with AF in the ARISTOTLE ties, and some pharmacological specificities of NOA may study, a randomized, double-blind, double-dummy trial be underlined in the context of their use in the elderly ]: [In this trial, 18,201 patients with AF were randomized Dabigatran etexilate is a prodrug that is quickly con- to take either apixaban (5 mg bid, or 2.5 mg in patients verted to the active form dabigatran, with up to 80 % with two or more of the following criteria: age at least eliminated through the kidneys. The elimination half-life 80 years, body weight less than 60 kg, plasma creatinine of dabigatran is twice as long and the area under the curve 1.5–2.5 mg/dL) or dose-adjusted warfarin (target INR is six times higher in patients with severe renal impair- 2.0–3.0). The rate of primary events (stroke or systemic ment than in those without renal impairment. – embolism) was 1.27 %/year in the apixaban group and A PK model predicted an 11 % increase in dabigatran 1.60 %/year in the warfarin group (HR 0.79; 95 % CI exposure for every 10 mL/min decrease in CrCl from the 0.66–0.95; p 0.001 for non inferiority; p = 0.01 for second treatment day onwards ]. Approximately one- superiority). Haemorrhagic stroke was significantly less third of rivaroxaban and one-quarter of apixaban is common in the apixaban group (HR 0.51; 95 % CI excreted unchanged by the kidneys . PK studies 0.35–0.75; p 0.001) as well all cases of stroke. Major indicate that decreased renal function correlates with bleedings were significantly less frequent in the apixaban increased rivaroxaban concentrations [Higher group (HR 0.69; 95 % CI 0.60–0.80; p 0.001). ICH was plasma concentrations of NOA may increase the risk of also significantly less frequent in the apixaban group bleeding and may be anticipated during anticoagulation in elderly subjects [Renal function declines with 0.30–0.58; p 0.001). Of note, 31 % of the included increasing age and moderate renal impairment is patients were aged 75 and older, and the ARISTOTLE reported in more than 50 % of patients with AF who study is the only NOA trial in AF with an age-adjusted are over the age of 80 years ]. Only 20 % of patients dose (Table ). No interaction with age was observed for had moderate renal insufficiency in the ROCKET trial the primary endpoint or for major bleeding.
]. Furthermore, elderly patients with severe renal NOA that are easier to use and might offer similar or impairment were excluded from randomized clinical better levels of stroke prevention with a similar or reduced trials evaluating NOA (CG CrCl 30 mL/min for risk of bleeding should lead to an increase in the use of dabigatran and rivaroxaban, 25 mL/min for apixaban).
antithrombotic therapy in the management of elderly AF In the RELY study, less than 20 % of the patients had a patients. Moreover, the risk of ICH should be considered CrCl of less than 50 mL/min and 0.02 % had a body rather than the risk of all major haemorrhages. In elderly weight lower than 50 kg .
AF patients, ICH is associated with high rates of mortality As seen in Sect. , warfarin has numerous well- and morbidity. The incidence of ICH is low, 0.7 % documented interactions with other drugs and this (including haemorrhagic stroke), in elderly patients treated factor may be problematic in an elderly population with warfarin in the BAFTA (Birmingham Atrial Fibrilla- likely to require additional medications for concomitant tion Treatment of Aged) study [However, ICH does V. Siguret et al.
disorders. Advantages of NOA over warfarin clearly are based on the measurement of anti-Xa activity, include fewer drug interactions. However, since xabans whereas for dabigatran they are based on the measure- are catabolized by CYP3A4, it is essential for clinicians ment of the inhibition of thrombin. However, to date, to be cautious about concomitant use of rivaroxaban there are limited data supporting or describing the and apixaban with CYP3A4 inhibitors and inducers, as relationship of these tests for assessing the degree of the pharmacokinetics of the NOA will be altered in anticoagulation and whether these test measurements such settings ]. In addition, all marketed NOA are result in improved clinical outcomes, especially in the substrates of P-glycoprotein (P-gp), a drug efflux elderly [Data are lacking regarding the NOA drug transporter. The concomitant use of several substrates concentrations' relationship to the bleeding potential, or inhibitors of P-gp is likely to be frequent in the for example, in trauma and surgical patients.
elderly: Jungbauer et al. [estimated that 42 % of In conclusion, a widespread use of NOA is expected patients with AF were treated with at least one P-gp among elderly AF patients, but caution seems to be rec- modulator. Such interactions may lead to an increased ommended because of the limited experience with the exposure of patients to NOA, the extent of which is not NOA in the frail elderly. Careful consideration should be well known. For example, amiodarone and verapamil, given to the appropriateness of these agents in patients with which are P-gp inhibitors, increase dabigatran plasma fluctuating renal function. For elderly patients currently concentrations [Whether interactions between receiving NOA therapy, it could be recommended to con- NOA and P-gp substrates or inhibitors have a signif- tinue monitoring renal function at least annually and more icant impact on safety outcomes in the elderly remains often for those with moderate renal impairment. The risk of poorly documented.
overdose is increased in this population, with no routine The requirement for a twice-daily dosage regimen for coagulation test and no antagonist available. Data obtained dabigatran and apixaban may be problematic for from specific tests could help in the management of medication adherence. Compliance is important given patients in some special situations. Increased vigilance is the relatively short duration of anticoagulant activity.
warranted for bleeding events among elderly patients as Data are limited on specific agents used to reverse NOA gain popularity and more data accumulate via spe- anticoagulant effects in patients receiving NOA. For cific clinical trials and registries [Finally, utilization of patients with normal renal function, plasma concentra- NOA may also be hampered by cost. Consequently, despite tions of these drugs fall relatively quickly upon its proven inadequacies and the need for close laboratory discontinuation. Drug discontinuation is usually suffi- supervision, treatment with VKA might continue as the cient to reverse anticoagulant activity. However, rapid dominant therapy for patients with AF, especially in the reversal may be needed in cases of severe bleeding or setting of limited financial resources. Physicians may also emergency surgery, and few treatments are available to delay using these promising newer agents in their elderly antagonize anticoagulant activity induced by NOA.
patients as they await safety data in the ‘real world' ].
Dialysis, recombinant activated factor VII, oral acti-vated charcoal administration and prothrombin com- Conflicts of interest V. Siguret has participated in expert meetings plex concentrates are treatment options, but their for Poxel, Bayer and BMS-Pfizer. I. Gouin-Thibault has participated clinical effectiveness and safety has yet to be proven, in expert meetings for Bayer, BMS and Boehringer Ingelheim.
especially in the elderly , ].
E. Pautas has participated in training sessions for Bayer and Sanofi.
P. Gaussem has no conflicts of interest to declare.
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Induction of Diploid Eggs With Colchicine During Embryo Sac Development in Populus By J. WANG1),2), X. Y. KANG1),2),*), D. L. LI2), H. W. CHEN2) and P. D. ZHANG1),2) (Received 22nd August 2009) induction of 2n pollen, due to easy screening by their Diploid (2n) eggs were induced by treating developing size. JOHNSSON and EKLUNDH (1940) first induced 2n