How do we manage serious gastrointestinal adverse events associated with anti-thrombotic therapy?

Abstract

Antithrombotic therapy (ATTs) is increasingly used worldwide for preventing primary or recurrent thrombotic events. Moreover, newer oral anti-platelet drugs and anti-coagulants have been introduced for clinical use, accelerating the number of patients under ATT. Not infrequently, these drugs are used in combination. These drugs, however, are well-known for adverse events in which gastrointestinal bleeding (GIB) is most common. Bleeding during ATT can be fatal, but even when patients survive, their prognosis is rather poor. Therefore, it is imperative to minimize such events. So far, co-prescription of proton pump inhibitor (PPI) has been documented to be the most effective in reducing upper GI injury and bleeding, though deliberate use of PPIs is required to minimize drug interaction and associated adverse events with acid suppression. In addition, we should note that PPI is not effective in preventing mid- or lower-GI injury/bleeding for which only limited evidence on preventive measures is available.

Keywords:

• anti-coagulants
• anti-platelet drugs
• anti-thrombotic therapy
• gastrointestinal bleeding
• gastrointestinal ulcer
• proton pump inhibitor

Regular users of anti-platelet and anti-coagulant drugs, collectively called as anti-thrombotic drugs (ATDs), are increasing due to growing elderly population, availability of newer ATDs and heightened awareness of their health benefits as recommended by guidelines [1–3]. However, their use is associated with serious and sometimes fatal gastrointestinal (GI) events.

Moreover, cessation of ATDs due to gastrointestinal bleeding (GIB) or during endoscopic and surgical interventions may precipitate the recurrence of underlying diseases such as ischemic heart diseases or occlusive cerebrovascular diseases, leading to life-threatening events. Therefore, we need to pay special attention to prevent the GI complications in patients on ATD therapy.

Method

As the number of reference allowed in this review is limited to 20, majority of the references were selected from review articles searched under a term of ‘anti-platelet drug’ or ‘anti-coagulant’ or ‘anti-thrombotic therapy’ in conjunction with ‘GI injury’ or ‘GI bleeding’ using PubMed as a database. Articles dealing with human subjects published in English in the last several years were selected for reference. Original articles are also included, when necessary.

Anti-platelet drugs & GI complication

The most important, by far the most cost–effective, and widely used anti-platelet drug is low-dose aspirin (LDA). Therefore, despite the increase in GIB associated with LDA use (around 1/1000 patient years in general population) [2,4,5], it remained the mainstay of anti-platelet therapy. Advanced age, concomitant use of other drugs such as NSAIDs and ATDs are among the factors that further elevate the risk of bleeding [5].

Similar to traditional NSAIDs, LDA-associated GI injury also occurs in mid- and lower GI tract [6,7]. Among them, it should be noted that LDA doubled the risk of diverticular bleeding [7], which accounts for the most frequent cause of lower GIB as colonic diverticulum is quite common in elderly population.

Dual combination therapy with other anti-platelet agent, most often with clopidogrel, a thienopyridine derivative that inhibits adenosine diphosphate receptor (P2Y12), is recommended in guidelines when patients succumb to acute coronary syndrome or undergo coronary stenting. However, a combination of two anti-platelet agents increases the risk of GIB [5,8], requiring appropriate prevention, which will be discussed later.

Initially, clopidogrel was thought to have a better safety profile on the GI toxicity compared to LDA. However, evidence on the increased risk of GIB and even ulcerogenic effects of clopidogrel has been reported [8,9]. Newer and more potent P2Y12 antagonists, such as prasugrel and ticagrelor, have similar or even a higher risk of GIB [10].

Another class of anti-platelet agent, cilostazol, a phosphodiesterase-3 inhibitor, showed a safer toxicity profile [11], although it is mostly used for the prevention of cerebrovascular diseases as it causes palpitation that might raise a concern on precipitating angina.

Anti-coagulants & GI complications

Warfarin, a classical anti-coagulant acting as a vitamin K antagonist, is still widely used despite its narrow safety margin and notoriously diverse drug and food interactions, requiring frequent measurement of prothrombin time and dose adjustment. To circumvent these limitations, target inhibitors of coagulation factors have been introduced into clinical use [3]. Warfarin itself causes fewer GI mucosal injuries, but if combined with anti-platelet drugs, risk of GIB sharply increases: hazard ratios (95% confidence interval) of GIB when warfarin is used in combination with aspirin, clopidogrel and aspirin plus clopidogrel are 2.30 (2.03–2.60), 3.46 (2.19–5.46), and 5.38 (3.48–8.32), respectively [12].

Dabigatran, a direct thrombin inhibitor, was associated with higher GI adverse events than warfarin [13], though hemorrhagic stroke was reduced. The use of dabigatran should require special attention in patients with impaired renal function, since the major route of drug excretion is through the kidneys.

A number of direct inhibitors of factor Xa have also been introduced. These include rivaroxaban, apixaban and edoxaban, which showed better efficacy in reducing stroke or systemic embolic events, but accompanied a slightly elevated risk of GIB compared with warfarin [3,13].

Management of GI bleeding in patients on ATD

Acute upper GIB during the ATD therapy can be managed by appropriate endoscopic hemostatic techniques such as placing metal clips combined with high dose of parenteral proton pump inhibitor (PPI) in the majority of cases. However, the prognoses of patients with such bleeding episodes are shown to be quite poor [14]. One of the reasons might be due to the cessation of antithrombotic therapy (ATT) after hospitalization following acute bleeding. If the cessation is over 7 days, a risk of recurrence of co-morbidity that required ATDs increases, which may eventually lead to fatal outcome. Indeed, a controlled study clearly showed that those under continuous use of anti-platelet medication had better survival rate as compared with those who stopped medication, despite the increase in GIB in the latter [15]. It is vitally important, therefore, to continue ATD or re-institute the ATD once hemostasis is achieved under co-therapy with anti-secretory drugs.

For scheduled intervention such as surgical operation and endoscopic therapy, continuation of ATD as much as possible is also desirable. For example, patients who underwent cardiac stenting should be switched to heparin before the procedure to minimize the duration of interruption of ATT and resume heparin after confirmation of hemostasis (so-called bridging). An excellent guide on how we manage ATT at the peri-procedural period for gastroenterologists is published [16].

Prevention of upper gastroduodenal injury & complications

As stated above, GIB in patients on ATT predicts worse prognosis and demands high medical cost. Therefore, those who are planned to receive ATT should be informed on their bleeding risks and be advised for taking appropriate preventive measures based on their risks. Eradication therapy should be offered if Helicobacter pylori positive, but it requires about 2 months for confirming eradication, which may be impractical in actual clinical settings. Patients having high risk factors should be given anti-secretory drugs. For LDA-associated ulcer prevention, PPI is superior to histamine H2 receptor antagonists (H2RA) [17]. A number of trials showed that standard dose, or even a half dose of PPI, effectively prevents ulcer relapse: relapse rate in 15 mg of lansoprazole was 3.7 versus 31.7% in control at 361 days and 20 mg esomeprazole was 1.75 versus 18.8% in control at 48 weeks according to our clinical trial data. Increasing the dose of PPI may not further enhance the preventive effect as reported in OBERON trial. For clopidogrel, there was a concern on its interaction with PPI compromising anti-thrombotic effects. Although the results of observational studies are conflicting in this regard, it is now realized that such an interaction demonstrated in vitro may not extrapolate to clinical situation. Indeed, the only double-blind, prospective controlled trial data clearly showed that a combination of PPI with clopidogrel did not influence adverse cardiac events while significantly reducing adverse GI complications [18]. Therefore, there should be no hesitation in the co-administration of PPI with clopidogrel. For newer P2Y12 antagonists, no large-scale prevention trials have been reported, but similar preventive measures should be taken for high-risk patients considering their negligible metabolic interactions with PPI. Fortunately, PPI seems to be similarly effective without worrisome loss of preventive effect even when dual anti-platelet drugs are administered [19].

For preventing GIB in patients on warfarin, close monitoring of prothrombin time with dose adjustment is mandatory. Furthermore, if patients have risk factors, they should receive preventive measure with anti-secretory drugs, in most cases PPI. In this case, some PPIs sharing common metabolic disposition pathway through CYP3A4 might increase the warfarin concentration. As new target inhibitors of coagulation factors do not have proven antidotes, PPI co-prescription should be considered for patients at risk.

In a real-world clinical practice, however, it was shown that gastroprotective co-therapy was underutilized for patients on ATT. Educational efforts both for doctors and patients should, therefore, be strengthened.

Prevention of mid or lower GI injury & bleeding

As previously mentioned [5–7], LDA and possibly thienopyridines may cause lower GI injury and increase the risk of mid (small intestine) or lower GIB from diverse lesions including diverticulum, angiodysplasia, ulcers and tumors. Bleeding from small intestine, though technically more demanding, can be managed by double-balloon enteroscopy [6] similar to colonic bleeding, using metal clipping or radiofrequency ablation depending on the nature of the lesions.

Unfortunately, no reliable measures have been established for preventing mid- or lower GIB in patients on ATD therapy, though misoprostol was shown to be effective in reducing LDA-induced intestinal injury in a trial involving a small number of subjects. A large prospective, controlled trial is warranted, considering the increasing number of cases complicated with lower GIB which is more common in patients with dual antiplatelet therapy co-prescribed with PPI [20].

Financial & competing interests disclosure

Sugano K received research grants from Takeda Pharma Inc., Eisai Inc., and Dai-ichi Sankyo Inc. Sugano K also received honoraria for lectureship from Takeda Inc. Sugano K served as an advisory member for clinical trials conducted by Takeda Inc. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.