Therapeutic bleeding risk

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Bleeding risk with various therapies is often poorly understood. An indication such as myocardial infarction with a high mortality may have benefits against bleeding risk that are not seen in another indication such as atrial fibrillation. Also remember that in some situations such as the use of warfarin after a treated gastrointestinal bleed on warfarin, mortality is much higher in those whose warfarin is permanently stopped[1]. Evaluating haemorrage risk has become even more complex with the entry of new anticoagulants, each of which has slightly different bleeding profiles. While serious bleeding is often feared with anticoagulation, in real life the risk of bleeding may be much higher if the patient is placed upon more than one drug whose action is on platelets[2]. Also other risk factors for bleeding often play a role. Indeed combination therapy risks are often not adjusted for important additional risk factors such as renal failure, age or drug interaction. And of course the definition of the bleed and significance of a bleed will vary. So the risk of intracranial bleeding on warfarin suddenly increases markedly over the age of 85[3] while the risk of a gastrointestinal bleed increases from age 70 [4]. which means patients over 85 have increased risks from serious bleeds rarely seen in younger patients. We have good quality data from Japanese[5] and predominantly Caucasian populations suggesting race does not alter risk on a population basis.

Contents

General

There is a challenging diverse literature. Much of the data is biased towards outcomes easily measured such as gastro-intestinal bleeds and other life threatening bleeds tend to be presented as case reports and may not even be formally recognised as an adverse reaction report to an anti-platelet agent or SSRI. A doctor who bases his recommendations for therapy on analogy and over simplistic extrapolation and risk assessment certainly can do harm, as can those who overestimate risk and do not offer indicated therapy. Different agents have different risks of say intrcranial haemorrhage and gastrointestinal haemorrhage with differing dose response risks of either. This article will concentrate on some of the more difficult risk benefit areas. Broadly on the MATCH trial criteria[6] of a life threatening or serious bleeding event[7]:

  1. A single anti-platelet agent is associated with a 1.2% (literature randomised trial range 0.2% and 3.2%) absolute risk in all adults treated of a serious bleeding event / year
  2. Dual anti-platelet therapy is associated with a 2% absolute risk in all adults treated of a serious bleeding event / year
  3. Warfarin therapy is associated with a 2% absolute risk in all adults treated of a serious bleeding event / year
  4. Combination antiplatelet and warfarin therapy is associated with a 3.5% absolute risk in all adults treated of a serious bleeding event / year

Combination Therapy

While this usually refers to two or more drugs that affect the coagulability of the blood, such as aspirin and ginkgo it is often just as problematical due to metabolic drug interactions. Some of the later antiplatelet agents marketed after clopidogrel have combined with aspirin both greater antiplatelet effectiveness and bleeding risk which may make the combination unattractive in those with highest bleeding risk presenting with a classic indication for such a combination such as a myocardial infarction.

Odds ratio of risk of serious upper GI bleeds
Number needed to harm by serious upper GI bleeds

The relative risk is not necessarily additive. There is a difference between clinical trials and real life. For example in real life a doctor may be more likely to use clopidogrel and aspirin in any patient who initially presented with a non ST elevation MI whatever their age because this is a well established indication with the limits of the original work buried in time. See the DAPT prediction score in those who have had percutaneous coronary intervention (PCI) for a risk benefit analysis.

Clopidogrel and Aspirin

In the real world you give 124 patients treatment to harm one with a serious GI bleed.[8]. It is only in coronary artery disease secondary prevention that benefit is likely to outweigh risk, and indeed in stroke and atrial fibrillation we know that we have better choices in long term secondary prevention.[9] It took up until 2018 to define a high risk cerebrovascular disease group who would benefit for up to 21 days dual therapy[10].

Prasugrel and Aspirin

Prasugrel has an increase in major bleeding risk over clopidogrel and aspirin but has net benefit in reducing cardiovascular events after PCI, especially in young diabetics[11]. In STEMI the increased bleeding risk may be confined to those who need CABG[12].

Aspirin and Dipyridamole

You give 595 patients treatment to harm one with a serious upper GI bleed.[13]

Aspirin and Warfarin

Warfarin and Aspirin do not do the same job.

LogoWarningBox4.pngWarfarin + Aspirin: This is at least almost always a bad idea in those without a high risk of an ischaemic heart disease event

Random aspirin for patients on warfarin is warned against in the patient-carried record booklet and is clearly a bad idea. However there remains space for discussion over combining aspirin and warfarin in certain high potential benefit patients. It is not and should not be a common occurrence, and every instance should have a clear rationale. See therapeutic bleeding risk for fuller context of the issues.

Aspirin combined with warfarin at therapeutic INR has a moderate harm ratio of one serious upper GI bleed per 184 patient years of treatment.[14]. It is therefore likely to be beneficial relative to the particular harm of bleeding in selected indications such as after a myocardial infarction [15] and acute coronary syndromes.[16] In practice, given other harms and as the evidence base after myocardial infarction is distinctly mixed, [17][18][19] unless your patient actually has characteristics of the recruitment population of the successful trials, a prescriber is likely to be doing net harm. Thus, few would consider using this proven therapeutic combination in the majority of elderly patients and, indeed, dangerous extrapolation from the clinical trials to subgroups excluded from the trials such as the very old, patients in renal failure and non-compliant is to be deprecated.

In patients with atrial fibrillation and ischaemic stroke the SPORTIF trials show that aspirin and warfarin is likely to be ineffective or harmful with no reduction in stroke, systemic embolism, or myocardial infarction compared to warfarin alone and an incremental rate of major bleeding of 1.6% per year over warfarin alone[20] In peripheral vascular disease we also know the combination is likely to be ineffective or harmful[21] being no more effective than antiplatelet therapy alone in preventing major cardiovascular complications and associated with an increase in life-threatening bleeding.

Triple therapy

LogoWarningBox4.pngWarfarin + Aspirin + another antiplatelet: This is at least almost always a very bad idea, but a fair one when the patient has acute or subacute unstable coronary arteries, and stenting combined with atrial fibrillation or a mechanical heart valve. The other antiplatelet should almost always be clopidogrel

Unhappily the safety of concomitant aspirin, clopidogrel, and warfarin therapy after percutaneous coronary intervention is a function of the warfarin therapy with a hazard ratio of 5 and number needed to harm of 7[22]. Short term triple therapy in those with a strong indication to be on warfarin is accepted, with until 2016 atrial fibrillation being one of these strong indications, as overall all cause mortality is reduced[23]. PIONEER AF-PCI defined that after PCI with stent placement either low dose rivaroxaban combined with dual antiplatelet therapy or moderate dose rivaroxaban combined with a P2Y12 inhibitor was superior to the then standard of care which was 'triple' therapy with warfarin and dual antiplatelet therapy[24]. Accordingly a move away from warfarin in this indication is to be expected. ESC consensus guidelines on what to do in patients on prior antithrombotic therapy for atrial fibrillation, who present with acute coronary syndrome and/or undergo percutaneous coronary intervention/coronary stenting exist. [25] Essentially the antiplatelet agents are given as well as the anticoagulant for the period of highest thrombotic risk with some modification if the risk of haemorrhage is high. In acute coronary syndrome, standard therapy is used with oral anticoagulation generally being withheld while INR > 2.0. Triple therapy is now recommended for 3 to 6 months, possibly longer in those at highest coronary artery disease risk. However the INR control must be tight between 2 to 2.5. It is noted that those at highest risk of embolic event (eg metal heart valves) INR up to 3 does not contraindicate radial artery access PCI. For elective metal stents offer 1 month of triple therapy, elective 'olimus coated stents get 3 months triple therapy and to 12 months an antiplatelet and anticoagulant, while elective paclitaxel coated stents get 6 months triple therapy, then up to 12 months an antiplatelet and anticoagulant. This last regime also applies to all stents used in primary PCI. If risk of haemorrhage is high, use bare metal stents in all indications and up to 4 weeks of triple therapy, then in elective patients revert to warfarin but in primary PCI acute coronary syndrome patients give 6 months antiplatelet and anticoagulant before reverting to anticoagulation alone.

Other oral anticoagulants and double or triple therapy

This is not an area without an evidence base but prescribing should be within the evidence base and this may require a switch to less convenient agents such as warfarin for greatest safety. In particular clinicians should note that the doses of drugs such as rivaroxaban are lower in some proven indications for triple therapy after myocardial infarction.

SSRIs and NSAIDS

This combination has a surprisingly high harm ratio of one upper GI bleed per 62 to 75 patient years of treatment. [26].

Dabigatran and antiplatelets

Co-administration of aspirin 81mg and 150 mg dabigatran etexilate twice daily increased the risk for any bleeding from 12% to 18% in a phase 2 trial. The bleeding risk in patients (approx 20%) on antiplatelets was similar with dabigatran and warfarin in RE-LY[27]. The 150mg bd dose of dabigatran combined with antiplatelets maintained its superior primary outcome to warfarin combined with antiplatelets[28]. It is suspected that in usual practice in AF aspirin and warfarin are co-prescribed less than the 20.8% of patients in RE-LY. Detailed analysis suggests that at the 110mg dabigitran dose those on no aspirin had a lower major bleeding rate than those on warfarin and no aspirin[27]. Thus patients who need to continue aspirin and will be on a lower dose of dabigatran than 150mg do not gain any advantage compared to being on warfarin and aspirin.

Dabigatran and dual antiplatelet therapy

There is a dose-dependent increase in serious bleeding risk with addition of dabigatran to aspirin and clopidogrel with hazard ratio of 1.8 (95% CI 0.7 - 4.5) for 50 mg, 2.2 (0.9 - 5.3) for 75 mg, 3.9 (1.7 - 9.0) for 110 mg and 4.3 (1.9- 9.8) for 150 mg[29].

Oral anti-factor Xa drugs and antiplatelets

PIONEER AF-PCI defined that after PCI with stent placement either low dose rivaroxaban combined with dual antiplatelet therapy or moderate dose rivaroxaban combined with a P2Y12 inhibitor was superior to the then standard of care which was 'triple' therapy with warfarin and dual antiplatelet therapy[24]. RECORD no separate data analysis on bleeding risk for those on aspirin at the same time as either warfarin or rivaroxaban is available but at randomisation about 40% of patients were on antiplatelet agents and outcome did not appear to differ with prior aspirin use which was allowed to continue[30]. The combination with dual antiplatetlet therapy increases the risk of bleeding about three fold. This is problematical for possible indications when the combination has no synergistic effect on clinical outcomes and mean that with full anticoagulation dose of the oral anti-factor Xa drug it is likely to be ineffective or harmful[31][32]. However reduced dose (2.5mg bd) rivaroxaban is synergistic to aspirin and clopidogrel in acute coronary syndrome with tolerable bleeding risk and a 1.6% gain in mortality[33].

Anticoagulation

Heparin

At therapeutic doses with indicated monitoring, and careful patient selection, the risk of bleeding is little different to warfarin but the data is incomplete. There is now up to 6 month data for the low molecular weight heparins with the evidence for dalteparin showing that the bleeding risk is unchanged while clinical benefit is doubled compared to warfarin.[34]. The bleeding risk at prophylatic doses is complicated by much of the evidence base being from short term courses after surgery.[35]However in medical patients using low molecular weight heparin avoids 7.7 episodes of major bleeding/1000 patients compared with low dose unfractionated heparin.[36]

Oral Anticoagulation

Vitamin K antagonists

Bleeding risk with age
Bleeding risk is an exponential function of INR

There is a very good evidence base to access the risk with warfarin. It is suggested that a validated score such as HAS-BLED score be used in routine clinical practice. However this only applies to warfarin and indeed the evidence base is evolving as it was only recently understood that warfarin increases the relative risk of intercranial bleeds compared to other anticoagulants and causes less gastrointestinal bleeds than some. Also the excess mortality associated with permamently stopping warfarin after gastro intestinal bleeds and minimimal risk of further GI bleeds on those whose warfarin was restarted was only recently recognised[1]. Risk is a function of:

  • Age (poorly for bleeding, much stronger for death or life threatening events)[37]
  • Race (risk intracranial haemorrhage increases white<black<hispanic<asian by 4 fold[38])
  • Renal function
  • Hepatic function
  • Other comorbidites
  • Control (see also Typical risk graph of haemorrhage risk verus INR). Bleeding risk is increased in first 3 months of therapy, and poor anticoagulation control in the first 3 months of therapy continues.

The context is that in one recent study of warfarin use in non valvular atrial fibrillation 170 major hemorrhages were identified during 15,300 person-years of warfarin therapy and 162 major hemorrhages occurred during 15,530 person-years off warfarin therapy.[39]. The absolute risk of a life threatening or fatal complication of oral anticoagulation increases from 1.1/100 patient-years at 65 years to 3.4/100 patient-years in those over 80[40]. The rate of major haemorrhage is 0.9/100 patient years in those aged < 80 years and 1.9/100 patient years in those 80 or older[41]. A study of nursing home residents in the USA has recently emphasised the risks associated with warfarin in a supervised care environment where serious, life-threatening, or fatal events occurred at a rate of 2.5 per 100 resident-months (0.3 per patient year, 30/100 patient-years !) with almost 60% being considered preventable [42]. However many consider warfarin underused in such settings[43]. Possibly the explanation for such differential views is that it is not age but rather the less easily measured dependency that is the risk factor that the studies have failed to identify as important for warfarin risk in the community[44]. Previous ischaemic stroke is known to increase bleeding risk by about 2.5 times (95% confidence interval: 1.3 to 4.8 times)[41].

Dementia and Oral Anticoagulation

Cognitive dysfunction is a risk factor for poor warfarin control. However the true risk is probably mainly due to impaired medication management capacity which is not just a function of cognition and also depends on factors such as presence of family support[45]. However neuropathology that causes cognitive impairment would also be associated with increased risk of cerebral micro haemorrhages and falls. Even mild cognitive impairment is associated with a time in therapeutic range (TTR) below the median and extremes in high INR, but many studies suggest this is not a major issue. Some studies have suggested that using a cut off of MMSS score of 26 does not show a significant difference in outcome in the two groups[46]. In other studies atrial fibrillation patients with an MMSE score less than 26 have more bleeding (9.6% versus 7% per 100 patient-years, p=0.04) and loss the stroke reduction benefit (vascular events 6.7% versus 3.6% per 100 patient-years, P=0.002).[47]. Earlier studies with lower MMSS cut offs, say 23 did identify this risk[48]. Given that 50% of patients with dementia are dead in 5 years, the gains in stroke prevented in the atrial fibrillation indication of perhaps 5% per annum will cause continuing debate in the less cognitively impaired.

Falls and Oral Anticoagulation

Despite clinical practice to the contrary it has long been known that risk of falling was not an important independent factor in determining optimal antithrombotic therapy[49]. Both patients and doctors tend to be conservative as

  • The risk factors for falls in the elderly are very similar to the risk factors for adverse outcomes in the elderly
  • Patients who fall have different risk benefit profiles to those that don't
  • Anticoagulation does increase risk of fatal outcome from a fall if that fall results in trauma[50]

Falling as a risk factor for adverse outcomes with established Vitamin K antagonist anticoagulation has been studied. There is an interesting issue of selection bias which may be why in hospital fallers on warfarin are less likely to have serious traumatic intracranial haemorrhage than those on aspirin or clopidogrel.[51] The highest quality study published[52] shows that those at high risk of falls are not typical for patients on oral anticoagulation and seem to have a higher risk of stroke in non-rheumatic AF. Thus they benefit absolutely by being treated. One qualification to this objective evidence is that contrary to some earlier work, the effect of pre-existing oral anticoagulation on outcome of closed head trauma suggests a doubling of mortality (to 40%)[53][54].

Events per 100 patient years in non-rheumatic AF[55]

AF Controls High falls risk Comment
Risk of Stroke 6.9 13.7 Doubles absolute benefit by treating high risk of falls group
Intracranial hemorrhage 1.1 (1.0-1.3) 2.8 (1.9-4.1) Trebles absolute risk of ICH in high risk of falls group
Overall absolute gain 5.8 10.9 Unknown selection bias

Direct thrombin inhibitors

Compared to warfarin, dabigatran etexilate produced in each 1000 patients treated 56 fewer intracranial haemorrhages or haemorrhagic strokes which is its main advantage over warfarin[56]. However it produced more gastrointestinal bleeds than warfarin and accordingly appears not be the right choice in patients with a high potential for gastrointestinal blood loss.

Factor Xa inhibitors

Rivaroxaban and apixaban both cause fewer intracranial haemorrhages or haemorrhagic strokes than warfarin. For every 1000 patients treated for 1.8 years apixaban prevented major bleeding in 15 patients and haemorrhagic stroke in 4[57].

Risk factors for adverse outcome with new oral anticoagulants

Renal impairment is associated with an increased risk of bleeding with both dabigatran and rivaroxaban. There is preliminary evidence of poorer outcome with major trauma presentations on these agents, as expected by their relative irreversibility. There is no evidence for increased risk with fallers or dementia. However in cross over trials where a transition between the longer acting warfarin and a shorter acting new oral anticoagulant occurred, thrombotic events seemed to be associated with likely incomplete anticoagulation with the new oral agents.

Dual anticoagulants

The advent of the new oral anticoagulants has resulted in patients being given two anticoagulants as a mistake. Even prophylatic dose of heparins and full anticoagulation with another agent causes an unacceptable incidence of bleeding complications within quite short treatment periods. Accordingly based on regulatory recommendations (eg UK) only use dual anticoagulation during bridging therapy.

Anti-Platelet Agents

All increase risk about twice with this risk being a function of:

  • Age
  • Renal function

Falls and anti-platelet agents

Like with oral anticoagulation, being on aspirin before a fall may increase the likelihood of inhospital mortality if you suffer serious injury from the fall[58].

Aspirin

The major bleeding risk doubles with doses <100mg compared to >200mg (CURE study, although overview of risk benefit from all trials is too finally balanced to call at doses less than 325mg/day). This bleeding risk is heavily biased towards upper GI bleeds. The absolute rate increase with low dose aspirin above placebo for GI bleeds is 0.12% per year (95% CI: 0.07-0.19%) with a number-needed-to-harm of 833 patients (95% CI: 526-1429). [59]It must be remembered that other antiplatelet agents have very similar total bleeding risk to aspirin.

Clopidogrel

To prevent one major GI bleeding episode annually 883 patients (95% CI, 357-∞) would need to be treated with clopidogrel rather than aspirin[60] and both have the same over all haemorrhage rate. In the CAPRIE study aspirin 325mg had the same over all bleeding rate of 9.3% compared to clopidogrel 75mg.

Prasugrel

See prasugrel but in some high risk of thrombotic event populations, even if there is evidence of an increase in bleeding risk, it is a better choice than clopidogrel.

Dipyridamole

Total bleeding risk similar to aspirin and clopdogrel.

Glycoprotein IIb/IIIa receptor inhibitors

The incidence of significant bleeding is about 3% with eptifibatide and is correlated with[61]

  • age
  • failure to allow for renal function

NSAIDs

All increase risk, with COX 2 activity less so acutely but definitely questionably so in long term use[62]. There is a strong correlation with the degree of COX 1 inhibition so low dose ibuprofen is rather safe[63], but doses of 1.2g daily less so [64].

SSRIs

Risk increases with age and previous upper GI bleeds.[65]. As it is consistently reported and contributes an additive risk in polypharmacy situations where the patient is likely to be treated by more than one clinician, sometimes off label, this risk may deserve prospective thought.

Ginkgo

Risk is unknown due to lack of standardisation but appears to exist.[66]

Non-Associations

Beta blockers and calcium channel blockers are not associated epidemiologically.[67]

References

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