New Drugs in Interventional Cardiology

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Citation
Asia-Pacific Cardiology 2007;1(1):36-9
DOI
https://doi.org/10.15420/apc.2007:1:1:36

Balloon percutaneous transluminal coronary angioplasty expands the arterial lumen, stretching and disrupting the atherosclerotic plaque and vessel wall and redistributing the atherosclerotic plaque along its longitudinal axis. The subsequent elastic recoil of the vessel wall and intimal hyperplasia may lead to restenosis in 10–30% of cases, and in about 5–6% of patients the initial balloon dilatation may cause coronary dissection, which can result in abrupt vessel closure. These potential complications are preventable with coronary stenting. Stenting also significantly lowers restenosis rates compared with balloon angioplasty.

Currently, more than 80% of percutaneous coronary interventions (PCIs) include stenting. The initial stents were bare-metal stents (BMS); however, because of the occurrence of in-stent restenosis in 10–30% of patients within 12 months after BMS implantation (predominantly due to neointimal hyperplasia), drug-eluting stents (DES) are now preferred, especially in highly restenotic lesions and for treating in-stent restenosis. Balloon dilatation ‘injures’ the plaque and vessel wall: the denuded endothelium and the balloons, wires and stents are foreign bodies, hence PCI is associated with an increased incidence of thrombosis and thromboembolism. Therefore, the drugs used in interventional cardiology are predominantly those that act on the thrombotic cascade, and include antiplatelet (aspirin, clopidogrel and glycoprotein IIb/IIIa inhibitors) and antithrombotic (intravenous unfractionated heparin, low-molecular-weight heparin [LMWH] and direct thrombin inhibitor) agents. PCI requires one or more antiplatelet agent combined with an antithrombin. This article will concentrate predominantly on the newer drugs.

Aspirin

Aspirin inhibits the enzyme cyclo-oxygenase and blocks the synthesis of thromboxane A2, which promotes platelet aggregation. Aspirin is an established standard for all patients undergoing PCI. The minimum dose appears to be 75mg and, since its antiplatelet effect is seen within 60 minutes, it is generally recommended to be given at least two hours before the procedure. Aspirin resistance has been described in some patients.

Thienopyridine Derivatives

Thienopyridine derivatives inhibit the adenosine diphosphate (ADP) receptor of platelets. Aspirin and thienopyridine derivatives have synergistic effects, and they are used in combination unless the patient is aspirin-sensitive or -intolerant. The thienopyridine derivatives are: ticlopidine, at a loading dose of 500mg followed by 250mg twice daily (bid); clopidogrel; and newer thienopyridine derivatives such as prasugrel, AZD 6140 and cangrelor.

Clopidogrel

The importance of dual antiplatelet agents post-PCI, especially after stenting, has been well established. However, the loading dose of clopidogrel and the duration of dual antiplatelet therapy has recently become an issue, particularly with reports of late stent thrombosis and very late stent thrombosis following implantation of DES. The standard of care based on the PCI-CURE1 and Clopidogrel for Reduction of Events During Observation (CREDO)2 studies is a loading dose of 300mg at least six hours prior to PCI, followed by 75mg daily. In a randomised study of 190 patients, the incidence of non-responsiveness (defined as <10% of absolute change in platelet aggregation) was reduced from 28 to 8% with a 600mg loading dose.3 Another randomised study of 60 patients confirmed that a 600mg loading dose of clopidogrel resulted in higher plasma concentrations of the active metabolite and less platelet aggregation at four hours compared with the 300mg loading dose.4 No additional benefit was seen with the 900mg loading dose. Hochholzer et al.5 performed platelet aggregation studies in 1,001 patients before clopidogrel 600mg and at catheterisation. The full antiplatelet effect of clopidogrel 600mg was achieved after two hours. The different loading doses were assessed in the Anti-platelet Therapy for Reduction of Myocardial Damage during Angioplasty 2 (ARMYDA-2) trial,6 in which 255 patients undergoing PCI were randomised to either clopidogrel 600mg or 300mg administered four to eight hours before PCI. The rate of peri-procedural myocardial infarction (MI) was lower in the group that received the 600mg loading dose. Based on these data, perhaps the loading dose should be 600mg instead of 300mg and should be administered at least two hours prior to PCI. Sub-acute and late stent thrombosis are rare following PCI. However, their presentation tends to be dramatic and their consequences can be life-threatening.

They present with acute MI, which carries a high risk of mortality. The duration of dual antiplatelet therapy is debatable, but according to results such as those from the Basel Stent Cost-effectiveness Trial – Late Thrombotic Events (BASKET-LATE)7, the authorities currently recommend a period of at least one year of dual antiplatelet therapy. However, the issue is still not totally resolved.

Cilostazol

Cilostazol inhibits the phosphodiesterase pathway of platelet activation. It also has antithrombotic activity. In the Cilostazol for RESTenosis (CREST) study, patients who had undergone successful intra-coronary stenting were randomised to receive either cilostazol 100mg daily for six months or placebo in addition to the usual combination of aspirin and clopidrogel. The primary end-point showed a significantly higher minimal luminal diameter within the stent and in-segment. There were also significantly lower in-stent and in-segment restenosis rates in those patients who received cilostazol compared with placebo. However, the major adverse cardiac event (MACE) rate was similar in the two groups.8

Prasugrel

A new thienopyridine receptor antagonist, prasugrel, was evaluated in the Joint Utilization of Medications to Block platelets Optimally – Thrombolysis In Myocardial Infarction 26 (JUMBO-TIMI 26),9 and was found to be safe, with no increased risk of bleeding complications compared with clopidogrel. There was a lower incidence of 30-day MACE in the prasugrel group. To further assess the efficacy and safety of prasugrel in a larger population of patients in the clinical setting, an ongoing clinical trial, TRITON-TIMI 38,10 will enrol approximately 13,000 patients across the acute coronary syndrome (ACS) spectrum to compare the efficacy and safety of prasugrel and standard-dose clopidogrel. The primary end-point will be the composite of cardiovascular death, MI and stroke. Important secondary end-points include bleeding, recurrent ischaemia and urgent target vessel revascularisation.

AZD 6140

AZD 6140 is an oral non-thienopyridine reversible direct antagonist (not a pro-drug) of the platelet P2Y12 receptors, metabolised by CYP3A4. Due to its rapid onset of action (less than one hour), it requires no loading dose, but has a short half-life of 12 hours necessitating twice-a-day administration.

Phase II development was completed with two dose-ranging studies, DISPERSE-1 (in which four dose regimens were tested) and the DISPERSE-2/TIMI33 study (in which two dose regimens were tested versus clopidogrel).11 In the latter trial, although there were no meaningful differences between the three groups for the composite endpoint of cardiovascular death, MI and stroke, rates of total bleeding were similar, and the dose selected for AZD 6140 was 180mg twice a day. Some of the side effects reported include dyspnoea (most cases occurring within 30 days of treatment initiation), uric acid elevations and bradycardia (sinus pauses and atrio-ventricular block). Ongoing studies include the PLATelet inhibition and patient Outcomes (PLATO) trial, a phase III study on 18,000 patients with ACS (unstable angina, ST-segment elevation MI [STEMI] and non-ST-segment elevation MI [NSTEMI]) undergoing PCI or not. The primary objective is to compare AZD 6140 180mg bid with clopidogrel 75mg for the prevention of vascular events (composite of death from vascular causes, MI and stroke).12

Cangrelor

Cangrelor is a novel, rapidly acting, intravenous, specific antagonist of platelet aggregation that works by binding to the adenosine diphosphate (ADP) P2Y12 receptor subtype. The aim of the initial phase II study was to assess the safety and pharmacodynamics of cangrelor in patients undergoing PCI. Initial experience with intravenous cangrelor during PCI suggests an acceptable risk of bleeding and adverse cardiac events, while achieving rapid, reversible inhibition of platelet aggregation by competitive binding to the ADP P2Y12 platelet receptor, with less prolongation of bleeding time than seen with the glycoprotein IIb/IIIa receptor antagonist abciximab.13 Ongoing clinical studies include a phase III trial with acute PCI patients comparing intravenous cangrelor with clopidogrel 600mg. The primary objective is to compare the two treatments in terms of prevention of vascular events (composite of allcause mortality, MI and urgent revascularisation at 48 hours).

Antithrombin Therapy

Antithrombin therapy is an important component therapy in PCI for the prevention of thrombosis. The thrombin inhibitors are: unfractionated heparin; LMWH; and the direct thrombin inhibitors hirudin, bivalirudin and argatroban.

Unfractionated Heparin

Unfractionated heparin is the thrombin inhibitor most commonly used in PCI. The dose can be titrated by the simple measurement of activated clotting time (ACT). A weight-adjusted heparin dose of 50–70IU/kg is generally used and further heparin is administered during PCI to achieve an ACT of around 300 seconds if no GPIIb/IIIa is given, or an ACT of >200 seconds if GPIIb/IIIa is given. Heparin is used intra-procedurally, and the arterial sheath is normally removed after the procedure when ACT is <150–180 seconds.

Low-molecular-weight Heparin

High-risk ACS patients are usually treated with LMWH at the time of diagnosis and then taken to coronary angiography with the aim of revascularisation. If suitable, the patient is treated with PCI. As there is no simple anticoagulant monitoring for LMWH, the dose of LMWH in this situation is empirical. No additional antithrombin is needed if the last dose was given less than eight hours before the procedure. If the last dose was eight to 12 hours before the procedure, bolus intravenous enoxaparin at a dose of 0.3mg/kg is recommended. If the last dose was more than 12 hours before the procedure, conventional anticoagulation can be commenced. Due to the limitations of unfractionated heparin, several alternative antithrombin agents have been evaluated. The Superior Yield of the New Strategy of Enoxaparin Revascularization and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trial compared enoxaparin and unfractionated heparin in high-risk ACS patients planned for early invasive therapy. At 30 days, enoxaparin was found to be non-inferior to unfractionated heparin in reducing death or non-fatal re-infarction.14 At follow-up, there was a fairly high rate of recurrent cardiac events with no significant difference between those who received enoxaparin and those treated with unfractionated heparin.

Direct Thrombin Inhibitors

Hirudin, bivalirudin and argatroban have been evaluated as alternatives to heparin during PCI.

Hirudin

In the Hirudin in a European Trial Versus Heparin in the Prevention of Restenosis after PTCA (HELVETICA) study,15 1,141 patients with ACS undergoing PCI received aspirin and were randomly assigned to heparin or one of two regimens of hirudin. Early cardiac events were lower with hirudin, but the clinical outcomes were similar between the groups at seven months. Lepirudin is a synthetic direct thrombin inhibitor approved as an alternative to heparin in patients with heparin-induced thrombocytopoenia. The dose is 0.4mg/kg bolus, 0.15mg/kg/hour (to be adjusted for renal impairment).

Bivalirudin

Bivalirudin is a synthetic direct thrombin inhibitor that inhibits thrombin-mediated platelet activation, has a short plasma half-life and does not require anticoagulant monitoring. Bivalirudin compared with heparin in a trial of 4,098 patients with unstable angina undergoing PCI did not reduce the likelihood of hospital death, MI or emergent coronary artery bypass graft (CABG) surgery, but did reduce bleeding complications.16 In the post-infarct angina patients, bivalirudin significantly lowered the rate of major ischaemic complications and lowered rates of bleeding. In the Randomized Evaluation of PCI Linking Angiomax to Reduced Clinical Events (REPLACE- 2)17 trial, 6,010 patients undergoing PCI were randomly assigned to receive bivalirudin 0.75mg/kg bolus plus 1.75mg/kg/hour for the duration of PCI either with or without the GPIIb/IIIa inhibitors abxicimab or eptifibatide.17

The primary end-point of 30-day composite of death, MI, urgent revascularisation or in-hospital major bleeding was 9.2% in the bivalirudin group and 10% in patients in the heparin + GPIIb/IIIa inhibitor group (p=0.32). Bivalirudin + GPIIb/IIIa inhibitor was not inferior to heparin + GPIIb/IIIa inhibitor in reducing acute ischaemic events, and was associated with less bleeding. Based on the Acute catheterisation and Urgent Intervention Triage Strategy (ACUITY)-PCI substudy,18 bivalirudin can safely replace heparin and synthetic GPIIb/IIIa inhibitors in ACS patients undergoing PCI, with similar rates of ischaemia and less bleeding at 30 days. ACUITY-PCI included 7,789 patients from the ACUITY19 trial who underwent PCI. They were randomly assigned to one of three groups: heparin + GPIIb/IIIa inhibitor, bivalirudin + GP IIb/IIIa inhibitor or bivalirudin alone.

The primary end-point – major bleeding at 30 days – was significantly lower in the bivalirudin-only group. There were no significant differences in ischaemic events among the three groups. Therefore, bivalirudin may be particularly useful in patients with heparin-induced thrombocytopoenia and in those at high risk of bleeding, including elderly patients. The dose is 0.75mg/kg bolus, 1.75 mg/kg/hour for the duration of procedure (to be adjusted for severe renal impairment).

Argatroban

Argatroban is a synthetic direct thrombin inhibitor that is approved as an alternative to heparin for patients with heparin-induced thrombocytopoenia. The dose is 350mg/kg bolus, 25μg kg/min (to be adjusted for hepatic impairment).

Fondaparinux

Fondaparinux is a synthetic factor Xa inhibitor that has been shown to be non-inferior to enoxaparin in the primary end-point of death, MI or refractory ischaemia in patients with STEMI-ACS.20 Fondaparinux significantly reduces mortality and re-infarction in STEMI patients without increasing bleeding compared with placebo or unfractionated heparin when treated with either fibrinolytic therapy or primary PCI.21 In a pilot study evaluating the use of intravenous fondaparinux during elective or urgent PCI in 350 patients, the incidence of total bleeding was similar to that for heparin (6.4% in fondaparinux versus 7.7% in unfractionated heparin; p=0.61). The efficacy end-points were also similar.22

Glycoprotein IIb/IIIa Inhibitors

Glycoprotein IIb/IIIa activation is the final common pathway of platelet aggregation. The established GP IIb/IIIa inhibitors are: abciximab; eptifibatide; and tirofiban.

Abxicimab

Abxicimab is beneficial in patients undergoing PCI for ACS or STEMI; however, its benefit in elective PCI patients is less clear. The safety and efficacy of abxicimab have been demonstrated in many clinical trials, first in the Evaluation of the 7E3 for Prevention of Ischaemic Complications (EPIC) trial,23 followed by the Evaluation of PTCA to Improve long-term Outcome by Abxicimab GPIIb/IIIa Blockade (EPILOG)24 and the Evaluation of Platelet IIb/IIIa Inhibit for Stenting Trial (EPISTENT).25

The Same-Day Home Discharge After Transradial Coronary Stenting With a Single Abxicimab Bolus (EASY) trial randomised 1,005 patients who underwent trans-radial stent implantation with abxicimab bolus to either a 12-hour abxicimab infusion and overnight hospitalisation or bolus only and discharge four to six hours after PCI.26 Clinical outcomes at 30 days and six months were similar in the two groups.

The Randomized Early versus Late Abxicimab in Acute Myocardial Infarction Treated With Primary Coronary Intervention (RELAx-AMI) Trial27 evaluated 210 patients with first AMI undergoing primary PCI randomised to abxicimab either in the emergency room (early group: 105 patients) or in the catheterisation laboratory after coronary angiogrphy (late group: 105 patients). Primary end-points were TIMI flow grade, corrected TIMI frame count (cTFC) and myocardial blush grade (MBG) and left ventricular function recovery. Early abxicimab administration improved pre-PCI angiographic findings, post-PCI tissue perfusion and one-month left ventricular function recovery, possibly by starting early revascularisation of the infarct-related artery. It remains unknown whether GPIIb/IIIa should be initiated immediately (upstream) or should be withheld until PCI is performed (deferred). ACUITY TIMING28 was a prospective randomised trial examining outcomes associated with two different time-points of GPIIb/IIIa administration. In this trial, 4,605 patients received upstream GPIIb/IIIa inhibitors while 4,602 patients received deferred GPIIb/IIIa inhibitors. The GPIIb/IIIa inhibitor used in the majority of patients was eptifibatide. There was no difference in the clinical outcome composite of ischaemic events and bleeding complications at 30 days between the two treatment groups.

Eptifibatide

The Integrilin to Minimise Platelet Aggregation and Coronary Thrombosis-II (IMPACT-II) trial29 compared bolus followed by different infusion doses of eptifibatide compared with placebo. There was no significant difference in the primary end-point of death, MI, unplanned CABG or repeat PCI or coronary stenting. The infusion dose of eptifibatide was insufficient. A larger dose was used in the Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPIRIT)30 in patients undergoing coronary stenting, and eptifibatide significantly reduced the composite of death, MI and urgent target vessel revascularisation. Major bleeding was infrequent but more significant in the eptifibatide than the placebo group (1.3 versus 0.4%). Current guidelines on the use of GPIIb/IIIa inhibitors recommend GPIIb/IIIa in patients with unstable angina/NSTEMI undergoing PCI, and recommend abixicimab in STEMI patients.

Tirofiban

Tirofiban was evaluated in the Randomized Efficacy Study of Tirofiban for Outcomes and Restenosis (RESTORE)31 trial in 2,139 patients undergoing PCI within 72 hours of ACS. The 30-day composite end-point was 16% lower in the tirofiban group. In a comparative trial of tirofiban versus abciximab in 4,809 patients scheduled for PCI with stenting, the composite end-point of death, MI and target vessel revascularisation at 30 days was more frequent in the tirofiban group than in the abciximab group (7.6 versus 6.0%; p=0.038).32 Subsequent studies suggested that the dose of tirofiban used may have been inadequate to achieve optimal anticoagulation, and larger doses were known to improve platelet inhibition.

Fibrinolytics

In a small study by Sezer et al., 41 patients undergoing primary PCI were randomly assigned to receive intra-coronary streptokinase (250kU) or no additional therapy. In this pilot trial, the administration of intra-coronary streptokinase immediately after primary PCI improved myocardial perfusion but not long-term left ventricular size or function.33 This hypothesis-generating study showed that the intra-coronary administration of streptokinase after primary PCI exerts a beneficial effect on the coronary microvasculature. This small study warrants further analysis in larger clinical studies aimed at minimising reperfusion injury.

Other Drugs in Percutaneous Coronary Intervention

Other drugs used during PCI are vasodilators, including nitroglycerine, verapamil and adenosine. They are often injected directly intra-coronary to treat intra-coronary vasospasm and poor no-reflow. Nitroglycerine and verapamil are prepared as 100ugm/ml and injected in aliquots of 100–200ugm at a time. For adenosine, intra-coronary boluses between 24ug and 4mg have been used.

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