HORIZONS-AMI Published: Bivalirudin, Taxus Stay Strong at 3 Years

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The final report of the HORIZONS-AMI trial delivers the same consistent message as the 30-day, 1-, and 2-year results: The direct thrombin inhibitor bivalirudin significantly decreases bleeding and mortality in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI) compared with heparin and a glycoprotein IIb/IIIa inhibitor (GPI). In addition, drug-eluting stents (DES) are safe and effective in reducing repeat procedures compared with bare-metal stents (BMS) in the same patients.

Three-year results from the HORIZONS-AMI (Harmonizing Outcomes with RevascularIZatiON and Stents in AMI) trial are published online June 13, 2011, ahead of print in the Lancet. The findings were first presented in September 2010 at the annual Transcatheter Cardiovascular Therapeutics symposium in Washington, DC.

For HORIZONS-AMI, researchers led by Gregg W. Stone, MD, of Columbia University Medical Center (New York, NY), randomized 3,602 STEMI patients at 123 centers in 11 countries who were undergoing primary PCI to receive bivalirudin (n = 1,800) or heparin plus a GPI (n = 1,802). In a second randomization, 3,006 of the patients were assigned in a 3:1 ratio to receive a Taxus paclitaxel-eluting stent (n = 2,257; Boston Scientific, Natick, MA) or an otherwise identical BMS (n = 749).

At 3 years, bivalirudin significantly reduced major bleeding (non-CABG), reinfarction, cardiac death, and all-cause death compared with heparin plus a GPI (table 1).

Table 1. HORIZONS-AMI 3-Year Outcomes: Drug Arm

 

Bivalirudin
(n = 1,800)

Heparin + GPI
(n = 1,802)

P Value

Major Bleeding

6.9%

10.5%

0.0001

Reinfarction

6.2%

8.2%

0.04

Cardiac Mortality

2.9%

5.1%

0.001

All-Cause Mortality

5.9%

7.7%

0.03


The reported reduction in mortality translates to 18 lives saved per every 1,000 patients treated with bivalirudin. While the bleeding reduction with bivalirudin occurred primarily within the first 30 days, the other benefits held by bivalirudin over heparin plus a GPI steadily continued to grow over time.

In the stent analysis, Taxus patients experienced a 40% reduction in ischemic TLR compared with BMS patients. Among the subset of 2,000 patients who did not undergo routine angiographic follow-up, ischemic TLR was still 33% less likely with Taxus (table 2).

Table 2. HORIZONS-AMI 3-Year Outcomes: Stent Arm

 

Taxus

BMS

P Value

TLR

9.4%

15.1%

< 0.0001

TLR: No Routine Angiography

14.8%

10.2%

0.006


Rates of all-cause mortality, cardiac mortality, reinfarction, and stroke were all similar between the 2 groups. Definite or probable stent thrombosis was also equivalent between the stent groups, although the overall rate was unusually high at just under 5%.

“This shows the long-term effects of having made 2 different major decisions at the time of randomization, and those are: which adjunct pharmacology regimen to use in patients with STEMI undergoing primary PCI, and then for patients who require a stent, which stent to use, whether a paclitaxel-eluting stent or a bare-metal stent,” Dr. Stone told TCTMD in a telephone interview.

‘Nothing Trumps Mortality’

He added that the importance and clinical relevance of the findings are clear. “Nothing trumps mortality, and so the fact that deciding up front to use the direct thrombin inhibitor bivalirudin instead of heparin and a IIb/IIIa inhibitor leads to fairly marked early reductions in cardiac and all-cause mortality, which are sustained or even increased late, is a very important finding that should guide practice,” Dr. Stone said. “And the second major finding is that drug-eluting stents, even the first-generation paclitaxel-eluting stent, appear to be safe and effective in reducing restenosis and repeat recurrent ischemia requiring repeat revascularization procedures after primary angioplasty.”

In an editorial accompanying the study, Debabrata Mukherjee, MD, of Texas Tech University Health Sciences Center (Lubbock, TX), agreed that “Stone and colleagues’ landmark study should help define optimum antithrombotic treatment and stent type for primary [PCI].”

Since the results first started coming out in 2008, HORIZONS-AMI has been doing just that. “Clearly the uptake of bivalirudin not only in the United States but around the world is increasing in STEMI because of this trial,” Dr. Stone said. “Also, people are much more comfortable using DES in STEMI in appropriate situations. I think people still aren’t using DES in STEMI in every case. For simple lesions in large vessels, they’re still happy with bare-metal stents, but I think now for more complex cases—diabetics, smaller vessels, longer lesions—people have learned from HORIZONS that you can safely use a DES and not worry about an increased risk of stent thrombosis.”

Stent Thrombosis Rates, Other Issues Remain

Still, the higher than expected stent thrombosis rates are concerning, Dr. Stone noted. “That’s something to be very vigilant about,” he said.

Dr. Mukherjee agrees, noting in his editorial that the rate is several times higher than the 1% seen after elective PCI at 4 years. Therefore, “future studies will need to assess the optimum duration of dual antiplatelet therapy after primary [PCI], the function of newer and more potent P2Y12 inhibitors, the role (if any) of genetic testing that might better define subgroups at risk, and the value of newer-generation thromboresistant designs of drug-eluting stents (including nanotechnology) to further improve outcomes,” he writes.

And there are other unanswered questions, such as why the results continue to improve with bivalirudin when the main bleeding reductions occur within the first 30 days. “It may be due to the late adverse effects of transfusions, or to long-term effects from stopping life-saving medications because of transfusions, or other factors that we just don’t understand,” Dr. Stone said. “The fact that late reinfarction seems to be different as well is also a new observation. This is the first bivalirudin study with more than 1-year follow-up, so this needs to be replicated in additional studies.”

Note: Dr. Stone and several other coauthors are faculty members of the Cardiovascular Research Foundation, which owns and operates TCTMD.

 


Sources:
1. Stone GW, Witzenbichler B, Guagliumi G, et al. Heparin plus a glycoprotein IIb/IIIa inhibitor versus bivalirudin monotherapy and paclitaxel-eluting stents versus bare-metal stents in acute myocardial infarction (HORIZONS-AMI): Final 3-year results from a multicenter, randomised controlled trial. Lancet. 2011;Epub ahead of print.

2. Mukherjee D. Antithrombotics and stent type for primary PCI. Lancet. 2011:Epub ahead of print.

 

 

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Disclosures
  • The study was sponsored by the Cardiovascular Research Foundation under an investigational device exemption from the US Food and Drug Administration, with funding from Boston Scientific and The Medicines Company.
  • Dr. Stone reports having served as a consultant for Abbott Vascular, AstraZeneca, Boston Scientific, Bristol-Myers Squibb/Sanofi, Eli Lilly, Medtronic, Merck, and The Medicines Company.
  • Dr. Mukherjee reports publishing several textbooks of cardiovascular medicine and receiving royalties from the publishers.

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