4.3 Interventional Pharmacology: Data-Driven Best Practices

These proceedings summarize the educational activity of the 16th Biennial Meeting of the International Andreas Gruentzig Society held January 31-February 3, 2022 in Punta Cana, Dominican Republic

Faculty Disclosures     Vendor Acknowledgments

2022 IAGS Summary Document

Statement of the problem or issue

From the first percutaneous coronary intervention (PCI) done by Andreas Gruentzig in the 1970s, antithrombotic therapy has been used, usually a combination of antiplatelet and anticoagulation therapy. Aspirin (ASA) and heparin were used during the early years of balloon angioplasty, typically in higher doses than currently in use now: ASA 325-500 mg and heparin 10,000 IU. Beginning in the 1980s, it became possible to monitor levels of anticoagulation with ACT during PCI in the cath lab and then afterward at the bedside. The level of ACT attained was adopted from cardiopulmonary bypass surgery, where “adequate ACTs” had been judged to be 300-500 seconds. Subsequent work noted higher bleeding rates with ACT >350 seconds, and heparin doses were adjusted to achieve lower ACTs closer to 250 seconds. Heparin typically was given in repeated bolus doses to arrive at this ACT level during a PCI procedure (about every 30 minutes) due to the short half-life and variable therapeutic response. More recently, intravenous bivalirudin, a direct thrombin inhibitor, has used the same level of ACT to define an “adequate level” of anticoagulation. Bivalirudin is given in a continuous infusion after an initial bolus dose. This approach does not require repeated ACT measurements during the PCI procedure. There have been very few RCTs comparing heparin and bivalirudin, so the majority of catheterization laboratories use what is customary to them, as either anticoagulant appears to be safe and effective.

A major breakthrough in antiplatelet therapy came in the 1990s when agents became available that could block the final common pathway of platelet activation, the glycoprotein (GP) IIb/IIIa receptor. The first such agent was abciximab, an antibody to the glycoprotein receptor, which clinically reduced adverse ischemic outcomes in PCI, but also produced higher bleeding rates. Eptifibatide and tirofiban, both of which are reversible GP IIb/IIIa inhibitors, were later introduced. In aggregate, all of these agents reduced thrombotic and ischemic events after PCI in both stable and ACS patients (including STEMI), as proven in RCTs. Observational studies during this period found that heparin dosing could be reduced to achieve ACTs just above 200 seconds, and this was associated with less bleeding but still retained the anti-ischemic benefits.

With the introduction of bare-metal stents in the late 1990s, it became clear that although GP IIb/IIIa receptor inhibitors were very effective in reducing acute stent thrombosis, patients remained vulnerable to later stent thrombosis, particularly with drug-eluting stents. Observational studies suggested that oral clopidogrel (an irreversible inhibitor of the platelet ADP surface receptor) had important antiplatelet effects that continued over the long term, especially when combined with ASA. Subsequent RCTs found oral clopidogrel loading doses of 600 mg were required prior to the PCI procedure (with ASA and heparin administered as usual). Large RCTs with other ADP receptor inhibitors, oral prasugrel (irreversible) and oral ticagrelor (reversible), provided both short-term and long-term anti-ischemic effects that were superior to clopidogrel. However, minor increases in bleeding were noted with both of these agents. The majority of PCI procedures (elective, urgent, and emergency) are now performed with one of these oral agents along with ASA and heparin. There have been no adequately powered comparative studies with the more potent agents (prasugrel and ticagrelor) that differentiate a clear superiority between these agents.

The oral ADP antagonists take on average about 60-120 minutes to achieve therapeutic blood levels, which is reasonable for most patients, even many acute coronary syndrome (ACS) patients. However, this time delay is inadequate for STEMI patients undergoing primary PCI, or in other cases when patents are given oral loading doses on the catherization table for an ad hoc PCI procedure, where immediate ADP antagonism is required. However, as an alternative, the intravenous ADP antagonist cangrelor (given as a bolus and infusion for up to 4 hours) has been found to be effective in reducing ischemic events, including stent thrombosis, in the first 48 hours after PCI when compared with oral clopidogrel, ASA and either heparin or bivalirudin. There is limited experience combining cangrelor with intravenous GP IIb/IIIa inhibitors.

Gaps in knowledge

The optimal combination of anti-platelet and anticoagulant agents is largely unknown due to the historical development of these therapies in PCI. There are 18 possible permutations of existing agents. Only about half of these combinations have been tested in RCTs during PCI. Additionally, the majority of these trials have been conducted in ACS patients undergoing PCI, and very few have included large populations of PCI patients with either stable ischemic heart disease or STEMI. The majority of PCI operators and cardiac catherization laboratories use therapies that they have worked with for a while and are comfortable with, suggesting there is no real consensus on what to use outside of ASA. There have been insufficient direct head-to-head RCTs of newer agents, and most studies explore an experimental therapy added on top of standard existing therapies, rather than exploring a complete replacement of existing therapies.

In the early phase of diagnostic angiography in the 1970s, intravenous heparin was routinely used for angiography when it was given during brachial cut-down procedures to prevent brachial artery thrombosis. This habit was carried over to when angiography was performed using the femoral access. This approach was largely dropped in the early 1990s. Administering intravenous heparin during diagnostic angiography has seen a resurgence with the use of radial access in the early 2000s as radial artery thrombosis was observed. As ad hoc PCI is now increasingly performed after radial cardiac catherization the majority of patients receive 5000 units of intravenous heparin even before the PCI is contemplated. This has led to a resurgence of heparin for all types of PCI irrespective of the indication. Little is known about alternative anticoagulation approaches for radial PCI.

The majority of PCI antithrombotic trials were carried out in ACS populations, and very few trials have addressed optimal antithrombotic therapy for non-ACS patients undergoing elective PCI. Fortunately, ischemic events are very rare, as are bleeding events in stable, elective PCI patients. The one exception would be patients undergoing high-risk PCI procedures (low ejection fraction, multivessel PCI, or atherectomy) where adverse events such as thrombosis and periprocedural MI remain high. No RCTs have addressed the most appropriate antithrombotic therapy in this population. The majority of PCI procedures for chronic total occlusion (CTO) use heparin as anticoagulation due to the ability to reverse the anticoagulation if coronary perforation is observed. Similarly, short-acting intravenous ADP antagonists are preferred since the biological effect is very brief (15 minutes) after the infusion is turned off. This approach has not been subjected to a RCT.

Possible solutions and future directions

As is evident from the above discussion, the majority of changes in antithrombotic therapies have come from careful clinical observations, similar to the evolution of antithrombotic therapies in bypass surgery. RCTs have explored use of the newer agents, but these trials have seldom included head-to-head comparisons. New antithrombotic therapies may be developed in the future and the challenge will be how these should be tested as there is no clear standard of care for antithrombotic therapy in PCI. ASA is a given, but beyond that there are many possibilities that are unlikely to be included in any future RCTs of new agents.

One solution, which has largely been adopted already, is to use more potent antiplatelet therapies for the more complex and high-risk PCI patients. This appears logical, but no observational study has addressed this approach. To move the field of antithrombotic therapy in PCI forward, we should ideally collect careful clinical and angiographic data on the majority of patients that undergo PCI procedures. Some national registries in Sweden, the United Kingdom, and the USA are poised to do so, but these may lack the fidelity to collect the important angiographic data needed to best risk-stratify these patients.