Dr. Michael McDaniel can be contacted at firstname.lastname@example.org.
Can you tell us about the creation of the acute coronary syndromes algorithm at Emory University?
The Emory ACS algorithm1 is the result of an ongoing effort that began a few years ago, and is, at its heart, an attempt to maximize quality and value in the services we provide to our patients. Value was one of the most important things emphasized by
our leadership in the algorithm development and something that, quite frankly, I had not heard a lot about before this initiative. The guidelines from the American College of Cardiology/American Heart Association (ACC/AHA) do emphasize the efficacy and safety of various therapies, but the guidelines traditionally have not added ‘value’ as one of the key metrics when considering therapies, whether a medicine, a procedure, or a diagnostic test. Emory’s real goal with standardization and ACS algorithms was to try to maximize quality and maximize value. It was a new emphasis, at least to me. To begin, we created a multidisciplinary group, pulling members from the emergency department, laboratory medicine, the CCU, general cardiology, imaging cardiology, interventional cardiology, and rehab medicine, and tried to come up with a comprehensive algorithm that would consider all patients presenting with definite or possible acute coronary syndromes. We sought to standardize care, starting in the emergency department, all the way through to the cath lab, and then on to discharge. Our cardiology leadership challenged us to define the one best therapy that maximizes value for each scenario. Value encompasses the safety and efficacy of the therapy, but also the cost of the therapy. Our multidisciplinary group met on multiple occasions, went through the ACC/AHA guidelines, and reviewed the individual studies in detail. All our recommendations were brought to the entire group, and upon agreement, we then presented the standardized algorithms to our medical practice committees and our transitions of care committee. The final piece was education: educating faculty, residents, fellows, and the rest of the house staff.
Another major effort behind standardization is implementation. With our IT support, we worked on developing standardized order sets for each point on the pathway, whether it was the CCU, ED, or cath lab. One important aspect of these order sets is the elimination of choices. The order sets use pre-checked boxes to reflect the standard pathways, and eliminate those aspects that are not part of the algorithm. Clinicians can choose other things, but they have to actively go against an order set in order to do so. They have to either uncheck boxes or actively order things outside of the order sets to come up with different therapies.
Our multidisciplinary group continues to meet on a regular basis in order to keep the algorithm updated. When we do decide to update anything, we will dispense it to the group either through email communications or at our conferences.
How does tirofiban fit into the ACS algorithm?
Two years ago, as we worked to create the algorithm, we had two glycoprotein IIb/IIIa inhibitors (GPIs) on formulary: abciximab (ReoPro) and eptifibatide (Integrilin). We didn’t actually have tirofiban (Aggrastat) on the formulary. One of our first goals was to consider the three different GPIs, determine the differences between these agents, and then decide when to use a GPI in ACS.
As we reviewed the data for tirofiban compared to the other GPIs, we noticed that the efficacy data for tirofiban was actually quite strong with the high-dose bolus regimen. The platelet function data for tirofiban compared to abciximab or eptifibatide essentially showed at least similar if not better platelet inhibition whether the timing was at 10 minutes or 8 hours. In addition, the randomized data also demonstrated similar efficacy. Probably the largest trial was MULTISTRATEGY, which enrolled 745 patients with ST-elevation myocardial infarction (STEMI) receiving fairly contemporary treatment, in that these patients were treated with aspirin and clopidogrel up front, and then randomized to either high-dose tirofiban or abciximab.2 The trial showed equal efficacy with either of the two GPIs, abciximab or high-dose tirofiban, very similar safety in terms of bleeding, and similar overall mortality. In addition, the meta-analysis of the randomized data echoed these findings in ST-elevation MI.3 The meta-analysis showed a similar efficacy between high-dose bolus tirofiban and abciximab, whether it was through surrogate markers such as TIMI-3 flow or ST-segment resolution, or some of the harder outcomes such as reinfarction or death. Lastly, the real-world registry data show similar findings. The totality of evidence suggested that GPIs offer similar efficacy and similar safety. However, when we talked to our pharmacy, there was a big difference in cost. We found a significant cost savings with the use of tirofiban as compared to abciximab or eptifibatide. As value is defined as quality outcome divided by cost, when you are able to achieve a similar quality outcome at a lower cost, then that choice is, by definition, a more valuable therapy.
The second and more difficult decision was determining when GPIs are needed. While this continues to evolve, we felt GPIs are most needed in patients with large thrombus burdens and ST-elevation MI, and in particular, with radial access use. Our adoption of radial percutaneous coronary intervention (PCI) has increased significantly over the last three years and is our preferred approach for STEMI. Based on the increased use of radial access, we moved from the use of bivalirudin back to the use of GPIs. Benefits of bivalirudin compared to GPIs seem to be predominantly driven by patients who undergo PCI from the femoral approach. In HORIZONS4, ACUITY5, and EUROMAX6, the bleeding reduction benefits of bivalirudin were driven primarily by patients who got femoral access and are at least attenuated by the radial approach. Thus, we have moved back to more aggressive GPI use with the radial PCI in STEMI.
What do the ACC/AHA guidelines say about glycoprotein IIb/IIIa inhibitors?
The ACC/AHA guidelines do a wonderful job of summarizing the data and providing clinicians with practice guidelines and recommendations. Where the guidelines fall short, traditionally, has been that cost is not used as part of the equation. Value has not traditionally been part of the ACC/AHA guidelines. All three glycoprotein IIb/IIIa inhibitors thus have similar recommendations in the 2011 ACC/AHA PCI guidelines. However, while the efficacy and safety may be similar, for most institutions, the costs are not. Recently the ACC/AHA published a statement that cost-value methodology will be added to the practice guidelines and performance measures.7 In the future, the concept of value will move into the guidelines, which will be even more important as our health care system changes from one emphasizing volume to one focused on quality and value.
Can you share some of the history of tirofiban up to the high-dose bolus approval by the FDA?
The initial dosing of tirofiban studied was a lower than the current dose recommended in PCI guidelines and FDA labeling. The trial that led to its decreased use in the United States was the TARGET study.8 Compared to abciximab, in TARGET, the lower-dose tirofiban fell short in terms of its overall efficacy, although most of this was driven by periprocedural MI data. Subsequent studies looked at the platelet inhibition data, and found less platelet inhibition with the low-dose bolus of tirofiban compared to the other glycoprotein IIb/IIIa inhibitors.9 Later, a higher tirofiban dosing strategy was studied and demonstrated at least similar, if not superior efficacy in terms of platelet inhibition compared to both eptifibatide and abciximab.10 The efficacy data on hard outcomes such as mortality, target vessel revascularization, and bleeding outcomes with the high-dose tirofiban dosing, suggest that all these GPIs are essentially equally efficacious and safe as discussed previously. Most of the head-to-head comparisons have been against abciximab in STEMI and the randomized data, meta-analyses, and real-world registry data all demonstrate similar outcomes except for perhaps lower thrombocytopenia with tirofiban compared to abciximab.
Has it been a smooth transition to the tirofiban high-dose bolus regimen?
In my personal opinion, the transition was very smooth. There are a few clinicians who feel strongly about using intracoronary bolus. The intracoronary bolus I think is an interesting story in and of itself. Initial, smaller studies suggested efficacy, but the more recent large, randomized data suggests there is not a real benefit to an intracoronary bolus compared to an intravenous (IV) bolus.11 My view is that similar efficacy can be achieved with IV use as compared to an intracoronary bolus of a GPI. With that said, you will still find people who feel strongly about intracoronary bolus use. The high-dose bolus of tirofiban is a larger volume amount than other GPIs. It takes a large syringe to administer the bolus intracoronary, which may be surprising the first time a physician uses it intracoronary. Overall, this is has not been an issue and is balanced by the fact that tirofiban does not need to be buffered with blood like eptifibatide when administered intracoronary.
You talked a bit about how bivalirudin might not provide the same value if you go radial. Could you also address the recent HEAT-PPCI trial that looked at bivalirudin vs heparin?
Bivalirudin is a very interesting story. The most recent trials, including HEAT-PPCI12, NAPLES III13, as well as the BRAVE 4 study14, suggest that compared to heparin monotherapy, there may not be that much benefit to bivalirudin monotherapy. HEAT-PPCI is a single-center, large, randomized trial where 1812 patients undergoing primary PCI for STEMI were randomized to either heparin or bivalirudin with provisional GPI. GPI use in the overall trial was lower than what we see in many other trials, with approximately 15% use in both arms. The trial failed to show bleeding safety with bivalirudin and actually found an efficacy benefit to unfractionated heparin, showing less stent thrombosis and recurrent myocardial infarction. Similar reductions in stent thrombosis with heparin and GPI compared to bivalirudin were also seen in other studies, such as HORIZON and EUROMAX. Together, these three trials suggest that bivalirudin monotherapy may not offer adequate early antiplatelet inhibition, particularly in STEMI. However, the more interesting trial is the NAPLES III trial, which was presented at the 2014 ACC meeting, but is not yet published. NAPLES III randomized about 830 patients to bivalirudin or heparin (70 U/Kg) in elective PCI in patients with high bleeding risk: advanced age, female, anemia, or renal insufficiency. In this higher bleeding risk population, there was no benefit in terms of reduction of bleeding with bivalirudin monotherapy compared to unfractionated heparin monotherapy. In addition, there was no difference in efficacy between these agents. I think that’s important, because in the group that would most likely benefit from bivalirudin, those patients with higher bleeding risk based on bleeding risk scores, there was no efficacy or safety benefit to bivalirudin. In all fairness to bivalirudin, there are a lot of registry data, observational trials, and meta-analyses that suggest the opposite to NAPLES III and HEAT-PPCI, in that these data show a reduction in bleeding with bivalirudin.
At present, we are in the process of looking at our bivalirudin use, and will wait until all the data is published and judge bivalirudin based on its value.
Have you been able to quantify any cost savings with tirofiban use?
I have not been able to get exact numbers, but we have seen a significant reduction in total costs in our multi-hospital system. Between our hospitals we see a lot of patients with acute coronary syndromes. Our ACS algorithms have largely omitted upstream use of GPIs, as most patients are preloaded with aspirin and clopidogrel. This reduction is upstream use did reduce our total GPI costs, although this has been somewhat balanced by any increase in GPI use in STEMI, especially with more radial access usage. However, the larger benefit in terms of cost came from the switch from other GPIs to tirofiban. We found that we could maintain our efficacy and safety at a lower cost, which by definition provides better value to our patients.
- McDaniel M, Ross M, Rab ST, Keadey M, Liberman H, Fantz C, et al. A comprehensive acute coronary syndrome algorithm for centers with percutaneous coronary intervention capability. Crit Pathw Cardiol. 2013 Sep; 12(3): 141-149.
- Valgimigli M, Campo G, Percoco G, Bolognese L, Vassanelli C, Colangelo S, et al; Multicentre Evaluation of Single High-Dose Bolus Tirofiban vs Abciximab With Sirolimus-Eluting Stent or Bare Metal Stent in Acute Myocardial Infarction Study (MULTISTRATEGY) Investigators. Comparison of angioplasty with infusion of tirofiban or abciximab and with implantation of sirolimus-eluting or uncoated stents for acute myocardial infarction: the MULTISTRATEGY randomized trial. JAMA. 2008 Apr 16;299(15):1788-99.
- De Luca G, Ucci G, Cassetti E, Marino P. Benefits from small molecule administration as compared with abciximab among patients with ST-segment elevation myocardial infarction treated with primary angioplasty: a meta-analysis. J Am Coll Cardiol. 2009 May 5; 53(18): 1668-1673. doi: 10.1016/j.jacc.2009.01.053.
- Stone GW, Witzenbichler B, Guagliumi G, Peruga JZ, Brodie BR, Dudek D, et al; HORIZONS-AMI Trial Investigators. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med. 2008 May 22; 358(21): 2218-2230.
- Rosner GF, Kirtane AJ, Genereux P, Lansky AJ, Cristea E, Gersh BJ, et al. Impact of the presence and extent of incomplete angiographic revascularization after percutaneous coronary intervention in acute coronary syndromes: the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial. Circulation. 2012 May 29; 125(21): 2613-2620.
- Steg PG, van ‘t Hof A, Hamm CW, Clemmensen P, Lapostolle F, Coste P, et al; EUROMAX Investigators. Bivalirudin started during emergency transport for primary PCI. N Engl J Med. 2013 Dec 5; 369(23): 2207-2217.
- Anderson JL, Heidenreich PA, Barnett PG, Creager MA, Fonarow GC, Gibbons RJ, Halperin JL, Hlatky MA, Jacobs AK, Mark DB, Masoudi FA, Peterson ED, Shaw LJ; ACC/AHA Task Force on Performance Measures; ACC/AHA Task Force on Practice Guidelines. ACC/AHA statement on cost/value methodology in clinical practice guidelines and performance measures: a report of the American College of Cardiology/American Heart Association Task Force on Performance Measures and Task Force on Practice Guidelines. Circulation. 2014 Jun 3; 129(22): 2329-2345.
- Topol EJ, Moliterno DJ, Herrmann HC, et al. Comparison of two platelet glycoprotein IIb/IIIa inhibitors, tirofiban and abciximab, for the prevention of ischemic events with percutaneous coronary revascularization. N Engl J Med. 2001; 344: 1888-1894.
- Kabbani SS, Aggarwal A, Terrien EF, DiBattiste PM, Sobel BE, Schneider DJ. Suboptimal early inhibition of platelets by treatment with tirofiban and implications for coronary interventions. Am J Cardiol. 2002 Mar 1; 89(5): 647-650.
- Danzi GB, Capuano C, Sesana M, Mauri L, Sozzi FB. Variability in extent of platelet function inhibition after administration of optimal dose of glycoprotein IIb/IIIa receptor blockers in patients undergoing a high-risk percutaneous coronary intervention. Am J Cardiol. 2006 Feb 15; 97(4): 489-493.
- Desch S, Wöhrle J, Hambrecht R, Rittger H, Birkemeyer R, Lauer B, et al. Intracoronary versus intravenous abciximab bolus in patients with ST-segment elevation myocardial infarction: 1-year results of the randomized AIDA STEMI trial. J Am Coll Cardiol. 2013 Sep 24; 62(13): 1214-1215.
- Shahzad A, Kemp I, Mars C, Wilson K, Roome C, Cooper R, et al; for the HEAT-PPCI trial investigators. Unfractionated heparin versus bivalirudin in primary percutaneous coronary intervention (HEAT-PPCI): an open-label, single centre, randomised controlled trial. Lancet. 2014 Jul 4. pii: S0140-6736(14)60924-7.
- Kumbhani DJ. Trial Summary NAPLES III. Available online at http://www.cardiosource.org/Science-And-Quality/Clinical-Trials/N/NAPLES-III.aspx. Accessed August 5, 2014.
- Schulz S, Richardt G, Laugwitz KL, Morath T, Neudecker J, Hoppmann P, et al; and for the Bavarian Reperfusion Alternatives Evaluation (BRAVE) 4 Investigators. Prasugrel plus bivalirudin vs. clopidogrel plus heparin in patients with ST-segment elevation myocardial infarction. Eur Heart J. 2014 May 9. [Epub ahead of print].