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Efficacy and safety of novel antithrombotic strategies

Since AHA 2011 five interesting studies have been presented or published on the efficacy and safety of novel antithrombotic strategies.

Venous Thromboembolism


Patients with heart failure have a high risk of stroke1, but antithrombotic therapy in stroke prevention in this condition has not been evaluated on a large scale.

In the WARCEF trial 2,305 patients with heart failure in sinus rhythm an ejection fraction of less than 35% were randomized to warfarin (with an INR of 2.0 to 3.5) or aspirin (325 mg daily) for the prevention of stroke or death, and were followed for a mean of 3.5 years.2 The primary endpoint (ischemic stroke, hemorrhagic stroke or death) occurred in 302 (26.4%) of patients in the warfarin
group and 320 (27.5%) in the aspirin group (HR 0.93; 95% CI 0.79-1.10, p = 0.40, figure 1). Ischemic stroke was seen in 29 (2.5%) warfarin patients and 55 (4.7%) aspirin patients (HR 0.52; 95% CI 0.33-0.82, p = 0.005). However, major bleeding occurred in 66 (5.8%) patients on warfarin and 31 (2.7%) patients on aspirin (HR 2.21; 95% CI 1.42-3.47, p < 0.001), whereas intracranial hemorrhages was not different (7 vs 6) nor was death (268 vs 263 respectively).


Stroke or death in WARCEF
Fig 1. Stroke or death in WARCEF

When compared to aspirin routine oral anticoagulation for heart failure in sinus rhythm reduces ischemic stroke but at the cost of increased but not intracranial bleeding, and thus cannot be advised. The trade-off of aspirin versus no antithrombotic therapy at all remains to be established.


For patients with symptomatic pulmonary embolism a new oral treatment regimen has been developed. In the EINSTEIN-PE trial 4,831 patients with acute symptomatic pulmonary embolism were randomized to oral rivaroxaban alone (15 mg twice daily for 3 weeks, followed by 20 mg
once daily), or to subcutaneous enoxaparin followed by a vitamin K antagonist for 3, 6, or 12 months.3
For the primary efficacy outcome (symptomatic recurrent venous thromboembolism) rivaroxaban was non-inferior to control: 50 events with rivaroxaban (2.1%) and 44 events in the standard-therapy group (1.8%) : HR 1.12, 95% CI 0.75- 1.68, noninferiority margin, 2.0, p  = 0.003, figure 2). Major bleeding was
seen in 26 patients (1.1%) in the rivaroxaban group and 52 patients (2.2%) in the control group (HR 0.49, 95% CI 0.31- 0.79, p = 0.003, figure 3). Intracranial hemorrhage occurred in 1 patient in the rivaroxaban group and in 10 in the control arm (p = 0.005)


Recurrent venous thromboemlism in EINSTEIN-PE

Fig 2. Recurrent venous thromboembolism in EINSTEIN-PE

All cause-mortality in the CABG cohort in TRITON-TIMI 38

Fig 3. Major bleeding in EINSTEIN-PE

Thus, rivaroxaban is a simple oral and effective alternative to enoxaparin/warfarin in the prevention of recurrent thromboembolism in symptomatic patients with pulmonary embolism with an excellent safety profile including intracranial hemorrhage.


From the well-known TRITON trial on prasugrel versus clopidogrel in ACS patients undergoing PCI the CABG data have became available and were published.4

The TRITON-CABG cohort consisted of 346 patients (2.5% of the TRITON population) that underwent isolated CABG during the trial. At least one dose of clopidogrel/prasugrel in the last 7 days prior to surgery was given in over 70% of patients. There were no differences in time to last drug before CABG. Chest tube drainage per patient was increased by prasugrel (655 + 580 ml vs. 503 + 378 ml, p = 0.05), whereas red cell transfusion was similar (2.1% vs. 1.7%, p = 0.44). Re-exploration for bleeding had to be done in 11 prasugrel patients and in 4 on clopidogrel. However, there was a striking difference in all-cause mortality (figure 4)


CV death, MI, stroke and TIMI major bleeding in TRILOGY

Fig 4. All cause-mortality in the CABG cohort in TRITON-TIMI 38

Despite more bleeding and re-exploration prasugrel showed lower early and long-term mortality after CABG for prior ACS. The same observation on early and late mortality benefit with ticagrelor was done in the much larger CABG cohort in PLATO (n = 1,261) without an increase in major bleeding5. This raises the question whether the stronger platelet inhibitors are more protective in coronary surgery after ACS, or that clopidogrel has an inherent harm in CABG. 


In patients with ACS the new platelet P2Y12 receptor blockers ticagrelor and prasugrel are superior over clopidogrel in the prevention of death5 and MI6,7 Prasugrel had only been tested in patients undergoing PCI for ACS and its role in ACS managed medically was unclear so far.
In the TRILOGY study 7,243 patients younger than of 75 years on aspirin for with NSTE-ACS managed medically prasugrel 10 mg qd was given for a maximum of 30 months and compared to clopidogrel 75 mg daily8. Nearly half the patients underwent angiography before randomization that took place 4 days after the index event. Cross-over to an invasive strategy was seen in 8% of patients. At a median follow-up of 15 months the primary endpoint (CV death, MI or stroke) occurred in 13.9% on prasugrel 16.0% with clopidogrel (HR 0.91, 95% CI 0.79-1.05, p = 0.21, figure 5). TIMI major bleeding was similar (1.1% vs 0.8%, HR 1.31, 95% CI 0.85-2.11, p = 0.27, but TIMI major and minor bleeding was increased by prasugrel (1.9% vs 1.3%, HR 1.54, 95% CI 1.06-2.23, p = 0.02). Rates of life-threatening, fatal or intracranial bleeding were similar.
 

CV death, MI, stroke and TIMI major bleeding in TRILOGY


Fig 5. CV death, MI, stroke and TIMI major bleeding in TRILOGY

     Thus, routine prasugrel in NSTE-ACS patients managed medically is not superior to clopidogrel with regard to CV death, MI or stroke, but at the cost of more major and minor bleeding. These results are at odds with those in ACS patients managed medically with ticagrelor9. But in that large PLATO substudy (n= 5,216) ticagrelor was given very early after presentation, the crossover rate to angiography was 40% and the risk was higher (CV death at 1 year with clopidogrel 7.2% versus 4% in TRILOGY). The lack of benefit of a stronger platelet inhibition in this condition was also seen in GUSTO-IV ACS, where abciximab was given in a mainly non-intervened poluation10. Apparently, clopidogrel is still the best antiplatelet treatment in ACS treated medically.

Oral anticoagulation is required in patients with mechanical heart valves and in most patients with atrial fibrillation. When such patients have to undergo PCI with stenting, also aspirin and clopidogrel are indicated. However, this triple therapy is known to increase the risk of serious bleeding. Omitting oral anticoagulants may lead to an increased risk for ischemic stroke and death, whereas clopidogrel is essential in the prevention of stent thrombosis. Therefore omitting aspirin in warfarin patients with coronary artery disease may be an option given the favorable results of two large randomized post-infarct trials11,12, in which full intensity oral anticoagulation alone was superior to aspirin in reducing reinfarction and stroke. Withholding aspirin in stented patients was tested against triple therapy (warfarin, clopidogrel and aspirin) in the WOEST trial presented at ESC 2012.
In this open-label multicenter study 573 patients on oral anticoagulants undergoing stenting were randomized to clopidogrel alone (dual therapy), or to clopidogrel plus low-dose aspirin (triple therapy). At 1 year the primary outcome (TIMI major, minor and minimal bleeding) occurred in 19.5% in the dual therapy group and in 44.9 % in the triple therapy group (HR = 0.36, 95%CI 0.26-0.50, NNT = 4, figure 6). MI (3.3% vs 4.7%), stroke (1.1% vs 2.9%), target vessel revascularization (6.2% vs 5.7%), or stent thrombosis (1.5% vs 3.2%) did not differ significantly between the groups, but all-cause mortality at 1 year was lower in the dual therapy group  than in the triple therapy group (2.5% vs 6.4%, NNT = 26, p = 0.027).
 

Total TIMI bleeding in the WOEST trial 

Fig 6. Total TIMI bleeding in the WOEST trial

  
  Thus, triple therapy after stenting in warfarin-treated patients doubles the bleeding rate when compared to dual therapy where aspirin is left out (NNH = 4). Although the excess bleeding was not unexpected, this the first study to confirm the risk in a randomized quantitative way. Interestingly, thrombotic risk including stent thrombosis was not increased by omitting aspirin, and all-cause mortality was more than halved. As shown previously in the pre-clopidogrel era, these results cast doubt about the efficacy and safety of aspirin in coronary patients otherwise protected with oral anticoagulation as well with an alternative platelet inhibitor.





References


Loh E  St John Sutton M, Wun CC, et al. Ventricular dysfunction and the risk of stroke after myocardial infarction. N Engl J Med 1997;336: 251-257

Homma S, Thompson JLP, Pullicino PM et al. Warfarin and aspirin in patients with heart failure and sinus rhythm. N Engl J Med 2012;366:1859-1869

EINSTEIN-PE investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012;366:1287-1297

Smith PK. Goodnough LT, Levy JH, et al. Mortality benefit with prasugrel  in the TRITON-TIMI 38 coronary artery bypass graft cohort: risk-adjusted retrospective data analysis. J Am Coll Cardiol 2012;60:388-396

Held C, Asenblad N, Bassand JP, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes undergoing coronary artery bypass surgery: results from the PLATO (Platelet Inhibition and Patient Outcomes) trial. J Am Coll Cardiol 2011;57:672-684

Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361:1045-1057

Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007;357:2001-2015

Roe MT, Armstrong PW, Fox KAA, et al. Prasugrel versus clopidogrel for acute coronary syndromes without revascularization. N Engl J Med 2012 in press

James SK, Roe MT, Cannon CP, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes intended for non-invasive management: substudy from prospective randomised PLATelet inhibition and patient Outcomes (PLATO) trial. BMJ 2012;342:d3527

 GUSTO-IV ACS investigators. Effect of glycoprotein IIb/IIIa receptor blocker abciximab on outcome in patients with acute coronary syndromes without early coronary revascularisation: the GUSTO IV-ACS randomised trial. Lancet 2001;357:1915-1924

Van Es RF, Jonker JJC, Verheugt FWA, Deckers JW, Grobbee DE. Aspirin and coumadin after acute coronary syndromes (the ASPECT-2 study): a randomised controlled trial. Lancet 2002:360:109-113

Hurlen M, Abdelnoor M, Smith P, Erikssen J, Arnesen H. Warfarin, aspirin, or both after myocardial infarction. N Engl J Med 2002;347:969-974

 

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.