Is Bleeding a Necessary Evil?
Is Bleeding a Necessary Evil?
The emergence of new and effective OACs has changed the landscape of thromboprophylaxis for stroke prevention in AF. The US FDA and the EMA have now approved dabigatran, rivaroxaban and apixaban for the prevention of stroke in non-valvular AF. Rather than the more straightforward choice between superior anticoagulation with warfarin and inferior antiplatelet therapy with aspirin, clinicians will soon be tasked with choosing between a selection of effective therapeutic options, although at present the evidence to support one NOAC over another is limited (Table 7).
It is clear that patients unable and unwilling to take warfarin ought to be considered for treatment with a NOAC (Table 8). There should also be a low threshold for switching patients with erratic INRs to an alternative OAC agent. The benefit of warfarin is dependent on the quality of the INR control, often reflected by the TTR. An increased time in TTR is associated with fewer bleeding complications, as well as fewer strokes and other vascular complications. A low TTR can completely negate the benefit of warfarin, whereas home monitoring can improve the quality of the anticoagulation. Patients with a low TTR seem to derive the greatest benefit from NOACs so it could be argued that a patient well-established on warfarin with good INR control and no issues with monitoring ought not to be transitioned to a new agent. However, dabigatran has been demonstrated to significantly reduce ICH and that this clinical benefit persists regardless of the level of INR control.
It can be problematic to offer comparisons between drugs tested in separate trials with distinct designs and study populations. RE-LY was an open trial with a PROBE (Prospective Randomised Open Blinded Endpoint) design, and this lack of blinding may have influenced event interpretation. One analysis of PROBE versus double-blind trials for stroke prevention in AF has recently been published, which concluded that while there are differences in outcome between PROBE and double-blind trials, they do not appear to be design-related, and that the exacting requirements of double-blinding in AF trials may not be necessary. Rivaroxaban was tested in a higher-risk population in ROCKET-AF than apixaban or dabigatran in the moderate-risk populations of ARISTOTLE or RE-LY, respectively: 32% of patients in RE-LY had a CHADS2 of 0–1, compared with <1% with ROCKET-AF. There were also differences in the quality of INR control in the warfarin arms of the different trials: the TTR was 55% in ROCKET-AF, compared with 62% in ARISTOTLE and 64% in RE-LY. Therefore, truly meaningful comparisons between the NOACs can only be gleaned by head-to-head comparisons in randomized trials. In the absence of comparative trials, cautious inter-trial comparisons are required to help clinicians determine the optimal antithrombotic strategy, alongside consideration of individual patient characteristics, drug tolerability and cost. As such, various network meta-analyses and indirect comparisons have been published. While such comparisons have various limitations, they do suggest that for efficacy end points the NOACs are broadly comparable, but for safety end points, dabigatran 110 mg b.i.d. and apixaban may be associated with less major bleeding.
A recent meta-analysis has suggested that the NOACs are more efficacious than warfarin for the prevention of stroke in AF (RR: 0.78; 95% CI: 0.67–0.92), but this analysis essentially considers that all the NOACs are the same, and the trials are homogeneous. Furthermore, the risks of ICH – the most devastating and feared consequence of anticoagulation – were markedly reduced with the new agents (RR: 0.49; 95% CI: 0.36–0.66). The data for other major bleeding and gastrointestinal bleeding were less conclusive. Another recent analysis modeled data for the net clinical benefit of NOACs balancing ischemic stroke against ICH, using data from the Danish National Patient Registry. In patients at high risk of stroke (CHA2DS2-VASc ≥2), the NOACs were superior to warfarin for net clinical benefit, regardless of the risk of bleeding. When stroke risk and bleeding risk are high, the new drugs had an even greater net clinical benefit.
All NOACs exhibited a significant reduction in ICH when compared with warfarin. Dabigatran 150 mg and apixaban both demonstrated reduced stroke rates compared with warfarin, whereas dabigatran 110 mg and rivaroxaban were non-inferior to warfarin. Only dabigatran was proven to significantly reduce the rates of ischemic stroke, whereas only apixaban demonstrated a statistically significant mortality benefit over warfarin.
In their trials, both dabigatran and rivaroxaban have been found to cause more gastrointestinal bleeding than warfarin; dabigatran also showed an increased rate of dyspepsia (perhaps related to the drug's tartaric acid core), with this being the major contributor to drug discontinuation. It may be prudent, therefore, to utilize apixaban in patients unsuited to warfarin that are known to have gastrointestinal upset.
Recent data from the US FDA has also shown that major bleeding rates are not higher than those associated with warfarin. These data are reinforced by a large propensity-matched 'real-world' nationwide cohort study of post-marketing dabigatran use from Denmark, which showed that stroke and systemic embolism were not significantly different between warfarin- and dabigatran-treated patients. Adjusted mortality was significantly lower with both dabigatran doses (110 mg b.i.d.: propensity-matched group stratified HR (aHR): 0.79; 95% CI: 0.65–0.95; 150 mg b.i.d.: aHR: 0.57; 95% CI: 0.40–0.80), when compared with warfarin. Pulmonary embolism was lower compared with warfarin for both doses of dabigatran. Also, less intracranial bleeding was seen with both dabigatran doses (110 mg b.i.d.: aHR: 0.24; 95% CI: 0.08–0.56; 150 mg b.i.d.: aHR: 0.08; 95% CI: 0.01–0.40). The incidence of myocardial infarction (MI) was lower with both dabigatran doses (110 mg b.i.d.: aHR: 0.30; 95% CI: 0.18–0.49; 150 mg b.i.d.: aHR: 0.40; 95% CI: 0.21–0.70). Gastrointestinal bleeding was lower with dabigatran 110 mg b.i.d. (aHR: 0.60; 95% CI: 0.37–0.93) compared with warfarin, but not dabigatran 150 mg b.i.d.
Rivaroxaban is the only new option that offers once-daily (od) dosing, which can be considered a slight advantage over dabigatran and apixaban. Twice-daily dosing may promote forgetfulness, which is a particularly important consideration for NOACs with short half-lives, where missed doses may place the patient in a prothrombotic state. There is also evidence that rivaroxaban is effective in patients with an acute coronary syndrome (ACS); however, the effect of the AF prophylaxis dose (20 mg od) plus dual antiplatelet therapy in the setting of an ACS has not been specifically examined. Dabigatran has been shown to cause a small numerical but non-significant increase in MI. Clinicians may be tempted to avoid dabigatran in patients with previous MIs, but these results must be taken in the context of the favorable overall net clinical benefit of dabigatran in terms of reduced stroke, cardiovascular events and vascular mortality. In the large Danish 'real-world' study previously described, MIs were significantly lower in dabigatran-treated AF patients, compared with those on warfarin.
Renal function is a further consideration when deciding on an antithrombotic strategy. Dabigatran and rivaroxaban must be used with caution in patients with renal insufficiency. Dabigatran is contraindicated in patients with severe renal impairment, and the lower dose of 110 mg is advised for patients with reduced creatinine clearance (30–49 ml/min). Interestingly, the US FDA approved the dose of 75 mg b.i.d. for patients with impaired renal function, despite the fact that this dose has not been studied in a randomized controlled trial. A reduced dose of rivaroxaban 15 mg od has been recommended for patients with impaired renal function and those with a high bleeding risk (HAS-BLED ≥3). There were fewer fatal bleeds with rivaroxaban (0.28% vs. 0.74% per 100 patient-years; p = 0.047) at this reduced dose. The rates of ICH were similar between rivaroxaban and warfarin (0.71 vs. 0.88 per 100 patient-years; p = 0.54), suggesting that impaired renal function may attenuate rivaroxaban's benefit in terms of reducing ICH.
Patients with severe renal impairment (creatinine clearance <25–30 ml/min) or those on renal replacement therapy were excluded from all three trials. In these patient groups, it would seem prudent to treat with warfarin until robust evidence is available to support the use of NOACs. In terms of assessing their stroke risk, renal impairment does not independently improve the predictive value of stroke risk scores such as CHADS2 or CHA2DS2-VASc. This is perhaps not surprising, given that renal impairment is associated with the risk factors (e.g., age, hypertension, diabetes, heart failure, vascular disease, etc.) that make up the components of those scores.
Clinicians are advised to monitor renal function 12-monthly in cases of mild impairment, 6-monthly in moderate impairment and frequently during clinical conditions that predispose to a decline in renal function (intercurrent infection, hypovolemia, dehydration, commencement of nephrotoxic medication). Serum creatinine and estimates of creatinine clearance must be interpreted with caution in older patients, when muscle mass is likely to have declined.
Generally speaking, well-informed patients tend to be more compliant with medications, and this is again crucial considering the implications of missed doses, especially with the short-acting new drugs. Patients are predominantly concerned with stroke and death, and are generally willing to accept increased bleeding risks to avoid a stroke. The use of decision-aid tools sees fewer patients opting for OAC. Introduction of the NOACs should theoretically see a shift in patients' preferences toward favoring anticoagulation, with fewer bleeding complications and the absence of mandatory clinic visits for monitoring. These benefits are offset by our inherently limited experience with the new drugs, despite the reassuring nature of currently available safety and efficacy data, and their cost.
Choice of Agent
The emergence of new and effective OACs has changed the landscape of thromboprophylaxis for stroke prevention in AF. The US FDA and the EMA have now approved dabigatran, rivaroxaban and apixaban for the prevention of stroke in non-valvular AF. Rather than the more straightforward choice between superior anticoagulation with warfarin and inferior antiplatelet therapy with aspirin, clinicians will soon be tasked with choosing between a selection of effective therapeutic options, although at present the evidence to support one NOAC over another is limited (Table 7).
It is clear that patients unable and unwilling to take warfarin ought to be considered for treatment with a NOAC (Table 8). There should also be a low threshold for switching patients with erratic INRs to an alternative OAC agent. The benefit of warfarin is dependent on the quality of the INR control, often reflected by the TTR. An increased time in TTR is associated with fewer bleeding complications, as well as fewer strokes and other vascular complications. A low TTR can completely negate the benefit of warfarin, whereas home monitoring can improve the quality of the anticoagulation. Patients with a low TTR seem to derive the greatest benefit from NOACs so it could be argued that a patient well-established on warfarin with good INR control and no issues with monitoring ought not to be transitioned to a new agent. However, dabigatran has been demonstrated to significantly reduce ICH and that this clinical benefit persists regardless of the level of INR control.
It can be problematic to offer comparisons between drugs tested in separate trials with distinct designs and study populations. RE-LY was an open trial with a PROBE (Prospective Randomised Open Blinded Endpoint) design, and this lack of blinding may have influenced event interpretation. One analysis of PROBE versus double-blind trials for stroke prevention in AF has recently been published, which concluded that while there are differences in outcome between PROBE and double-blind trials, they do not appear to be design-related, and that the exacting requirements of double-blinding in AF trials may not be necessary. Rivaroxaban was tested in a higher-risk population in ROCKET-AF than apixaban or dabigatran in the moderate-risk populations of ARISTOTLE or RE-LY, respectively: 32% of patients in RE-LY had a CHADS2 of 0–1, compared with <1% with ROCKET-AF. There were also differences in the quality of INR control in the warfarin arms of the different trials: the TTR was 55% in ROCKET-AF, compared with 62% in ARISTOTLE and 64% in RE-LY. Therefore, truly meaningful comparisons between the NOACs can only be gleaned by head-to-head comparisons in randomized trials. In the absence of comparative trials, cautious inter-trial comparisons are required to help clinicians determine the optimal antithrombotic strategy, alongside consideration of individual patient characteristics, drug tolerability and cost. As such, various network meta-analyses and indirect comparisons have been published. While such comparisons have various limitations, they do suggest that for efficacy end points the NOACs are broadly comparable, but for safety end points, dabigatran 110 mg b.i.d. and apixaban may be associated with less major bleeding.
A recent meta-analysis has suggested that the NOACs are more efficacious than warfarin for the prevention of stroke in AF (RR: 0.78; 95% CI: 0.67–0.92), but this analysis essentially considers that all the NOACs are the same, and the trials are homogeneous. Furthermore, the risks of ICH – the most devastating and feared consequence of anticoagulation – were markedly reduced with the new agents (RR: 0.49; 95% CI: 0.36–0.66). The data for other major bleeding and gastrointestinal bleeding were less conclusive. Another recent analysis modeled data for the net clinical benefit of NOACs balancing ischemic stroke against ICH, using data from the Danish National Patient Registry. In patients at high risk of stroke (CHA2DS2-VASc ≥2), the NOACs were superior to warfarin for net clinical benefit, regardless of the risk of bleeding. When stroke risk and bleeding risk are high, the new drugs had an even greater net clinical benefit.
All NOACs exhibited a significant reduction in ICH when compared with warfarin. Dabigatran 150 mg and apixaban both demonstrated reduced stroke rates compared with warfarin, whereas dabigatran 110 mg and rivaroxaban were non-inferior to warfarin. Only dabigatran was proven to significantly reduce the rates of ischemic stroke, whereas only apixaban demonstrated a statistically significant mortality benefit over warfarin.
In their trials, both dabigatran and rivaroxaban have been found to cause more gastrointestinal bleeding than warfarin; dabigatran also showed an increased rate of dyspepsia (perhaps related to the drug's tartaric acid core), with this being the major contributor to drug discontinuation. It may be prudent, therefore, to utilize apixaban in patients unsuited to warfarin that are known to have gastrointestinal upset.
Recent data from the US FDA has also shown that major bleeding rates are not higher than those associated with warfarin. These data are reinforced by a large propensity-matched 'real-world' nationwide cohort study of post-marketing dabigatran use from Denmark, which showed that stroke and systemic embolism were not significantly different between warfarin- and dabigatran-treated patients. Adjusted mortality was significantly lower with both dabigatran doses (110 mg b.i.d.: propensity-matched group stratified HR (aHR): 0.79; 95% CI: 0.65–0.95; 150 mg b.i.d.: aHR: 0.57; 95% CI: 0.40–0.80), when compared with warfarin. Pulmonary embolism was lower compared with warfarin for both doses of dabigatran. Also, less intracranial bleeding was seen with both dabigatran doses (110 mg b.i.d.: aHR: 0.24; 95% CI: 0.08–0.56; 150 mg b.i.d.: aHR: 0.08; 95% CI: 0.01–0.40). The incidence of myocardial infarction (MI) was lower with both dabigatran doses (110 mg b.i.d.: aHR: 0.30; 95% CI: 0.18–0.49; 150 mg b.i.d.: aHR: 0.40; 95% CI: 0.21–0.70). Gastrointestinal bleeding was lower with dabigatran 110 mg b.i.d. (aHR: 0.60; 95% CI: 0.37–0.93) compared with warfarin, but not dabigatran 150 mg b.i.d.
Rivaroxaban is the only new option that offers once-daily (od) dosing, which can be considered a slight advantage over dabigatran and apixaban. Twice-daily dosing may promote forgetfulness, which is a particularly important consideration for NOACs with short half-lives, where missed doses may place the patient in a prothrombotic state. There is also evidence that rivaroxaban is effective in patients with an acute coronary syndrome (ACS); however, the effect of the AF prophylaxis dose (20 mg od) plus dual antiplatelet therapy in the setting of an ACS has not been specifically examined. Dabigatran has been shown to cause a small numerical but non-significant increase in MI. Clinicians may be tempted to avoid dabigatran in patients with previous MIs, but these results must be taken in the context of the favorable overall net clinical benefit of dabigatran in terms of reduced stroke, cardiovascular events and vascular mortality. In the large Danish 'real-world' study previously described, MIs were significantly lower in dabigatran-treated AF patients, compared with those on warfarin.
Renal function is a further consideration when deciding on an antithrombotic strategy. Dabigatran and rivaroxaban must be used with caution in patients with renal insufficiency. Dabigatran is contraindicated in patients with severe renal impairment, and the lower dose of 110 mg is advised for patients with reduced creatinine clearance (30–49 ml/min). Interestingly, the US FDA approved the dose of 75 mg b.i.d. for patients with impaired renal function, despite the fact that this dose has not been studied in a randomized controlled trial. A reduced dose of rivaroxaban 15 mg od has been recommended for patients with impaired renal function and those with a high bleeding risk (HAS-BLED ≥3). There were fewer fatal bleeds with rivaroxaban (0.28% vs. 0.74% per 100 patient-years; p = 0.047) at this reduced dose. The rates of ICH were similar between rivaroxaban and warfarin (0.71 vs. 0.88 per 100 patient-years; p = 0.54), suggesting that impaired renal function may attenuate rivaroxaban's benefit in terms of reducing ICH.
Patients with severe renal impairment (creatinine clearance <25–30 ml/min) or those on renal replacement therapy were excluded from all three trials. In these patient groups, it would seem prudent to treat with warfarin until robust evidence is available to support the use of NOACs. In terms of assessing their stroke risk, renal impairment does not independently improve the predictive value of stroke risk scores such as CHADS2 or CHA2DS2-VASc. This is perhaps not surprising, given that renal impairment is associated with the risk factors (e.g., age, hypertension, diabetes, heart failure, vascular disease, etc.) that make up the components of those scores.
Clinicians are advised to monitor renal function 12-monthly in cases of mild impairment, 6-monthly in moderate impairment and frequently during clinical conditions that predispose to a decline in renal function (intercurrent infection, hypovolemia, dehydration, commencement of nephrotoxic medication). Serum creatinine and estimates of creatinine clearance must be interpreted with caution in older patients, when muscle mass is likely to have declined.
Generally speaking, well-informed patients tend to be more compliant with medications, and this is again crucial considering the implications of missed doses, especially with the short-acting new drugs. Patients are predominantly concerned with stroke and death, and are generally willing to accept increased bleeding risks to avoid a stroke. The use of decision-aid tools sees fewer patients opting for OAC. Introduction of the NOACs should theoretically see a shift in patients' preferences toward favoring anticoagulation, with fewer bleeding complications and the absence of mandatory clinic visits for monitoring. These benefits are offset by our inherently limited experience with the new drugs, despite the reassuring nature of currently available safety and efficacy data, and their cost.