- Chapter 1: Evolution of Periprocedural Pharmacotherapy in Patients Undergoing Percutaneous Coronary Intervention
- Chapter 2: Oral Antiplatelet Therapy for Percutaneous Coronary Interventions
- Chapter 3: Parenteral Antiplatelet Agents
- Chapter 4: Antithrombotics
- Chapter 5: Fibrinolytic Therapy for STEMI
- Chapter 6: Coronary Vasoactive Agents
- Chapter 7: Vasoactive Agents in Cardiology
- Chapter 8: Sedation and Anesthesia in the Cardiac Catheterization Laboratory
- Chapter 9: Clinical Cases
Evolution of Periprocedural Pharmacotherapy in Patients Undergoing Percutaneous Coronary InterventionCHAPTER 1
“What's past is prologue…”
William Shakespeare: The Tempest, Act 2, Scene I
INTRODUCTION
The field of percutaneous coronary intervention (PCI) has made tremendous strides over the past few decades. Over this time frame, there has been a constant and relentless evolution in the procedural equipment (wires, balloons, and stents) as well as the periprocedural pharmacotherapeutic armamentarium. A discussion of this evolution is germane not just for historical and academic purposes, but also because this dictates current practice patterns in this field in many ways.
PROCEDURAL EVOLUTION
The credit for the first selective angiogram goes to Dr Mason Sones from Cleveland Clinic, who accidentally injected 30 cc of contrast agent into a patient's right coronary artery.1 The first coronary balloon angioplasty in humans was performed by Dr Andreas Gruentzig in 1977 in Zurich, Switzerland, when he passed a prototype, fixed-wire balloon catheter across a severe lesion in the left anterior descending artery.2 Refinements in balloon angioplasty systems and coronary guidewires culminated in the Angioplasty Compared to MEdicine (ACME) trial, the first randomized study comparing percutaneous transluminal coronary angioplasty (PTCA) with conventional medical therapy. Although procedural success rates were low (78.1%), patients undergoing balloon PTCA had better exercise tolerance and freedom from angina at 6 months.3
Metallic intracoronary stents were first implemented in the late 1980s for the emergency treatment of coronary dissection after angioplasty, but in the initial years were 4plagued by high rates of subacute closure (3–5%).1 Second-generation balloon-expandable stents were introduced toward the late 1990s, with varying amounts of cobalt, chromium, tantalum, or other metals, in addition to stainless steel, along with enhancements in strut design and delivery and deployment systems. The most popular intracoronary stent was the Palmaz–Schatz stainless steel stent, which was compared with balloon PTCA in the landmark BElgian NEtherlands STENT (BENESTENT) and Stent Restenosis Study (STRESS) trials.4,5 Both trials showed a marked reduction in restenosis and the need for a second revascularization procedure in the stent group. Intracoronary stents [also known as bare-metal stents (BMS)] soon became the predominant method of PCI, being used in > 90% of cases.
Although procedural success rates improved dramatically with stenting, restenosis remained a common problem. This was believed to be predominantly due to neointimal hyperplasia and matrix accumulation, and resulted in the development of drug-eluting stents (DES) with antiproliferative agents to reduce/mitigate restenosis. First-generation DES, sirolimus-eluting and paclitaxel-eluting (SES/PES) stents, significantly reduced target vessel revascularization and restenosis compared with BMS in pivotal trials,6–8 and were approved by the United States Food and Drug Administration (USFDA) in 2003 and 2004, respectively. By 2005, the use of DES skyrocketed, and accounted for 75–85% of all intracoronary stents placed in the United States.9 Concerns over very late (> 1 year) stent thrombosis with first-generation DES resulted in a label change by the USFDA in 200610,11; dual antiplatelet therapy (DAPT) was now recommended for a minimum of 12 months following DES implantation. This recommendation still stands today for all DES in the United States, including for second-generation DES such as everolimus-eluting and zotarolimus-eluting stents. These appear to have a lower risk of stent thrombosis,12 and have largely supplanted first-generation DES in clinical practice. Biodegradable or bioabsorbable stents are also sometimes referred to as third-generation DES, but are currently not available for clinical use in the United States.
PHARMACOLOGICAL STRATEGIES DURING PCI
Ischemia management is a key component of a PCI procedure. Our understanding of the coagulation cascade continues to improve, but there is a complex interplay between coagulative proteins, platelets, and cellular phospholipid membranes. Antiplatelet and antithrombotic agents remain the cornerstones for successful PCI, and have been used in various combinations from the outset.13,14
Balloon PTCA Era
The main agents used at that time were aspirin and unfractionated heparin (UFH).
Aspirin
Aspirin, or acetylsalicylic acid, was synthetically formulated in the late 19th century, and primarily used for its antipyretic and anti-inflammatory properties. It was also the first widely used antiplatelet agent for the secondary prevention of myocardial infarction (MI) and stroke, based on its observed efficacy in sentinel trials conducted in the 1970s–1980s such as Second International Study of Infarct Survival (ISIS-2).15 In the early days of coronary intervention, especially during the era of balloon PTCA, restenosis was a common problem. This was believed to be a platelet-initiated event (due to accumulation of platelets on the de-endothelialized intima), and aspirin was routinely used in the periprocedural management of these patients. Aspirin remains one of the cornerstones of peri- and postprocedural therapy even today. Recently, the Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent EveNTs/Optimal Antiplatelet Strategy for InterventionS-7 (CURRENT OASIS-7) trial suggested no benefit with high-dose aspirin (300–325 mg) over low-dose aspirin (75–100 mg).16
Unfractionated Heparin
It has been employed for anticoagulation from the early days of balloon angioplasty. The effect is dose-dependent, and active clotted time (ACT) monitoring in the cardiac catheterization laboratory during PCI is necessary because the required level of anticoagulation is beyond the range that can be measured using the activated partial thromboplastin time. In patients undergoing balloon PTCA, higher ACTs appeared to reduce the risk of abrupt closure and death or urgent revascularization.17
The dosing of UFH has undergone significant evolution during the history of PCI.18 Initial regimens involved high doses of UFH. For example, in the Bivalirudin Angioplasty trial comparing bivalirudin and UFH, the dose of UFH given was a 175 U/kg bolus followed by an infusion of 15 U/kg/h. Furthermore, if the ACT, a measure of antithrombin activity, was < 350 seconds, an additional 560 U/kg bolus was administered.19 In the BENESTENT trial, patients undergoing balloon PTCA alone received 10,000 U at the outset, followed by additional boluses as needed to keep the ACT > 350 seconds.4 Both weight-based and high-dose fixed regimens were also explored, with the weight-based regimens associated with shorter sheath dwell times.20 Bleeding and vascular complications were relatively high given the high ACT levels, but were considered a “necessary evil” given that ischemic complications were lowest when ACT was at least 300–350 seconds (Figs. 1.1A and B).21,22 With the advent of glycoprotein IIb/IIIa inhibitor (GPI) agents (see below), ACT levels around 250 appeared to provide the “sweet spot” between ischemia protection and bleeding risk (Figs. 1.2A and B).
Figs. 1.1A and B: Patients treated with unfractionated heparin alone.22 (A) Relationship between minimum active clotted time (ACT) and death, myocardial infarction (MI), or urgent revascularization at 7 days. (B) Relationship between maximum ACT and major or minor bleeding events at 7 days.
Figs. 1.2A and B: Patients treated with unfractionated heparin and abciximab.22 (A) Relationship between minimum active clotted time (ACT) and death, myocardial infarction, or urgent revascularization at 7 days. (B) Relationship between maximum ACT and major or minor bleeding events at 7 days.
Bare-Metal Stents Era
This phase/era oversaw the largest incremental changes in peri- and postprocedural pharmacotherapy.
Dipyridamole was introduced towards the latter part of the balloon PTCA era, and became a mainstay during the early BMS era. Warfarin was routinely administered in 6addition to antiplatelet therapy, with a goal international normal ratio (INR) of 2.0–3.5, in addition to DAPT. Warfarin and dipyridamole were typically discontinued 1 month after angioplasty.
Dipyridamole
It has a number of different actions on platelets, and has been primarily used in patients with ischemic strokes in combination with aspirin.23 Its most important action is probably to inhibit the cyclic guanosine monophosphate (cGMP) phosphodiesterase V enzyme, thereby enhancing the antiplatelet effects of the nitric oxide/cGMP signaling pathway.24 It was the first agent to be studied as an adjunct to full-dose aspirin (which led to the concept of DAPT during the balloon PTCA era in the 1980s. It was administered both orally (pre- and postprocedural) and intravenously (periprocedural). It did not appear to reduce the risk of restenosis following balloon PTCA, but did reduce the risk of periprocedural MI.25 It was also believed to induce ischemic preconditioning, thereby protecting the left ventricle during prolonged balloon inflations, as was typical for angioplasty procedures at that time.26 It was DAPT the agent of choice in the BENESTENT and STRESS trials with the Palmaz–Schatz stent.4,5
Warfarin
Recognizing the central role of thrombin in the pathophysiology of acute coronary syndrome (ACS), early trials such as the Warfarin Reinfarction Study (WARIS) and Antithrombotic Therapy in Acute Coronary Syndromes (ATACS) reported that warfarin with a goal INR > 2.0 was beneficial in improving patient outcomes.27,28 Warfarin with aspirin appeared to be superior to aspirin alone in patients with acute myocardial infarction (AMI).29,30 Warfarin use was thus common at this time. Based on these data, when BMS were introduced, a concern for subacute thrombosis drove early adoption of warfarin in post-PCI patients. Typically, high-dose heparin was utilized during the procedure (as described above). Warfarin was started immediately after the removal of the sheath and overlapping intravenous UFH was continued postprocedure until the INR was in the desired therapeutic range for at least 36 hours. Warfarin therapy was generally recommended for 1–3 months post-PCI.
While the above regimen of DAPT plus heparin/warfarin was an improvement over earlier rates of ischemic complications and abrupt vessel closure following angioplasty, subacute thrombosis rates were still fairly high (~3.5%), access site complications were common (~13.5%), and hospital length of stay was long (8–9 days), mostly due to the need for prolonged anticoagulation.31 This led to the concept of a heparin-coated Palmaz–Schatz stent, which was tested in the BENESTENT-II trial.32,33 With this type of stent, the addition of heparin to the stent was felt to allow discontinuation of routine postprocedural warfarin, and a DAPT regimen consisting of aspirin and ticlopidine 250 mg twice daily was introduced. When possible, the latter was administered at least 72 hours prior to the angioplasty procedure. Although heparin-coated stents were FDA approved around 1995, they fell out of favor for clinical use. The routine use of warfarin was, however, no longer necessary with the advent of ticlopidine.
Ticlopidine
It was the first agent in a new class of antiplatelet agents called thienopyridines to be systematically tested. The late 1990s saw four landmark trials published with ticlopidine (Table 1.1), the results of which resulted in a paradigm shift away from using routine anticoagulation postprocedurally, and toward DAPT alone with aspirin and ticlopidine for patients undergoing coronary stent implantation.34–38 Major adverse cardiac events (MACE) were lower with aspirin and ticlopidine, as were hemorrhagic and vascular complications compared with anticoagulation therapy. No differences were observed between the two regimens in the risk of restenosis at 6–12 months.
|
Also, the STARS trial further embellished the role of DAPT over aspirin monotherapy in this patient population (30-day stent thrombosis rates, 0.5% vs 2.7% for DAPT vs aspirin, respectively).38
Although a simplified DAPT regimen quickly became the standard of care for postprocedure management, intraprocedural ischemic complications remained an issue, despite the use of high doses of UFH (ACT goals 300–350 seconds). Patients presenting with ACS were frequently undergoing angioplasty on a background of aspirin and UFH alone. This resulted in the development of GPI for periprocedural anticoagulation, one of the most important advances in this field to date.
Glycoprotein IIb/IIIa Inhibitors
They inhibit glycoprotein IIb/IIIa, a complex of integrin found on platelets.39 The activation of the integrin complex enables the binding of fibrinogen, platelet–platelet adhesion, and endothelial adherence. The first GPI to be developed was abciximab, which is a chimeric monoclonal-antibody Fab fragment (and thus also known as c7E3 Fab) developed by Dr Barry Coller, a hematologist with a special interest in Glanzmann thrombasthenia.40
In the Evaluation of c7E3 for the Prevention of Ischemic Complications (EPIC) trial (published in 1994), a bolus and infusion of abciximab at the time of angioplasty (and continued for 12 hours postprocedure) was superior to abciximab bolus alone and placebo for MACE at 30 days, including a reduction in nonfatal MI and need for urgent repeat revascularization in patients undergoing high-risk angioplasty; all patients received a background therapy of aspirin and UFH.41 Similar results were observed in the Evaluation of PTCA to Improve Long-term Outcome by ReoPro GPI IIb/IIIa receptor blockade (EPILOG) trial in patients undergoing elective PTCA.42 Finally, in the c7E3 Fab AntiPlatelet Therapy in Unstable Refractory Angina (CAPTURE) trial (published in 1997), upstream abciximab started as an infusion 18–24 hours prior to angioplasty in patients with unstable angina significantly reduced the risk of 30-day nonfatal MI compared with placebo, particularly in patients who were troponin positive, again on a background therapy of aspirin and heparin.43
While abciximab was a large molecule that bound irreversibly to the glycoprotein IIb/IIIa receptor, other intravenous synthetic molecules such as lamifiban, tirofiban, and eptifibatide were smaller molecules with shorter half-lives and more rapid onset. Lamifiban was evaluated in the Platelet IIb/IIIa Antagonist for the Reduction of Acute coronary syndrome events in a Global Organization Network (PARAGON) A and B trials, but failed to show a clinical benefit and was thus not marketed clinically.44 In the Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) trial, patients presenting with an ACS were randomized to receive tirofiban alone, tirofiban with UFH, or heparin alone; all patients received aspirin. The tirofiban alone arm had to be stopped early due to excess mortality. The combination of tirofiban and heparin significantly reduced 30-day ischemic endpoints compared with heparin alone.45 The Platelet glycoprotein IIB/IIIA in Unstable angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) and Enhanced Suppression of the Platelet IIb/IIIa Receptor With Integrilin Therapy (ESPRIT) trials demonstrated similar efficacy of eptifibatide plus heparin over heparin alone.46,47 As a result of these trials, the addition of a GPI to UFH became the standard of care in patients undergoing angioplasty, especially for biomarker positive ACS. Eptifibatide is administered as a double bolus followed by infusion based on the design of the ESPRIT trial even today.47
The next important advance during this period was the introduction of another oral thienopyridine, clopidogrel.
Clopidogrel
Although ticlopidine helped reduce ischemic and bleeding complications compared with systemic anticoagulation, it was poorly tolerated. It also resulted in serious side effects such as neutropenia (~2%), bone marrow aplasia, and cholestatic jaundice.34 Clopidogrel was biochemically similar to ticlopidine, but did not appear to have the same side effect profile as ticlopidine. It was also more rapidly acting. Several clinical trials also demonstrated that, not only was clopidogrel better tolerated, but it also significantly reduced MACE rates compared with ticlopidine.48 By the turn of the century, clopidogrel had replaced ticlopidine as the adenosine diphosphate-receptor antagonist of choice in patients undergoing coronary stenting. The Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial confirmed the superiority of clopidogrel plus aspirin over aspirin alone in patients presenting with an ACS, including in those undergoing PCI.49,50
Low Molecular Weight Heparins
These are selective inhibitors of factor Xa and typically have one third of the molecular weight of UFH. They are believed to produce a more consistent dose response 8compared with UFH. Enoxaparin has the most robust data of the available low molecular weight heparins for use in PCI, particularly based on the results of the SafeTy and Efficacy of Enoxaparin in PCI patients, an internationaL randomized Evaluation (STEEPLE) trial in patients undergoing elective PCI (enoxaparin superior to UFH for reducing the risk of bleeding).51
Fondaparinux
It is a synthetic pentasaccharide that selectively inhibits factor Xa, with a long half-life that permits once daily dosing. In the Organization for the Assessment of Strategies for Ischemic Syndromes -5 (OASIS-5) trial comparing fondaparinux to enoxaparin, fondaparinux significantly reduced bleeding events, but was associated with an unacceptably high risk of catheter-related thrombosis. This appeared to be mitigated by administration of concomitant UFH.52 It is, therefore, currently not indicated as stand-alone antithrombotic therapy in patients undergoing PCI.
Direct Thrombin Inhibitors
Hirudin, an extract from the medicinal leech, was known to be a potent inhibitor of clot-bound thrombin. It was tested as an alternative to UFH in the balloon PTCA era, and was felt to reduce immediate cardiovascular events, but not on longer term follow-up.53 It also appeared to increase bleeding events. Hirulog, a synthetic analog of hirudin, was similarly tested in patients undergoing balloon PTCA, in comparison with high-dose UFH.54 Ischemic complications were similar, but bleeding was significantly reduced with hirulog.19 Since hirulog was a bivalent hirudin analog (unlike univalent analogs such as lepirudin and desirudin), it was renamed as bivalirudin. It was initially developed and marketed by Biogen, Inc, Cambridge, MA as Hirudin. However, the rights for this drug were purchased by the Medicines Company in 1997, and it has been relabeled and marketed as Angiomax since then.
Since the use of UFH and GPI was the prevailing standard in many catheterization laboratories at this time, trials were designed to demonstrate the superiority of bivalirudin over this combination, with the use of GPI as a bail-out strategy. Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events-2 (REPLACE-2) and Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) both demonstrated a significant reduction in bleeding in favor of bivalirudin monotherapy over the combination of UFH/GPI, but ischemic endpoints were similar.55,56 Bailout GPI use was necessary in 7–9% of patients receiving bivalirudin monotherapy; clopidogrel pretreatment was administered in the vast majority of patients (> 80%).
Drug-Eluting Stents Era
The DES era saw further intensification of the bivalirudin versus UFH/GPI debate. While UFH/GPI was still the favored combination for high-risk PCI such as patients with ST segment elevation myocardial infarction (STEMI), the routine use of clopidogrel in patients undergoing PCI resulted in ambiguity about the continued role of GPI for patients undergoing PCI,57 especially elective PCI.58 In the Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction Trial (HORIZONS-AMI) trial of patients presenting with STEMI, bivalirudin monotherapy appeared to increase the risk of acute stent thrombosis, but bleeding was lower with bivalirudin, as was mortality.59
Nationally, the use of bivalirudin as the antithrombotic agent of choice for patients undergoing elective PCI increased from approximately 25% in 2005 to 45% in 2009, with a commensurate decrease in the use of UFH/GPI. Similarly, for patients with non-ST segment elevation acute coronary syndromes undergoing PCI, the use of bivalirudin increased from approximately 15% to 25% during this time period; the use of UFH/GPI decreased from > 40% to approximately 28% over the same time frame. However, for patients undergoing primary PCI (PPCI) for STEMI, UFH/GPI remained the preferred strategy, with a minimal decline in use between 2005 and 2009.60 These data are somewhat dated, however, but more recent trends in utilization are unknown.
An important evolution over the past couple of years has been the re-emergence of UFH as the primary anticoagulant for PCI procedures. There are many reasons for this including cost, but two of the important ones are increasing transradial access (minimizing access site bleeding) and the advent of potent oral antiplatelet agents (accompanied by a drop in the use of GPI). More recent data are somewhat conflicting. How Effective are Antithrombotic Therapies in Primary Percutaneous Coronary Intervention (HEAT-PPCI) found similar rates of bleeding and lower rates of ischemic complications in patients undergoing PPCI with UFH compared with bivalirudin (81% transradial access, 14% GPI use overall).61 Other trials such as European Ambulance Acute Coronary Syndrome Angiography (EUROMAX), Bivalirudin in Acute Myocardial Infarction vs Heparin and GPI Plus Heparin Trial (BRIGHT), and Minimizing Adverse hemorrhagic events 9by TRansradial access site and systemic Implementation of angioX (MATRIX) continue to demonstrate a greater benefit on bleeding outcomes with bivalirudin compared with UFH for patients undergoing PPCI, although acute stent thrombosis rates appear higher with bivalirudin.62–64 Whether a prolonged infusion of bivalirudin can decrease this rate of stent thrombosis in PPCI is being analyzed.
Newer Antiplatelet Agents
Multiple studies have demonstrated that some patients will have decreased or minimal platelet inhibition after clopidogrel therapy.65 They are known as clopidogrel “poor responders,” or as has having “clopidogrel resistance.” Such patients are known to have a higher risk of adverse events post-PCI.66 For patients presenting with an ACS event, and undergoing PCI, two newer agents have shown greater efficacy.67,68 Prasugrel is a thienopyridine like clopidogrel, but achieves more reliable and consistent P2Y12 inhibition.69 Ticagrelor is a reversible allosteric inhibitor of the P2Y12 receptor, biochemically distinct from the thienopyridines, and also appears to have stronger antiplatelet efficacy compared with clopidogrel.70 The use of these newer agents does not appear to mitigate the higher risk of stent thrombosis with bivalirudin during PPCI, though longer bivalirudin infusions might.62 Cangrelor is a rapidly acting intravenous P2Y12 receptor antagonist that showed promising results in mitigating intraprocedural thrombotic events, without a significant increase in bleeding complications in clinical trials.71–75 In A Clinical Trial Comparing Cangrelor to Clopidogrel Standard Therapy in Subjects Who Require Percutaneous Coronary Intervention [PCI]) (CHAMPION-PHOENIX), in patients not pretreated with clopidogrel upstream, cangrelor significantly decreased ischemic events, including stent thrombosis, without a significant increase in transfusions. In a subgroup analysis of the CHAMPION-PHOENIX trial, cangrelor appeared to be superior to clopidogrel in reducing the risk of MI with a trend toward reduced stent thrombosis in patients undergoing PCI with bivalirudin as the primary anticoagulant; as such, the combination may be particularly attractive, assuming that the cost is not prohibitive.76 Cangrelor will likely have a role in the intraprocedural management of patients undergoing PCI in the future, pending approval by the US and European regulatory agencies.
Duration of DAPT Following PCI
Recommendations regarding the optimal duration of DAPT following PCI have undergone significant changes over the years. As discussed earlier, DAPT was typically prescribed for 1 month following BMS PCI. The landmark SIRolImUS-eluting balloon-expandable stent in the treatment of patients with de novo native coronary artery lesion study (SIRIUS) (SES) and Treatment of de novo coronary disease using a single pAclitaXel elUting Stent-IV (TAXUS-IV) (PES) trials mandated 3 and 6 months of DAPT post-PCI, respectively, and so the guidelines reflected this once these stents were approved. Concerns regarding very late stent thrombosis with first-generation DES resulted in a change in FDA labeling to a minimum of 12 months following PCI.10,77 More recently, trials have sought to modify the optimal duration of DAPT with second-generation DES to as short as 3 months on one end, and to as long as 30 months on the other.78–81 Shorter durations may be a possibility in low-risk patients (non-ACS) and patients receiving a second-generation DES.78 Longer durations appear to reduce cardiovascular events, but increase bleeding, and possibly all-cause mortality in non-ACS patients.81 The optimal duration following second-generation DES PCI remains unknown, and it is likely that a “one-size-fits-all” strategy may be abandoned in favor of a tailored approach in the future, based on an individual patient's ischemic and bleeding risk.
THE ROAD AHEAD
The past two to three decades have seen monumental advances in the field of periprocedural pharmacotherapy. Hand-in-hand with the procedural advances, PCI has moved from an era where having a cardiac surgeon on standby and readily available was necessary before every angioplasty to an era now where even complex multivessel interventions can be safely done without immediate availability of CABG. The next few years will likely continue to see similar advances on multiple fronts in the PCI realm.82 On the periprocedural pharmacotherapy side, newer and more potent agents are actively being investigated, even as our knowledge and understanding of platelet and vascular biology continue to evolve. Platelet function testing and genetic testing might produce a paradigm shift in antiplatelet therapy, though currently these remain research topics. The promise of “personalized medicine” could conceivably be realized with the application of these tools, although admittedly still in their infancy and in need of rigorous evaluation through randomized clinical trials. High-risk subsets, such as those with diabetes mellitus, may especially benefit.83 Thus, in light of its glorious past, the future of this field appears especially bright.10
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