Antithrombotic drugs, patient characteristics, and gastrointestinal bleeding: Clinical translation and areas of research

YBLRE-00388; No of Pages 9 Blood Reviews xxx (2015) xxx–xxx

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REVIEW

Antithrombotic drugs, patient characteristics, and gastrointestinal bleeding: Clinical translation and areas of research Alessandro Di Minno a, Gaia Spadarella b, Domenico Prisco c, Antonella Scalera b, Elena Ricciardi b, Giovanni Di Minno b,⁎ a b c

Department of Farmacia, Università degli Studi di Napoli “Federico II”, Naples, Italy Department of Medicina Clinica e Chirurgia, Università degli Studi di Napoli “Federico II”, Naples, Italy Department of Medicina Sperimentale e Clinica, Università degli Studi di Firenze, Largo Brambilla 3, 50134 Firenze, Italy

a r t i c l e

i n f o

Available online xxxx Keywords: Gastrointestinal bleeding Therapeutic context Patient characteristics Co-morbidities Antithrombotic drugs

a b s t r a c t Gastrointestinal bleeding (GIB) is a potentially fatal and avoidable medical condition that poses a burden on global health care costs. Current understanding of the roles of platelet activation and thrombin generation/activity in vascular medicine has led to the development of effective antithrombotic treatments. However, in parallel with a sustained coronary and cerebral flow patency, the increasingly intensive treatment with warfarin; direct oral anticoagulant drugs [DOACs], and/or with aspirin ± clopidogrel (or ±prasugrel or ±ticagrelor), has increased the burden of GIBs related to the use of antithrombotic agents. Compelling evidence concerning this issue is accumulating to indicate that: 1) the risk of GIB related to the use of antithrombotic drugs dramatically differs in different clinical settings; and 2) the characteristics of patients (e.g., severity of illness, comorbidities) in whom it is used exert a greater impact on the risk of GIB than the type of antithrombotic agent employed. The latter concept argues for the occurrence of GIB as reflecting the presence of patients at the highest risk for adverse outcomes. The HAS-BLED score identifies subjects at risk of bleeding among those untreated and those treated with warfarin, DOACs and/or low-dose aspirin. Its use within the frame of a severity score (e.g., the CHA2DS2-VASc score in patients with atrial fibrillation) helps balance the benefits and the risks of an antithrombotic treatment and identify those patients in whom the absolute gain (vascular events prevented) outweighs the risk of GIB. Potential implications of the latter information in settings other than atrial fibrillation is thoroughly discussed. © 2015 Published by Elsevier Ltd.

1. Introduction Gastrointestinal bleeding (GIB) is a serious medical condition that causes considerable morbidity and mortality and poses a tremendous burden on global health care costs [1,2]. The most common sources of upper GIB (UGIB, proximal to the ligament of Treitz) are peptic ulcer and gastritis, those of lower GIB (LGIB) are colonic diverticula and malignancy [3]. Important causes of acute and chronic small-bowel bleeding in the general population include malignancy, angiodysplasia and ulceration related to non-steroidal anti-inflammatory drugs (NSAID). Abbreviations:ACS, acute coronary syndrome; CAD, coronaryartery disease;AF, atrial fibrillation;Medill,medicallyill;OS, orthopedic surgery; PE,pulmonaryembolism; DVT, deep vein thrombosis; PE, pulmonary embolism; GIB, gastrointestinal bleeding;; NSAID, nonsteroidal anti-inflammatory drug; ASA, acetylsalicylic acid; DOAC, direct oral anticoagulant drug; PPI, proton pump inhibitor; RCT, randomized controlled trial; VKA, vitamin K antagonist; Api, apixaban; dab, dabigatran; edo, edoxaban; riv, rivaroxaban; OR, odds ratio; 95% CI, 95% confidence intervals; NNH, number needed to harm. ⁎ Corresponding author at: Dipartimento di Medicina Clinica e Chirurgia, Università degli Studi di Napoli “Federico II”, Via S. Pansini 5, 80131 Napoli, Italy. E-mail address: [email protected] (G. Di Minno).

Current understanding of the roles of platelet activation and thrombin generation/activity in vascular medicine has led to the development of effective antithrombotic treatments. However, in parallel with a sustained coronary and cerebral flow patency, these increasingly intensive treatment approaches have steadily augmented the burden of GIBs and of hospital and long-term outcomes related to the use of warfarin; antiplatelet agents, or DOACs. Compared to those without, patients with a history of coronary artery disease (CAD) have fewer cardiovascular events and deaths with the use of low-dose aspirin, commonly defined as 75 to 325 mg/d [4]. However, low-dose aspirin can damage both the upper and the lower gastrointestinal (GI) tract thus causing bleedings in both sites. Approximately 30–50% of patients on chronic treatment with antiplatelet agents develop endoscopic lesions, especially in the gastric antrum, that may be asymptomatic [5]. The combined use of warfarin dramatically increases the risk of major GIB in patients with atrial fibrillation (AF) who employ low-dose aspirin and/or clopidogrel [6]. Warfarin is currently the most commonly used oral anticoagulant Worldwide. Its indications include a wide range of clinical conditions most prevalent in the elderly such as prevention of recurrent venous thromboembolism (VTE) and of systemic thromboembolism and prevention of stroke in patients with AF and/or prosthetic heart

http://dx.doi.org/10.1016/j.blre.2015.03.004 0268-960X/© 2015 Published by Elsevier Ltd.

Please cite this article as: Di Minno A, et al, Antithrombotic drugs, patient characteristics, and gastrointestinal bleeding: Clinical translation and areas of research, Blood Rev (2015), http://dx.doi.org/10.1016/j.blre.2015.03.004

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valves [7]. However, older individuals are at greater risk of bleeding than their younger counterparts with similar diagnoses [8]. As a consequence, individuals with VTE and/or AF are often undertreated or not treated at all with warfarin therapy [9,10]. Moreover, warfarin has a wide variability in dose–response across individuals, a significant number of drug and dietary interactions and a narrow therapeutic window (between 2 and 3, as evaluated by the international normalized ratio [INR] value) [11]. The average time in which patient INR values range 2–3 (defined as time in therapeutic range [TTR]) are related to event rates [12], patients with an average individual TTR of N70% having a low risk of major bleeding [13]. Thus, warfarin requires close laboratory monitoring with frequent dose adjustment and tailored dosing to avoid bleeding complications [14]. New direct oral anticoagulant drugs (DOACs), approved for the prevention and treatment of VTE and of systemic and cerebral embolism in AF [15], are poised to replace warfarin for stroke prevention in the setting of AF [16]. Dabigatran (a thrombin inhibitor), rivaroxaban, apixaban and edoxaban (all factor Xa inhibitors) are easier to use than warfarin, with fewer drug and food interactions and no need for routine blood monitoring [17]. In spite of some differences in the individual data (Table 1), a meta-analysis of the four pivotal phase 3 trials in patients with AF (RE-LY, ROCKET AF, ARISTOTLE, and ENGAGE AF-TIMI 48 trials; 71,683 participants included, 42,411 of whom received a DOAC and 29,272 participants received warfarin) shows that, compared with warfarin, DOACs reduce stroke or systemic embolism by 19% (relative risk [RR] 0.81, 95% confidence intervals [CI] 0.73–0.91; p b 0.0001); hemorrhagic stroke (0.49, 0.38–0.64; p b 0.0001); intracranial hemorrhage (0.48, 0.39–0.59; p b 0.0001), and all-cause mortality (0.90, 0.85–0.95; p = 0.0003) [18]. The relative efficacy and safety of DOACs are consistent across a wide range of patients, and similar to those documented in studies on thromboprophylaxis with these agents [19]. However, compared with warfarin, the use of DOACs in patients with AF is associated with an increase in the risk of GIB (1.25, 1.01–1.55; p = 0.04) [18] similar to that documented in studies in clinical conditions other than AF [20]. The rate of GIBs related to the use of antithrombotic drugs is maximal in the scenario of acute coronary syndrome (ACS) and is independently associated with mortality and ischemic complications [21,22]. Antiplatelet treatment intensified by adding clopidogrel to aspirin has long been known to reduce fatal and non-fatal ischemic events in ACS patients [23]. Percutaneous intervention is being used in the current management of ACS and is usually performed in the presence of 3, 4, or even 5 antithrombotic drugs. Especially when antiplatelet agents are combined with anticoagulant medications (e.g., heparins, bivalirudin, warfarin), the capability of such drugs to act cumulatively as to the risk of GIB is clear. Here, epidemiologic Table 1 Phase III AF trials: rates of major bleedings and intracranial hemorrhages. Data from: Connolly et al. N Engl J Med 2009;361:1139–1151; Patel et al. N Engl J Med 2011;365:883–891; Granger et al. N Engl J Med 2011;365:981–992; Giugliano et al. N Engl J Med 2013;369(22):2093-104. DOAC

Warfarin

RRR (DOAC vs Warfarin)

p value

3.36 3.36 3.40 3.09 3.43 3.43

−19.4% −7.5% +2.5% −31.1% −20.2% −51.4%

0.003 NS NS b0.001 b0.001 b0.001

Intracranial hemorrhage (%/year) RE-Ly 110 0.23 0.74 Re-Ly 150 0.30 0.74 Rocket AF 0.50 0.70 ARISTOTLE 0.33 0.80 ENGAGE 60 mg 0.39 0.85 ENGAGE 30 mg 0.26 0.85

−68.9% −58.9% −34.4% −57.5% −53.8% −68.9%

0.001 0.001 0.02 b0.001 b0.001 b0.001

Major bleedings (%/year) RE-Ly 110 mg 2.71 Re-Ly 150 mg 3.11 Rocket AF 3.60 ARISTOTLE 2.13 ENGAGE 60 mg 2.75 ENGAGE 30 mg 1.61

evidence concerning the association between GIB and antithrombotic drugs, used alone and in combination is provided. With respect to the risk of GIB, current evidence regarding clinical settings and individual patient characteristics to be taken into account by physicians formulating an antithrombotic strategy is also summarized. 2. GIB and antithrombotic drugs: epidemiologic evidence 2.1. GIB and warfarin GIB affects an estimated 4.5% of warfarin-treated patients annually and is associated with a significant risk for death [24]. A history of major bleeding is an important predictor for future serious bleeding, suggesting that patients with GIB might be considered for discontinuation of warfarin therapy [25]. However, interruption or permanent discontinuation of warfarin therapy increases the risk of thromboembolic complications [26]. As to UGIB, endoscopic findings show that gastritis accounts for 18.2% (duodenitis accounting for an additional 9.1%); peptic ulcer for 17% and esophagitis for 11.4% respectively. As to LGIB, diverticula account for 23.4%, malignancy or adenoma for 13.8%; angiodysplasias for 10.8% and colitis and hemorrhoids for 5.4% each respectively. Normal mucosa is found in 21.6% of cases of UGIB and in 40.5% of cases of LGIB respectively (bleeding of unknown origin) [3]. Factors that influence the source and severity of GIB in patients taking warfarin include the concomitant use of aspirin, advancing age, previous GIB, AF, and co-morbidities (e.g., anemia, renal insufficiency) [27]. In patients on warfarin, the incidence of GIB increases as mean INR values increase [28]. A mean INR of 2.1 maximally discriminates patients without GIB; a mean INR ≥ 3.0 helps identify those at the highest risk of GIB [29]. Among GIB patients, up to 1/3 experiences the first bleeding episode within the first month of anticoagulation and 61.1% of the GIBs occur within the first year of anticoagulation [30]. This might be due to unstable intensity of anticoagulation during the early dosage adjustment period. A history of GIB increases the risk of GIB, further arguing for local causes as major determinants of such risk. Chronic liver disease increases bleeding risks in patients starting anticoagulant therapy [31]. Compared to those with VTE, candidates for anticoagulation with warfarin for AF are older, have more co-morbid conditions, and take more concurrent medications. In addition to having an increased risk of GIB (estimated to be 0.3–0.5% per year) AF patients have a higher absolute risk of (major) bleedings other than GI (e.g., hemorrhagic stroke) than the general population [32]. In early stroke prevention trials in AF, warfarin was associated with a rate of major GIB approximately three-fold higher than placebo (odds ratio [OR] = 3.21, 95% CI 1.32–7.82) [32]. Co-administering of an anti-platelet agent (e.g., aspirin) was associated with a risk of major GIB approximately twice higher than that seen with warfarin alone (OR = 2.66, CI 1.05–6.74). Age N 65 years was significantly associated with GIB. In particular, persons older than 80–85 years of age carry a significant risk of bleeding [33]. A slow rate of warfarin metabolism, an elevated risk of drug interactions (polypharmacy), and chronic illness increase the risk of bleeding in the elderly [34]. However, when cautiously used and optimized by specialized centers, warfarin therapy should not be withheld in the elderly simply because of age. In a large, prospective, observational study on 4039 individuals (median age: 84 years; mean age of those who bled: 85 years) who were newly started on warfarin therapy for either AF (74%) or VTE (26%) and were followed in Italian Anticoagulation Clinics, there was a higher incidence of major bleeding in the first 3 months (3.87 per 100 patient-years) than later (1.63 per 100 patient-years, relative risk, 2.4; 95% confidence interval, 1.66 to 3.37; p b 0.000) [35]. Their average time to a major bleeding was 14.2 months (range, 0.1 to 109 months), and the incidence of major bleeding was very low: 1.87 per 100 patient-years of observation (179 bleedings, 65/179 being GIBs). Of major bleedings, 30% (53/179, 0.55 per 100 patient-years) were intracranial and 14.5% (26/179) were fatal (2.7 per 1000 patient-

Please cite this article as: Di Minno A, et al, Antithrombotic drugs, patient characteristics, and gastrointestinal bleeding: Clinical translation and areas of research, Blood Rev (2015), http://dx.doi.org/10.1016/j.blre.2015.03.004

A. Di Minno et al. / Blood Reviews xxx (2015) xxx–xxx

years). All patients had high-quality dose management of warfarin (TTR of 62% among all participants). Of note, 82% of bleeds (147/179) occurred with the INR in the therapeutic range; the median INR at the time of bleeding was 2.5 (range, 1.0 to 13.8), and the rate of bleeding was higher in patients with VTE than in those with AF (RR, 1.4; 95% CI, 1.1 to 1.8; p b 0.03). On univariate analysis, male sex, age ≥85 years, VTE versus AF, history of bleeding, renal failure, active cancer, history of falls, and co-medications were significantly associated with bleeding. On multivariate analysis, only active cancer or a history of bleeding or of falls were independently associated with the risk. The overall incidence of major bleeding in this population was similar to that seen in the BAFTA trial (major bleeding on warfarin: 1.9% in patients ≥ 75 years old) [36]. 2.2. GIB and DOACs Compared with current standard care (warfarin, low-molecular weight heparin), the use of DOACs is associated with a significantly higher risk of GIB. As a whole, this risk is higher in patients treated for ACS (OR, 5.21; 95% CI: 2.58–10.53) or for DVT/PE (OR, 1.59; 95% CI: 1.03–2.44) than in those receiving thromboprophylaxis for orthopedic surgery (OR, 0.78; 95% CI: 0.31–1.96) [20]. In ACS, DOACs are administered on top of other antithrombotic medication. On the other hand, in patients treated for DVT/PE, the dose and the duration of the exposure to DOACs is higher than in patients receiving thromboprophylaxis for orthopedic surgery. This suggests an effect of patient characteristics and specific clinical settings on the risk of GIB. However, in patients with AF, rates of major GIB in the pivotal phase 3 trials (Table 2) argue for different GIB risks related to the use of different DOACs. GIB patterns from RE-LY, ROCKET-AF and ARISTOTLE trials provide additional information in the area. Both in the dabigatran 110 and 150 mg twice daily arms of the RE-LY, 47% of major GIB occurred in the lower GI tract and 53% occurred in the upper GI tract [37]. This rate of distribution of GIB in the dabigatran arms is at variance with the warfarin arm (25% and 75%, respectively), and also with aspirin- and NSAID-related GIBs, which is primarily UGIB [38]. In RE-LY, approximately 50% of major GIBs with dabigatran 150 mg twice daily met the criteria for lifethreatening bleeding [39]. The concomitant use of single or dual antiplatelet therapy increased the rate of extra-cranial bleeding associated with dabigatran 150 mg twice daily [40]. Older age, concurrent aspirin use and diabetes mellitus were associated with an increased risk of major GIB in patients receiving dabigatran [41]. Moreover, upper gastrointestinal non-bleeding events, especially gastroesophageal reflux, increased the risk of major GIB among subjects given dabigatran or warfarin (6.8% vs 2.3%, p b .001) [42]. In the ROCKET-AF, the majority of GIBs in the rivaroxaban arm was from the upper GI tract. The majority (87%) of them did not meet the criteria for life-threatening GIB. In addition, the incidence of life-threatening GIB was similar with rivaroxaban and with warfarin and there were fewer fatal GIBs in the rivaroxaban than in the warfarin arm (n = 1 and 5, respectively). Compared with

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those without (n = 13,455), patients with a major bleed (n = 781) were more likely to be older, current/prior smokers, to have a history of prior GIB, mild anemia, and a lower calculated creatinine clearance and less likely to be female or have a prior transient ischemic attack (TIA) or systemic embolization [43]. Most of these variables were also associated with an increased risk of major GIB in patients in the corresponding warfarin arm. GIB was the most frequent location of bleeding in the apixaban arm of the ARISTOTLE trial (31%). Two-thirds of GIBs involved the upper tract in that trial, and a concomitant use of single or dual antiplatelet therapy increased significantly the rate of GIB [44]. Older age, prior hemorrhage, prior stroke or TIA, diabetes, lower creatinine clearance, decreased hematocrit, aspirin therapy, and NSAIDs were independently associated with an increased risk of GIB in this setting. Due to the extensive exclusion criteria used in most trials with DOACs to enroll only those patients with a presumed low risk of GIB complications attributable to anticoagulants, it has been estimated that almost 25%–40% of future users were high-risk patients and the risk of hemorrhage could be as much as 3- to 15-fold higher in everyday practice, shifting unfavorably the balance between efficacy and safety of DOACs [45]. The recent data from the U.S. Food and Drug Administration (FDA) argue against this estimate. At the completion of a study in 134,000 Medicare patients 65 years or older in every day practice, the higher risk of major GIB with the use of dabigatran 150 mg BID as compared to warfarin did not exceed the rates reported in the RE-LY trial. Maximal GIB risk was found in females older than 75 years of age and in males older than 85 years of age [46]. Future studies with other DOACs are urgently needed to confirm and extend this reassuring information. 3. GIB and antiplatelet agents 3.1. Single agents Early studies on aspirin used as an anti-inflammatory and analgesic medication, documented GI tract damage similar to that of standard NSAIDs [47]. It is now clear that the risk of GIB increases with increasing doses of aspirin, is often ulcer-related, and is caused by aspirin-induced reduction of prostaglandin biosynthesis due to cyclooxygenase inhibition with a subsequent reduction of prostaglandin-mediated mucosal protection in the gastro-duodenum [48]. Results of the Women's Health Study [49] and of studies on the occurrence of VTE [50] argued for even low-dose aspirin as being associated with a high number of patients experiencing bleeding events and ulcers. The abnormally high risk of major bleeding events (e.g., intracerebral hemorrhage) in chronic users of low-dose aspirin has been recently confirmed in a populationbased study [51]. On the other hand, consistent with the concept that peptic ulcer is the most common upper GI complication among individuals on chronic treatment with NSAIDs or aspirin, the relative risk of developing an asymptomatic peptic ulcer is 4-fold more common among aspirin users than in those who do not chronically employ aspirin

Table 2 GIBs in studies on patients with AF : DOACs vs warfarin. Data from: Connolly et al. N Engl J Med 2009;361:1139–1151; Patel et al. N Engl J Med 2011;365:883–891; Granger et al. N Engl J Med 2011;365:981–992; Giugliano et al. N Engl J Med 2013;369(22):2093-104. DOAC

Dabigatran 110 mg twice daily arm Dabigatran 150 mg twice daily arm Rivaroxaban 20 mg once daily arm Apixaban 5 mg twice daily arm Edoxaban 30 mg once daily arm Edoxaban 60 mg once daily arm

Warfarin

GI events (n)

Life-threatening GI events (n)

Total pts. (n)

GI events (n)

Life-threatening GI events (n)

Total pts. (n)

133 182 224 105 129 232

67 94 52 (1 fatal event) ND ND ND

6015 6076 7111 9088 7002 7012

120 120 154 119 190 190

57 57 47 (5 fatal events) ND ND ND

6022 6022 7125 9052 7012 7012

DOAC/W (years-pts %)

RR (95% CI) GIB DOAC/W

1.12/1.02 1.51/1.02 2.00/1.24 0.76/0.86 0.82/1.23 1.23/1.51

1.10 (0.86–1.41) p: 0.43 1.50 (1.19–1.89) p b 0.001 1.46 (1.117–1.902) p b 0.001 0.879 (0.624–1.238) p = 0.33 0.67 (0.53–0.83) p b 0.001 1.23 (1.02–1.50) p = 0.03

ND: not determined.

Please cite this article as: Di Minno A, et al, Antithrombotic drugs, patient characteristics, and gastrointestinal bleeding: Clinical translation and areas of research, Blood Rev (2015), http://dx.doi.org/10.1016/j.blre.2015.03.004

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and/or NSAIDs [52]. The OR of major GIB varies from 1.55 (95% CI: 1.27– 1.90) for low-dose aspirin compared with nonuse and 1.93 (95% CI: 1.42–2.61) for the combined use of aspirin and anticoagulants (compared with low-dose aspirin) [53]. However, although low-dose aspirin increases the composite relative risk of any major bleeding, major GIB, and intracranial bleeding by 1.7–2.1 fold compared with placebo, estimates of the absolute increase is small: 769 patients (95% CI, 500–1250) would need to be treated with aspirin for 1 year to cause one additional major bleeding episode [54]. Compared with clopidogrel, aspirin increases the risk of GIB but not of other bleedings. Compared to aspirin, 883 patients (95% CI, 357–infinity) would need to be treated with clopidogrel for 1 year to prevent one major GIB. Guidance from the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents confirm and extend the concept that low-dose aspirin is associated with a 2- to 4-fold increase in GIBs, which increases with concomitant medication use [55]. Concomitant medication with clopidogrel and with anticoagulants increases the risk of GIB associated with low-dose aspirin, and drugs that inhibit gastric secretion (e.g., PPIs) decrease such risk [56]. Risk factors for UGIB include advancing age (N65 years of age); a history of gastric ulcer and/or of other co-morbidities (e.g., kidney/liver failure); the concomitant use of alcohol, tobacco or of medications (e.g., selective serotonin re-uptake inhibitors) in this setting [57]. With the exception of alcohol/tobacco use, all the factors predicting to UGIB are also involved in the risk of LGIB in subjects receiving aspirin [58]. Studies devoted to a regular use of aspirin or NSAIDs and risk of diverticulitis and of diverticular bleeding in the general population have also been analyzed. In a recent meta-analysis, LGIB accounted for 15–20% of GIBs, and diverticula were present in 30–40% of cases [59]. The relative risk of bleeding from diverticula was 1.73 (95% CI 1.31– 3.09) in men who had used aspirin regularly (≥2 times per week) and 2.24 (95% CI 1.63–3.09) in those who had used other NSAIDs. Another meta-analysis documented that, compared with men who denied taking these drugs, the use of aspirin at intermediate standard doses (325 mg tablets) and the frequency (4–6 days per week) was associated with the highest risk of bleeding (multivariable RR = 2.32; 95% CI, 1.34–4.02, and multivariable RR = 3.13; 95% CI, 1.82–5.38, respectively) [60]. Regular users of NSAIDs also had an increased risk of diverticulitis (multivariable RR = 1.72; 95% CI, 1.40–2.11) and of diverticular bleeding (multivariable RR = 1.74; 95% CI, 1.15–2.64). Similar to low-dose aspirin, clopidogrel administration increases the risk of UGIB and of LGIB. Using the National Health Insurance Research Database of Taiwan, 3238 clopidogrel users and 12,952 matched controls were extracted from a cohort dataset of 1,000,000 randomly sampled subjects [61]. The use of clopidogrel increased the risk of UGIB [HR: 3.66; 95% CI: 2.96–4.51] and of LGIB [HR: 3.52, 95% CI: 2.74–4.52]. Age, chronic kidney disease, a history of peptic ulcer bleeding, and use of aspirin and NSAIDs were independent risk factors for UGIB in the clopidogrel users. In addition to such factors, selective serotonin reuptake inhibitors independently predicted LGIB in this setting. 3.2. Combination treatments Similar to the results of the ACTIVE-A trial [62], a meta-analysis showed that low-dose aspirin (75–325 mg/d), alone or in combination with other medications, decreased the risk of all-cause mortality (RR, 0.93, 95% CI, 0.87–0.99), largely because of an effect in secondary prevention populations [55]. However, in parallel, the risk of major GIB increased not only with low-dose aspirin alone (1.55; 95% CI: 1.27–1.90), but also with aspirin combined with clopidogrel (1.86; 95% CI: 1.49–2.13 vs low-dose aspirin) or with anticoagulants (1.93; 95% CI: 1.42–2.61 vs low-dose aspirin) [53]. Importantly, PPIs reduced only in part the risk of major GIB in patients given low-dose aspirin (OR, 0.34; 95% CI, 0.21–0.57). With respect to combination treatments, results qualitatively similar to those reported above were found in the Nationwide registers from Denmark [63] and in the Health

Improvement Network UK primary care database analysis [64]. In the latter setting, compared with nonusers, the risk of UGIB was increased in current users of low-dose aspirin (RR, 1.80; 95% CI, 1.59 to 2.03) or of clopidogrel (RR, 1.67; 95% CI, 1.24 to 2.24). The risk was significantly higher when clopidogrel (RR, 2.08; 95% CI, 1.34 to 3.21), oral anticoagulants (RR, 2.00; 95% CI, 1.15 to 3.45), low-/medium-dose NSAID (RR, 2.63; 95% CI, 1.93 to 3.60), high-dose NSAID (RR, 2.66; 95% CI, 1.88 to 3.76), or high-dose oral corticosteroids (RR, 4.43; 95% CI, 2.10 to 9.34) were co-administered with low-dose aspirin. Also the risk of hospital admission for bleeding increases with the number of antithrombotic drugs used [65]. Out of 40,812 patients aged 30 years or older who had been admitted to hospital with first-time myocardial infarction (MI) between 2000 and 2005, 1891 (4.6%) patients were admitted to hospital with bleeding during a mean follow-up of 476.5 days (SD 142.0). In such setting, the NNH were 81.2 for aspirin plus clopidogrel, 45.4 for aspirin plus warfarin, 15.2 for clopidogrel plus warfarin, and 12.5 for triple therapy. Out of 1852 patients, 702 (37.9%) with nonfatal bleeding had recurrent MI or died during the study period compared with 7178 (18.4%) of 38,960 patients without non-fatal bleeding (HR 3.00, 2.75–3.27, p b 0.0001). Thus, treatment with triple therapy (or dual therapy with clopidogrel plus vit. K antagonist) should be prescribed only after a thorough individual risk assessment. 3.3. Newer antiplatelet agents To overcome the limitations of clopidogrel, two new antiplatelet drugs, prasugrel and ticagrelor, were evaluated in clinical trials in patients with CAD [66]. Prasugrel was evaluated in the TRITON TIMI 38 trial [67], ticagrelor, in the PLATO trial [68]. In both trials, the efficacy and safety of the combination of aspirin plus ticagrelor (or aspirin plus prasugrel) were tested versus the combination of aspirin + clopidogrel. The PLATO trial showed the superiority of a more robust platelet inhibition with ticagrelor compared with standard-dose clopidogrel in the prevention of recurrence of major ischemic events, particularly MI. However, in parallel with a higher efficacy, the use of this drug was associated with a higher (GI) bleeding tendency: HR 1.32, 95% CI: 1.01–1.72, p = 0.045 (Table 3). Chronic kidney disease and CABG were the predictors of such tendency [69]. Advantages and disadvantages comparable to those described for ticagrelor were observed for prasugrel in the TRITON-TIMI 38, the HR for a higher (GI) bleeding tendency in this setting being 1.46, 95% CI: 0.99–2.16, p = 0.05 [70]. In patients receiving prasugrel, variables with the highest strength of association with risk of serious bleeding were female sex, use of a glycoprotein IIb/IIIa inhibitor, duration of intervention, age, admission diagnosis of ST-elevation MI, femoral access for angiography, creatinine clearance, hypercholesterolemia, and arterial hypertension. 4. Antithrombotic agents, severity of illness and comorbidities: impact on GIBs Compelling evidence argues for the type of antithrombotic therapy used as exerting a smaller impact on the risk of GIB than the characteristics (e.g., comorbidities, severity of illness) of the patients in whom it is used. The risk of GIB associated with the use of DOACs is higher in patients treated for DVT/PE (or for AF) than in those receiving DOACs for thromboprophylaxis for orthopedic surgery [20]. In older patients treated with warfarin, the rate of major bleeding is higher in those with VTE than in those with AF (RR, 1.4; 95% CI, 1.1 to 1.8; p b 0.03) [35]. The data reported in the section on antiplatelet drugs extend to aspirin users the relevance of patient characteristics as to the risk of GIB. Moreover, in 13,819 patients with moderate- and high-risk ACS randomized to receive heparin plus a glycoprotein IIb/IIIa inhibitor, bivalirudin plus a glycoprotein IIb/IIIa inhibitor, or bivalirudin monotherapy (ACUITY trial), GIB within 30 days occurred in 178 patients (1.3%) [71]. Older age, baseline anemia, ST-segment deviation N or = 1 mm, cigarette smoking and diabetes mellitus were independent

Please cite this article as: Di Minno A, et al, Antithrombotic drugs, patient characteristics, and gastrointestinal bleeding: Clinical translation and areas of research, Blood Rev (2015), http://dx.doi.org/10.1016/j.blre.2015.03.004

A. Di Minno et al. / Blood Reviews xxx (2015) xxx–xxx

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Table 3 Major, fatal/life-threatening and fatal bleedings in the TRITON TIMI 38 and PLATO trials. Variable

TRITON TIMI 38 trial

Plato trial

Aspirin + prasugrel (6741 pts)

Aspirin + clopidogrel (6716 pts)

HR for prasugrel (95% CI)

p value

Aspirin + ticagrelor (9235 pts)

Aspirin + clopidogrel (9186 pts)

HR for ticagrelor (95% CI)

p value

Total bleedings Major

146

111

0.03

251

190

85

56

0.01

109

99

Fatal

21/85

5/56

0.002

13/109

13/99

1.32 (1.09–1.60) 1.10 (0.83–1.44) 1 (0.46–2.15)

0.003

Fatal/life threatening

1.32 (1.03–1.68) 1.52 (1.08–2.13) 4.19 (1.58–11.11)

Intracranial bleedings Major

19/146

17/111

0.74

27/251

14/190

19/85

17/56

0.74

27/109

14/99

Fatal

NA

NA

11/13

1/13

1.93 (1.01–3.66) 1.93 (1.01–3.67) 10.95 (1.41–84.73)

0.043

Fatal/life threatening

1.12 (0.58–2.15) 1.12 (0.58–2.15)

124/251

94/190

1.32 (1.01–1.72) 1 (0.66–1.49) 0

0.045

Gastrointestinal bleedings Major 63/146

43/111

Fatal/life threatening

NA

NA

47/109

47/99

Fatal

NA

NA

0/13

5/13

1.46 (0.99–2.16)

0.05

0.51 0.989

0.043 0.004

0.979

NA: not available.

predictors of GIB. Patients who suffered bleeding had significantly higher 30-day mortality rates than patients without bleeding. A longterm impact of bleeding on mortality for up to 1 year has also been reported [72,73]. Because patients who suffer major bleeding are likely to have antithrombotic therapies discontinued, the premature withdrawing of these therapies may partially explain any observed association between major bleeding and excess mortality. Thus, although GIB may be causally related to adverse outcomes in some patients, in the majority of cases it merely reflects the presence of patients at higher risk for adverse outcomes. In this respect, regardless of the antithrombotic agent to be employed, a baseline GIB-oriented clinical summary (Table 4) should be collected routinely from every patient, and the magnitude of the associated risk of morbidity and mortality must be seriously weighed by physicians formulating a management plan (i.e., defining the optimal antithrombotic strategy). Studies in real-world settings confirm the clinical value of such an approach. In ≈40,000 ACS patients enrolled in the Global Registry of Acute Coronary Events (GRACE), hospitalized with acute myocardial infarction, 2.8% experienced a major bleeding events (including GIB) during their hospital stay (≈ 49% of the major bleedings occurred the day of or the day after hospital admission) [74]. Although such bleeding occurred in only 1 in 35 patients, approximately 10% of deaths in the entire study population occurred in this high-risk patient subset (293/1140 deaths among hospital bleeders; 3605/38,647 deaths among non-hospital bleeders). Compared with those without, patients with major bleeding in hospital were more likely to die in the next 6 months (25.7% versus 9.3%; p b 0.001). Regardless of the antithrombotic agent(s) employed, bleeders were older, more severely ill, and more likely to undergo invasive procedures (exploratory surgery performed to manage bleeding, intra-aortic balloon pump, pulmonary artery catheter). An obvious consequence of the concept summarized above is that the risk of GIB related to the use of antithrombotic gents alone or in combination should be evaluated within each clinical setting. In patients with non-valvular AF, the use of adjusted dose-warfarin for stroke prevention increases the risk of major GIB approximately by three-fold (Table 5). Such rate is comparable to that seen in patients treated with apixaban, whereas the major GIB rate in patients treated with rivaroxaban or dabigatran 150 mg twice daily or with edoxaban 30 or 60 mg once daily is significantly higher. Different figures are obtained when DOAC-related GIB rates are evaluated in settings other than AF [20].

5. Clinical translation and areas of research These days, the use of any treatment should be based on the benefits and the risks for each individual patient. The HAS-BLED score has a better predictive value than older and newer bleeding risk assessment schemes as to the identification of subjects at risk of bleeding [75]. Such score allows clinicians to make an informed assessment of bleeding risk and helps identify modifiable risk factors for bleeding (e.g., uncontrolled blood pressure, labile INRs, concomitant use of aspirin, and alcohol excess) [76]. The HAS-BLED score has been validated for predicting bleeding risk in patients on no antithrombotic therapy; in those taking DOACs and/or aspirin; in those undergoing bridging therapy in both AF and non-AF patients [77], and in those on triple therapy following an ACS (in a cohort that included both AF and non-AF patients) [78]. The use of the HAS-BLED score within the frame of a severity score (e.g., the CHA2DS2-VASc score to stratify the risk of adverse outcomes in AF) [79], helps balance the benefits and the risks of antithrombotic treatments and identify the patients in whom the absolute gain in terms of vascular events prevented outweighs the risk of GIB. Such individualized context strategy is likely to help select those in whom to safely prescribe lower doses of DOACs (i.e., those associated with fewer GIBs in pivotal AF studies). While the relevance of this information as to settings other than AF is poorly understood, the use of a bleeding score in the

Table 4 Mitigating the risk of (upper) GIB in chronic use of antithrombotic drugs: baseline information. Baseline clinical summary

Conditions at the highest risk of GIB

GI

Uncomplicated peptic ulcer disease; gastro-esophageal reflux; diverticula, angiodysplasia; history of GIB. BW ≤60 kg; female sex; age N75 years; anemia; CrCl 30–50 ml/min; CAD; VTE treatment; AF; hypertension; diabetes mellitus; prior stroke/TIA or systemic embolization; active cancer; COPD; liver cirrhosis; history of falls; sleep apnea; concomitant alcohol/tobacco use. Chronic use of: PPIs; NSAIDs; aspirin; clopidogrel (thienopyridines); steroids; cyclooxygenase-2 inhibitors; selective serotonin reuptake inhibitors; warfarin; alendronate.

General

Polypharmacy

COPD: chronic obstructive pulmonary disease; TIA: transient ischemic attack.

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A. Di Minno et al. / Blood Reviews xxx (2015) xxx–xxx

Table 5 The relative risk of major GIB in the non-valvular AF population: study outcomes with low-dose aspirin (alone or in combination), warfarin or DOACsa,b. Treatment strategy

Comparator

RR

95% CI

Aspirin (or triflusal or indobufen) Aspirin + clopidogrel Adjusted-dose warfarin Adjusted-dose warfarin + aspirin Adjusted-dose warfarin + aspirin Dabigatran 150 mg twice daily Dabigatran 110 mg twice daily Rivaroxaban 20 mg once daily Apixaban 5 mg twice dailyd Edoxaban 30 mg once daily Edoxaban 60 mg once daily

Placeboc Aspirin Placebo Aspirin Adjusted-dose warfarin Adjusted-dose warfarin Adjusted-dose warfarin Adjusted-dose warfarin Adjusted-dose warfarin Adjusted-dose warfarin Adjusted-dose warfarin

1.92 1.93 3.21 4.72 2.66 1.50 1.10 1.46 0.88 0.67 1.23

1.08–3.41 1.46–2.56 1.32–7.82 1.35–16.49 1.05–6.74 1.19–1.89 0.86–1.41 1.12–1.90 0.62–1.24 0.53–0.83 1.02–1.50

a Data from: Coleman CI et al. Int J Clin Pract 2012;66 (1):53–63. Connolly et al. N Engl J Med 2009;361:1139–1151; Patel et al. N Engl J Med 2011;365:883–891; Granger et al. N Engl J Med 2011;365:981–992; Giugliano et al. N Engl J Med 2013;369 (22):2093-104. b Concurrent use of anti-platelet agents increases the risk of major GIB associated with rivaroxaban and of major extra-cranial bleeding (presumably including major GIB) associated with dabigatran or apixaban. c Incidence of GIB in placebo or control rms: 1.5% (data from: Lanas A et al. Clin Gastroenterol. Hepatol 2011;9:762–768). d In a head-to-head comparison in AF patients (mean follow-up: 1.1 year), the rate of GIBs was similar in 2791 pts that received 81–324 mg aspirin (n = 14) and in 2808 patients that received 5 mg apixaban (n = 12), HR: 0.86 (0.40–1.86), p = 0.71 (Connolly et al. N Engl J Med 2011; 364: 806–17)

frame of a comprehensive evaluation of the phenotypic severity currently helps personalize care in hemophilia patients [80]. The short half-life of the DOACs in the absence of renal or liver failure is an important advantage to the clinician confronted with major GIBs. In addition, antidotes that reverse the anti-coagulant effect of dabigatran [81] and of Xa inhibitors [82] are going to become currently available, allowing for standard therapeutic options in the case of GIBs (i.e., allowing for the management of acute GIB in the patient receiving any DOAC in a fashion entirely comparable to that of GIBs in subjects who are not receiving any antithrombotic agent). Preventive strategies can further mitigate the risk of GIBs in patients receiving DOACs. A history of established risk factors for GIB may lead to diagnostic tests (e.g., upper endoscopy/biopsy, colon cancer screening) and to therapeutic interventions (e.g., eradication of Helicobacter pylori) prior to starting the anticoagulant treatment. Adherence to appropriate dosing and scheduling and identification of modifiable and non-modifiable risk factors for bleeding will provide additional hints to lower the tendency to severe or even fatal GIBs. Over the last decade, while patient admissions for GIB decreased significantly owing to a decrease in UGIB, an increase in LGIB has been documented [83,84]. In particular, from 1996 to 2005, the rate of admissions for ulcer decreased from 54.6 to 25.8/100,000 pts/years of hospitalizations, and that for perforations decreased from 3.9 to 2.9/100,000 pts/years of hospitalizations. On the other hand, during the same time period, the rate of admissions for colonic diverticula increased from 3.3 to 8.0/100,000 pts/years of hospitalizations; that for angiodysplasias, from 0.9 to 2.6/100,000 pts/years of hospitalizations and that for perforation, from 1.5 to 2.3/100,000 pts/years of hospitalizations [83,84]. The use of proton pump inhibitors (PPI) given concomitantly from the beginning of therapy for secondary prevention of CAD or cerebrovascular events has proven to significantly reduce the risk of (U)GIB among NSAID users; among low-dose aspirin users; among patients taking clopidogrel [85,86], and among those treated with warfarin (especially when employed in combination with low-dose aspirin and/or clopidogrel) [87]. Accordingly, the use of PPI is recommended in patients with a history of GIB during warfarin anticoagulation and should be considered in any person with a risk factor for GIB receiving any type of antithrombotic agent [88]. In view of the facts that 1) a concurrent use of anti-platelet agents increases the risk of major GIB associated with rivaroxaban and of major extra-cranial bleeding (including major GIBs) associated with dabigatran, apixaban or

edoxaban; 2) many patients use DOACs for a considerable duration of time and 3) most of these patients have significant comorbidities, the concomitant PPI use should also be considered in this setting. However, with the exception of patients with AF that have received dabigatran (Table 6), data on the simultaneous use of DOACs and PPIs in the trials in which DOACs have been employed are poorly available. On the other hand, whether or not PPIs should be employed for LGIB would be only clarified by specifically designed trials and/or by trials such as the ongoing COMPASS trial [NCT01776424 — http://clinicaltrials.gov/ show/NCT01776424] in which rivaroxaban is used in combination with anti-platelet agents in patients with coronary or peripheral artery disease. The relevance of this information as to different clinical settings and/or other DOACs remains to be elucidated. It is presently unclear why the use of dabigatran, rivaroxaban, or edoxaban is associated with a higher rate of major GIB than the use of warfarin (or of apixaban or of low-dose edoxaban). One current hypothesis relates to the incomplete absorption of the DOACs across the GI mucosa and thus the potential for topical drug activity. While warfarin is over 95% absorbed (and the increase in major GIB observed in patients taking warfarin likely reflects the systemic anticoagulant action of the drug), all factor Xa inhibitors are administered as active drug, and are incompletely absorbed. The bioavailability of Factor Xa inhibitors, including apixaban, ranges 50–80% [3]. Accordingly, at least 1/5 of an active DOAC is recovered in the feces. However, the pro-drug dabigatran etexilate has only 6% oral bioavailability, which little argues for the topical anticoagulant activity hypothesis. On the other hand, vis-à-vis a number of GIBs comparable to warfarin in studies in AF individuals, apixaban has the lowest bioavailability (50%) and the longest absorption time. Another hypothesis relates to the impact of twice daily versus once daily dosing that is, compared with twice daily, once-daily dosing may cause higher peak anticoagulant effect systemically and/or intraluminally; lower trough levels and longer periods of time below a threshold concentration. Studies on genetic determinants of bleeding in AF patients receiving dabigatran [89], and population pharmacokinetics modeling relating the incidence of bleeding events with the exposure to edoxaban [90] argue for low trough levels of DOACs as being optimal predictors of a low risk of bleeding. Accordingly, in 1624 patients (18 pharmacokinetic studies) and in 585 patients (one phase II pharmacodynamic study) with edoxaban, the period of time during which the intrinsic factor X activity was ≤ 15% best predicted the risk of bleeding [91]. The trough level hypothesis is also consistent with the observation that, compared with standard dose, low-dose regimens of DOACs show overall reductions in stroke or systemic embolic events similar to warfarin (1.03, 0.84–1.27; p = 0.74), and a more favorable bleeding profile (0.65, 0 · 43–1.00; p = 0.05), with more ischemic strokes (1.28, 1.02–1.60; p = 0.045) [18]. Whether this is true in clinical settings other than AF is unknown so far. Physicians are presently confronted with the need to assess any risk factors for bleeding and the clinical situation when balancing the advantages and disadvantages of a chronic aspirin treatment. A high risk of major bleeding outweighs the potential benefit of aspirin use in the primary prevention setting [92]. In an individual-patient data meta-analysis of 24 randomized controlled trials involving approximately 66,000 individuals treated with long-term aspirin therapy for primary prevention [93], major GIB and extra-cranial bleeding events (0.10% vs 0.07% per year respectively; p always b0.0001) were increased, and their absolute risks were similar to those found in patients receiving aspirin for secondary prevention. However, estimated rates of the absolute excess of UGIBs dramatically differ according to aspirin dose and concomitant medication use. The numbers needed to harm (NNH) for a regular treatment with low-dose aspirin causing a major GIB vary approximately 100-fold, depending on a GIB history and the age of the patient [94]. Although relevant, these two variables only in part account for the predictable risk of GIB in chronic aspirin users in other clinical settings [20]. Continued aspirin treatment in secondary cardiovascular prevention in patients N50 years of age will result in 12,786 coronary and 7672

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A. Di Minno et al. / Blood Reviews xxx (2015) xxx–xxx

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Table 6 Baseline characteristics of AF patients in studies with DOACs: Relation to GIB. Data from: Connolly et al. N Engl J Med 2009;361:1139–1151; Patel et al. N Engl J Med 2011;365:883–891; Granger et al. N Engl J Med 2011;365:981–992; Giugliano et al. N Engl J Med 2013;369(22):2093-104. Characteristics

RE-LY D150

Median age (years) Age ≥ 75 years n, (%) Female sex n, (%) CHADS2 mean score (±SD) Hypertension n, (%) Diabetes mellitus n,(%) Previous use of VKA n, (%) Concomitant use of aspirin n, (%) Chronic use of PPI n, (%) Exclusion criteria (as related to the risk of GIB)

ROCKET AF D110

W

71.5 71.4 71.6 2466 (40.6) 2349 (39.1) 2423 (40.2) 2236 (36.8) 2150 (35.7) 2213 (36.7) 2.2 (±1.2) 2.1 (±1.1) 2.1 (±1.1) 4795 (78.9) 4738 (78.8) 4750 (78.9) 1402 (23.1) 1409 (23.4) 1410 (23.4) 3049 (50.2) 3011 (50.1) 2929 (48.6) 2404 (40) 2352 (38.7) 2442 (40.6) 847 (13.9) 812 (13.5 832 (13.8) GIB within the previous year

ARISTOTLE

ENGAGE

R

W

A

73 3082 (43.2) 2831 (39.7) 3.48 (±0.94) 6436 (90.3) 2878 (40.4) 4443 (62.3) 2586 (36.3)

73 3082 (43.2) 2832 (39.7) 3.46 (±0.95) 6474 (90.8) 2817 (39.5) 4461 (62.5) 2619 (36.7)

70 70 2850 (31.2) 2828 (31.1) 3234 (35.5) 3182 (35.0) 2.1 (±1.1) 2.1 (±1.1) 7962 (87.3) 7954 (87.6) 2284 (25) 2263 (24.9) 5208 (57.1) 5193 (57.2) 2859 (31.3) 2773 (30.5) 1683 (18.5)a 1667 (18.4)a Increased bleeding risk (no mention of GIB risk)

Clinically significant GIB within the previous 6 mo

W

E60

E30

W

72 2848 (40.1) 2669 (37.5) 2.8 (±1.0) 6591 (93.7) 2559 (6.4) 4140 (58.8) 2070 (29.4)

72 2806 (40.5) 2730 (37.9) 2.8 (±1.0) 6575 (93.5) 2544 (36.2) 4143 (59.2) 2018 (28.7)

72 2820 (39.9) 2641 (38.8) 2.8 (±1.0) 6588 (93.6) 2521 (35.8) 4138 (58.8) 2092 (28.7)

Overt GIB or active ulcer within the previous year

D110 dabigatran 110 mg; D150: dabigatran 150 mg; W: warfarin; R: rivaroxaban; A: apixaban; E60: edoxaban 60 mg; E30: edoxaban 30 mg; ASA: aspirin; VKA: vitamin K antagonists; GIB: gastrointestinal bleedings. a The ARISTOTLE study specified only the previous use of generic “gastric antiacid drugs”. In this study 752 pts in the apixaban group (8.2%) and 768 in the warfarin group (8.5%) were receiving NSAIDs.

cerebrovascular events prevented each year at the cost of 1023 extra UGIBs [95]. The favorable benefit–risk profile of aspirin is particularly relevant in ACS. While it is conceivable that the use of aspirin may be avoided in some AF patients at moderate–high risk of stroke undergoing percutaneous coronary intervention [96], such drug would still be required in the large majority of such patients [97]. Aspirin formulations with enteric coatings have been developed with the purpose of preventing the release of the active agent in the stomach, allowing for its absorption in the intestine. This strategy has shown a trend for reduced gastro-duodenal injury compared with uncoated aspirin [98], without impairing its antithrombotic effects. Withdrawing warfarin therapy was recently shown to increase the risk of death among individuals who had sustained GIB [99]. In particular, the decision not to resume warfarin therapy in the 90 days following a GIB was associated with an unexpectedly higher and not readily explained overall mortality, given that only 3 out of the 37 deaths in the group not resuming warfarin therapy were attributable to thrombosis. In current practice, the decision to not resume warfarin therapy takes place in sicker patients with more severe GIBs. A better understanding of the characteristics of the patients and of the relationships between major GIBs and mechanisms of death (e.g., adverse effects of resulting hypotension on end organs; acute anemia-mediated platelet and coagulation activation; adverse effects of blood transfusions; recurrent coronary ischemia) would help solve the dilemma whether and when to resume anticoagulation, and in turn decrease mortality in this high-risk setting. Conflict of interest G.D.M. and D.P. have served on advisory boards for and has received fees as a speaker at meetings organized by Boehringer-Ingelheim, Bristol-Myers Squibb, Pfizer, and Daiichi Sankyo. All the other authors have nothing to declare. References [1] Lanas A, García-Rodríguez LA, Polo-Tomás M, Ponce M, Alonso-Abreu I, Perez-Aisa MA, et al. Time trends and impact of upper and lower gastrointestinal bleeding and perforation in clinical practice. Am J Gastroenterol 2009;104(7):1633–41. [2] Parker DR, Luo X, Jalbert JJ, Assaf AR. Impact of upper and lower gastrointestinal blood loss on healthcare utilization and costs: a systematic review. J Med Econ 2011;14(3):279–87. [3] Desai J, Kolb JM, Weitz JI, Aisenberg J. Gastrointestinal bleeding with the new oral anticoagulants-defining the issues and the management strategies. Thromb Haemost 2013;110(2):205–12. [4] Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, MI, and stroke in high risk patients. BMJ 2002;324:71–86.

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Please cite this article as: Di Minno A, et al, Antithrombotic drugs, patient characteristics, and gastrointestinal bleeding: Clinical translation and areas of research, Blood Rev (2015), http://dx.doi.org/10.1016/j.blre.2015.03.004