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The flow of blood is critical for the survival of the individual. While taken for granted, blood is kept in its required liquid form by strong natural anti-coagulant forces. If it were not for these forces, the entire amount of blood in a human body could clot in about ten seconds.

When pro-coagulant forces start getting the upper hand, various undesirable consequences ensue, including blood clots in deep veins, heart chambers, and heart valves. At best, these clots impede blood flow. More insidiously, they dislodge, go through the blood stream, and lodge in the brain or in the lungs, leading to strokes or pulmonary emboli.

Atrial Fibrillation is one of these pro-coagulant conditions. This is an arrhythmia in which the upper chamber of the heart beats up to 500 times a minute, making the heart contraction ineffective and increasing the risk of a clot in the heart due to stasis of blood.

Warfarin has been used for over 40 years to counteract these pro-coagulant effects. It is a well known drug that is cheap, easily available, and with which doctors have the longest experience. However, it has several less than optimum attributes, including therapeutic level monitoring by regular blood testing due to its narrow therapeutic range, impact on this therapeutic range by diet and other medications, and a constant need for dose titration.

Warfarin works by inhibiting vitamin K dependant clotting factors, and so is also slow to take effect. On the plus side, if there is too much inhibition, it can be relatively easily reversed by administration of fresh frozen plasma in the acute setting or Vitamin K when the situation is not so urgent.

In order to circumvent the negative attributes of Warfarin, there has been a great effort by the pharmaceutical companies to develop better alternatives. For example, Sanofi-Aventis (NYSE:SNY)/Bristol-Myers' (NYSE:BMY) Plavix (Clopidogrel), developed initially as a potential alternative to Warfarin (but is a platelet aggregator inhibitor), had sales of $9.4 billion globally in 2010. Other companies include Bayer (Rivaroxiban) 1, BI (Dabigatran) 2, Pfizer (NYSE:PFE)/Bristol Myers' (Apixiban) 3, and Daiichi (Edoxaban). Most of these new inhibitors work by inhibiting factor X, and not the Vitamin K pathway of Warfarin. The advantage of these inhibitors is that there is a fixed dose, with no need for monitoring or drug titration. On the flip side, if the drug is too effective, it is very difficult to reverse its effect, unlike Warfarin.

This article attempts to compare some of these newer compounds by reviewing some their landmark trials, help shed some light on their safety and efficacy, and figure out if we have a potential winner in this race. These drugs were primarily studied in patients with atrial fibrillation as a therapeutic measure to prevent thrombi in the left atrium, and thereby Ischemic Strokes. Their primary approval thus far has been only for this indication. Although a direct head-to head-comparison is difficult, we attempt to highlight the similarities and differences in the tabular comparison below.

Table 1: All New OAC Trials - Basic Characteristics

Study

RELY

ROCKET-AF

ARISTOTLE

ENGAGE AF-TIMI 48

Drug

Dabigatran

Rivaroxiban

Apixiban

Edoxaban

Dose (In mg)

Frequency

150, 110

BID

20 (15*)

QD

5 (2.5*)

BID

60*, 30*

QD

Number in trials

18,113

14,266

18,206

>21,000

Design

PROBE

Double blind

Double blind

Double blind

Atrial Fibrillation criteria

AF x 1

< 6 mths

AF x 2

(>1 in <30d)

AF or Aflutter x 2

<12 mths

AF x 1

< 12 mths

% VKA naive

50%

38%

43%

40% goal

*Dose adjusted in patients with poor renal function.

**Max of 10% with CHADS-2 score = 2 and no stroke/TIA/SEE

PROBE = prospective, randomized, open-label, blinded end point evaluation

VKA = Vitamin K antagonist

As can be seen, the studies had a robust sample size with a large number of patients across the USA and other countries around the world, and were well conducted with appropriate study designs.

To assess efficacy, time spent in therapeutic coagulation range (time in INR between 2-3) was assessed.

Table 2: Time In Therapeutic Range (INR) in comparison arm in Trial

Study

RELY

ROCKET-AF

ARISTOTLE

ENGAGE AF-TIMI 48

Drug

Dabigatran

Rivaroxiban

Apixiban

Edoxaban

Dose

Frequency

150, 110

BID

20 (15*)

QD

5 (2.5*)

BID

60*, 30*

QD

Number in trials

18,113

14,266

18,206

>21,000

Design

PROBE

Double blind

Double blind

Double blind

Atrial Fibrillation criteria

AF x 1

< 6 mths

AF x 2

(>1 in <30d)

AF or Aflutter x 2

<12 mths

AF x 1

< 12 mths

% VKA naive

50%

38%

43%

40% goal

RELY

(Dabigatran)

ROCKET

(Rivaroxiban)

ARISTOTLE

(Apixiban)

Time in Therapeutic Range (TTR)

64%

67% Warfarin-experienced

61% Warfarin-naïve

Mean 55%

Median 58%

Mean 62%

Median 66%

Dabigatran and Apixiban did a better job when compared to Rivaroxiban in maintaining the INR within a therapeutic range

The main outcome to assess efficacy was the incidence of strokes or systemic embolism as listed below.

Table 3: Primary Endpoint of Stroke or Systemic Embolism: Non-inferiority Analysis

RELY

ITT Analysis

Dabigatran 110mg

1.53% per year

HR = 0.91

P<0.001

Dabigatran 150mg

1.11% per year

HR = 0.66

P<0.001

Warfarin

1.69% per year

ROCKET AF

Modified ITT

Rivaroxiban 20mg

1.7% per year

HR = 0.79

P<0.001

Warfarin

2.2% per year

ARISTOTLE

ITT Analysis

Apixiban 5mg

1.27% per year

HR = 0.79

P<0.001

Warfarin

1.60% per year

Apixiban 5 mg and Dabigatran 150 mg had the fewest strokes in patients with Atrial Fibrillation.

It is important to dissect out the kind of stroke - Ischemic stroke indicates lack of efficacy since the drug allowed a clot to form in the heart that then traveled to the brain, causing a stroke. In contrast, hemorrhagic strokes indicate over-thinning of the blood, leading to the side effect of bleeding in the brain. Apixiban and Dabigatran 150 mg were the most effective in reducing the incidence of Ischemic stroke.

Table 4: Ischemic Stroke

RE-LY

HR

ITT p-value

Dabigatran 110mg

1.34% / yr

1.20

0.35

Dabigatran 150mg

0.92% / yr

0.76

0.03

Warfarin

1.20% / yr

ROCKET AF

Rivaroxiban 20mg

1.62% / yr

0.99

0.92*

Warfarin

1.64% / yr

ARISTOTLE

Apixiban 5mg

0.97% / yr

0.92

0.42

Warfarin

1.05% / yr

Table 5: Hemorrhagic Stroke

RELY

HR

ITT p-value

Dabigatran 110mg

0.12% / yr

0.31

<0.001

Dabigatran 150mg

0.10% / yr

0.26

<0.001

Warfarin

0.38% / yr

ROCKET AF

Rivaroxiban 20mg

0.26% / yr

0.59

0.012*

Warfarin

0.44% / yr

ARISTOTLE

Apixiban 5mg

0.24% / yr

0.51

<0.001

Warfarin

0.47% / yr

It is interesting that though these drugs were more efficacious than Warfarin, they had fewer hemorrhagic strokes. If one was to equalize for Warfarin variability, the drugs were almost equal, especially Dabigatran and Apixiban.

Another way of looking at the side effects profile is major bleeding from/into sites other than the brain.

Table 6: Major Bleeding

RELY

HR

ITT p-value

Dabigatran 110mg

2.71% / yr

0.8

0.003

Dabigatran 150mg

3.11% / yr

0.93

0.31

Warfarin

3.36% / yr

ROCKET AF

Rivaroxiban 20mg

3.60% / yr

0.92

0.58

Warfarin

3.45% / yr

ARISTOTLE

Apixiban 5mg

2.13% / yr

0.69

<0.001

Warfarin

3.09% / yr

Apixiban had the fewest incidence of major bleeding, with Dabigatran 150 mg not statistically better than Warfarin.

Finally, comparing overall mortality in patients in these studies combines safety and efficacy.

Table 7: All Cause Mortality

RE-LY

HR

ITT p-value

Dabigatran 110mg

3.75% / yr

0.91

0.35

Dabigatran 150mg

3.64% / yr

0.88

0.051

Warfarin

4.13% / yr

ROCKET AF

Rivaroxiban 20mg

4.52% / yr

0.92

0.152

Warfarin

4.91% / yr

ARISTOTLE

Apixiban 5mg

3.52% / yr

0.89

0.01

Warfarin

3.94% / yr

As can be seen, Apixiban had the best mortality outcome, was at least as efficacious as Warfarin in reducing ischemic events and decreased the risk of major bleeding events the most when compared to the other agents.

Thus, it looks like we may have a potential winner - Apixiban. Probably Pfizer/ BMS' next blockbuster.

(This article was written with Parikshit Sharma, MD MPH, Cardiology Fellow at Wright Center in Scranton, Pennsylvania)

Reference:

  1. Patel MR, et al. N Engl J Med 2011; 365:883-891
  2. Connolly SJ, et al. N Engl J Med. 2009; 361:1139-1151
  3. Granger C, et al. N Engl J Med 2011; 365:981-992
Source: The Battle For The Anti-Coagulation Market