Applied Radiology

Dr. Pienvichit is a Staff Interventional Cardiologist at Ramathibodi Hospital, Mahidol University, Bangkok, Thailand. He received his MBBS degree in 1992 from the All India Institute of Medical Sciences. He completed his interventional fellowship at Lahey Clinic Medical Center, Burlington, MA.

Intervention in acute coronary syndrome (ACS) involves not only the mechanical treatment of an epicardial lesion, but also the pharmacologic management of a complex biological process involving plaque rupture, platelet activation, and thrombus formation. ^1,2 The role of antiplatelet agents is crucial, and they are now the standard of care in unstable angina (UA). ³ The widespread use of intracoronary devices has improved the results of mechanical revascularization. Despite these advances, many questions remain unanswered. This article will review the current information and controversies in ACS intervention.

The strategy: To cath or not to cath

The optimal ACS management strategy has been the subject of many debates. For acute myocardial infarction (AMI), the current data is consistently in favor of primary percutaneous coronary intervention (PCI) in institutions where a cardiac catheterization laboratory and a well-trained staff are available. Meta-analysis of clinical trials comparing primary PCI with intravenous thrombolysis demonstrated lower mortality (4.4% versus 6.5%; P = 0.02) and risk of death or reinfarction (7.2% versus 11.9%; P <0.001) with PCI. ⁴ The optimal strategy for UA and non-Q-wave myocardial infarction (NQWMI) patients is less clear due to conflicting results from randomized trials. The question is whether a routine, early invasive strategy offers an advantage over the conservative, ischemia-driven approach. Early PCI has the potential of aborting ischemia, salvaging myocardium, and preventing near-term events at the expense of procedure-related complications and up-front cost. With more than 1.3 million cases of UA and NQWMI presenting in the United States annually, this issue has substantial financial implications.

The findings of previous UA/ NQWMI trials were not in favor of an early invasive strategy. The multicenter Veterans Affairs Non-Q-Wave Infarction Strategies in Hospital (VANQWISH) trial found higher incidence of death or nonfatal MI ( P = 0.05) with the invasive strategy. ⁵ There was no significant difference in mortality from all causes at long-term follow-up (mean follow-up 23 months) between the two arms. In the Thrombolysis In Myocardial Infarction (TIMI) IIIB trial, the incidence of death or MI in the two strategy arms were not statistically different at 1 year (10.8% versus 12.2%; P = 0.42). ⁶ However, the early invasive patients had significantly fewer repeat admissions (26% versus 33%; P <0.001) and received fewer medications.

More contemporary trials, FRISC II (Fragmin and fast Revascularisation during InStability in Coronary artery disease) and TACTICS-TIMI (Treat Angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy) 18, demonstrated better outcomes with an early invasive strategy for UA or non-ST segment elevation MI (NSTEMI). ^7,8 These trials involved the use of glycoprotein (GP) IIb/IIIa receptor blockers, low molecular weight heparin (LMWH), and stents, reflecting the current interventional practice. In FRISC II, the rate of death or nonfatal MI at 6 months was lower in the invasive group compared with the conservative group (9.4% versus 12.1%; P = 0.031). Fewer patients in the invasive group had angina and with less severity than the conservative group. TACTICS-TIMI 18 trial administered (in addition to aspirin and heparin) tirofiban, a platelet GP IIb/IIIa agent, to UA/NSTEMI patients. The trial showed an 18% relative reduction in the primary endpoint (death, MI, or re-hospitalization for ACS) at 6 months with an invasive strategy compared with conservative strategy (15.9% versus 19.4%; P = 0.025). More importantly, patients with elevated cardiac troponin T (cTnT) had more than a 40% reduction in the primary endpoint with an invasive strategy, while cTnT-negative patients did equally well with either management strategy.

Closer examination of the older trials points to severe limitations of the VANQWISH and TIMI IIIB trials. ⁹ The mean time to revascularization in the early invasive group was 36 hours after admission in the TIMI IIIB trial and 8 days for VANQWISH. The delays could reduce the potential of myocardial salvage. These trials did not employ GP IIb/IIIa receptor blockers, LMWH, or stents as FRISC II and TACTICS-TIMI 18 did. Furthermore, the worse outcome in the VANQWISH invasive arm was attributable to the higher mortality (11.6%) in patients undergoing coronary artery bypass graft (CABG) surgery compared with those in the conservative group undergoing CABG (3.4%). Even with the drawbacks, one could conclude from VANQWISH and TIMI IIIB that the early invasive strategy performed at least as well as the conservative strategy.

Given the advances in PCI, an early invasive strategy leads to better outcomes, particularly in high-risk patients. For low-risk patients, the risks and financial cost of PCI must be balanced against the potential benefits.

Adjuvant therapies

Anticoagulation and antiplatelet medications play a critical role in ACS intervention and account for a large part of the improvement made in the clinical outcomes. UA patients treated with the standard regimen of aspirin, heparin, and beta-blockers have a 30-day death and nonfatal MI rate of 8% to 16%. ¹⁰ GP IIb/IIIa receptor blockers, LMWH, and thienopyridine derivatives can improve these outcomes significantly. Disagreement remains, however, regarding the choice of agent and the optimal time for administration.

Ticlopidine and clopidogrel

Currently, the thienopyridine derivatives (ticlopidine and clopidogrel) are used mainly for preventing subacute stent thrombosis. The STARS (Stent Anticoagulation Regimen Study) and ISAR (Intracoronary Stenting and Antithrombotic Regimen) trials demonstrated <1% stent closure at 30 days with ticlopidine and aspirin combination. ^11,12 Studies suggest that they may have additional benefits in ACS apart from their use in stenting.

Ticlopidine in UA is effective in reducing vascular death and nonfatal MI at 6 months when used in combination with conventional therapy (nitrates, ß-blockers, and calcium-channel blockers). ¹³ The benefit, however, is not superior to that of aspirin. The efficacy of clopidogrel in the treatment of UA was demonstrated in the CURE (Clopidogrel in Unstable Angina Prevent Recurrent Events) trial. ¹⁴ The primary composite endpoint (cardiovascular death, MI, or stroke) was reduced by 20% with the clopidogrel plus aspirin combination compared with aspirin alone (9.3% versus 11.5%; P = 0.00005). This apparent benefit started within 2 hours and reached 20% by the first day after randomization. Whether the positive outcome would be blunted with concomitant use of a GP IIb/IIIa is not known. Also unknown is the bleeding complication of those on clopidogrel who underwent CABG. Nevertheless, the results of the trial are encouraging, and expand on the implications of the the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial. ¹⁵ CAPRIE demonstrated long-term safety and efficacy of clopidogrel in reducing the annual risk of stroke, MI, and vascular death compared with aspirin (5.32% versus 5.83%; P = 0.043; relative risk reduction 8.7%) in patients with atherosclerotic cardiovascular disease.

Thienopyridine derivatives are indispensable to current interventional practice where stenting has dominated over other devices. They improve the outcome of ACS independent of stent usage. With a favorable hematologic profile, clopidogrel is the preferred agent over ticlopidine. ¹⁶

Low molecular weight heparin

There are many theoretical advantages of LMWH over unfractionated heparin (UH). ¹⁷ LMWH in ACS has proven to be beneficial in clinical studies. Meta-analysis of the TIMI 11B and ESSENCE (Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-wave Coronary Events) trials demonstrated sustained and significant reduction in the composite endpoint (death and nonfatal MI) of about 20% at 43 days (7.1% versus 8.6%; P = 0.02) with the use of enoxaparin in UA/NQWMI compared with UH. ^18-20 The FRISC-II trial randomized UA/NSTEMI patients to subcutaneous dalteparin (120 IU/kg) twice daily or placebo for 3 months. Among the noninvasive arm patients, there was a significant difference in the rates of death, nonfatal MI, and revascularization between dalteparin and placebo at 1 month (19.5% versus 25.7%; P = 0.001) and 3 months. At 6-month follow-up, however, these differences ceased to be significant.

Dosing of LMWH during PCI and safety in combination with other pharmacologic agents were addressed in the National Investigators Collaborating on Enoxaparin (NICE) 3 and NICE 4 trials. ^21,22 In the NICE 3 trial, enoxaparin (0.3mg/kg intravenously) was given in combination with a GP IIb/IIIa receptor blocker during coronary angiogram if more than 8 hours had elapsed from the last enoxaparin dose. The clinical outcomes and bleeding frequency were similar to those reported in large GP IIb/IIIa receptor blocker trials. The NICE 4 trial used 0.75 mg/kg of enoxaparin intravenously in combination with abciximab during PCI and had similar major bleeding rate as that of EPILOG. ²²

GP IIb/IIIa receptor antagonists

GP IIb/IIIa receptor blockers can reduce the risk of adverse cardiac events from coronary intervention. ^23-26 Our knowledge of these agents in ACS comes from clinical trials that are divided into "upstream," and "downstream" trials. The downstream trials are designed to study the benefits of GP IIb/IIIa antagonists on PCI when given in the perioperative period. Only a subset of the enrolled patients had ACS. The upstream trials are designed primarily as medical management of UA/NQWMI, but varying percentages of the patients (23% to 30%) went on to have PCI, blurring the distinction from the downstream studies. ^27,28 Confusion arises when these trials yield conflicting results.

Eptifibatide and tirofiban reduce the risk of adverse events when used in an upstream fashion. In the PURSUIT (Platelet glycoprotein IIb/IIIa in Unstable angina: Receptor Suppression Using Integrilin Therapy) trial, eptifibatide showed significant reduction in the composite endpoint (death or MI) compared with placebo at 30 days (14.2% versus 15.7%; P = 0.04). ²⁷ In the PRISM-PLUS (Platelet receptor inhibition in ischemic syndrome management in patients limited by unstable signs and symptoms) trial, tirofiban plus heparin had a significant reduction in the composite endpoint (death, MI, or refractory angina) at 30 days compared with heparin (18.5% versus 22.3%; P = 0.03). ²⁸

The issue of upstream abciximab is less clear. The results from the CAPTURE (c7E3 Fab Antiplatelet Therapy in Unstable Refractory Angina) and the more recent GUSTO IV ACS (Global Utilization of Streptokinase and t-PA for occluded coronary arteries trial IV in Acute Coronary Syndromes) trials point to different conclusions. ^29,30 The CAPTURE trial randomized refractory UA patients to abciximab bolus followed by continuous drip or placebo for 18 to 24 hours before PCI and for 1 hour after the procedure. Abciximab reduced the risk of cardiac event (deaths or MI) at 30 days (5.4% versus 9.4%, P = 0.012) compared with placebo. The more recent GUSTO IV ACS trial randomized NSTEMI patients to medical treatment with placebo or 24- or 48-hour abciximab infusion. Among the three arms, there was no significant difference in the primary endpoint (death or MI) or the need for revascularization at 30 days (8%, 8.2%, and 9.1%, respectively; P = not significant).

One theory to explain the different conclusions of the two trials is suboptimal continuous infusion dosing of abciximab in the GUSTO IV ACS trial. The initial benefit derived from the bolus dose is thought to be lost over time. This scenario was seen in the Au-Assessing Ultegra (GOLD) study, which monitored the effectiveness of standard GP IIb/IIIa antagonists dosing. After 8 hours of continuous drug infusion, the degree of platelet inhibition was highly variable. The risk of adverse events (death, MI, or urgent target vessel revascularization [TVR]) tripled for those patients with <70% platelet inhibition compared with those with >70% inhibition (25% versus 8.1%; P = 0.009). ³¹

Subgroup analysis of the CAPTURE trial reveals important findings. The cardiac troponin T (cTnT) positive patients (>0.1ng/mL) randomized to placebo had higher event rates compared with cTnT-negative patient at 30 days (19.6% versus 4.9%), similar to the GUSTO III trial, which showed higher 30-day mortality for the cTnT-positive patients (15.7% versus 6.2%; P = 0.001). ³² The benefit of abciximab was confined to those with elevated cTnT, reducing the adverse events from 19.6% to 5.8% at 30 days ( P = 0.001). ²⁹

The use of abciximab downstream (during intervention) is well supported by the EPIC (Evaluation of Platelet IIb/IIIa Inhibition for Prevention of Ischemic Complication), EPILOG (Evaluation in PTCA to Improve Long-term Outcome with Abciximab GP IIb/IIIa Blockade), and EPISTENT (Evaluation of Platelet IIb/IIIA Inhibitor for Stenting) trials. ^23-25 The EPIC trial studied high-risk angioplasty and directional atherectomy, which included UA and recent MI patients. There was a significant reduction in death and MI at multiple follow-up points up to 3 years (risk reduction 23%; P <0.05). The EPILOG trial extended the positive findings to urgent and nonurgent PCI. The EPISTENT trial showed statistically significant reduction in death, MI, and TVR with stent plus abciximab. At 6 months, the composite endpoint was 5.6% for the stent plus abciximab group, 7.8% for balloon angioplasty plus abciximab, and 11.4% for stent plus placebo ( P <0.01). Additionally, the EPISTENT diabetic substudy noted significant reduction in 6-month TVR among diabetic patients treated with stent and abciximab. ³³

Downstream eptifibatide was studied in ESPRIT (Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrin Therapy), but it was not an ACS trial. The trial included only patients undergoing elective stenting. Eptifibatide was given as a 180 µg/kg bolus, followed by 2 µg/kg/min infusion and another bolus 10 minutes later. ²⁶ The primary endpoint (death, MI, urgent TVR, or GP IIb/IIIa antagonist crossover at 48 hours) was reduced by 37% with eptifibatide (6.6% versus 10.5%; P = 0.002). These dosages were higher than those used in the earlier IMPACT II trial (Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis), which failed to demonstrate a positive outcome. ³⁴

The trial of downstream tirofiban has been disappointing. The TARGET trial (Do Tirofiban and ReoPro Give similar Efficacy Trial) showed the superiority of abciximab over tirofiban in lowering the incidence of death, MI, or urgent TVR at 30 days (6.0% versus 7.5%, P = 0.037) when these agents were used in non-AMI patients undergoing PCI with "intent-to-stent." ³⁵ Suboptimal dosing of tirofiban and non-GP IIb/IIIa effect(s) of abciximab have been advanced as explanations for the inferiority of tirofiban in this "equivalence" study.

GP IIb/IIIa antagonists are beneficial in ACS. The benefits are more apparent in the high-risk patients, e.g., those with elevated cardiac troponins. Further clinical trials designed with optimal dosing and direct comparison would settle many questions about these drugs. As no oral IIb/IIIa receptor blockers have proven to be of clinical benefit, they currently have no role in the management of ACS. ^36-38

Acute myocardial infarction

The outcomes of primary PCI for acute ST-elevation MI are superior to those of thrombolytics. ⁴ Primary PCI has consistently shown reperfusion rates in the range of 85% to 95% for end-of-procedure TIMI 3 flow, compared with the traditional 50% to 66% TIMI 3 flow at 90 minutes reported in the thrombolytic literature. ^39-45 Death or reinfarction rate at 6 months was reduced by more than 50% with primary PCI compared with tissue plasminogen activator (t-PA) (8.2% versus 17.0%; P = 0.02) in the PAMI trial (Primary Angioplasty in Myocardial Infarction). ⁴⁰ The composite endpoint of death, reinfarction, and stroke at 6 months was also lowered by more than 60% (8.5% versus 23.2%, P = 0.02) with PCI compared to thrombolytic therapy in the STOP-AMI ( Stent versus Thrombolysis for Occluded Coronary Arteries in Patients with Acute Myocardial Infarction) trial. ⁴²

The current success of primary PCI is due in part to stenting. In the PAMI-Stent trial, a 35% reduction in the composite endpoint (death, recurrent MI and TVR) was seen with stenting compared to balloon angioplasty alone (12.6% versus 20.1%; P <0.01). ⁴⁶ Stenting of the culprit lesion resulted in less restenosis at 6 months compared with balloon angioplasty alone (27% versus 52%; P <0.005). ⁴⁷

GP IIb/IIIa antagonists during AMI intervention show inconsistent benefits. In the ADMIRAL (Abciximab before Direct angioplasty and stenting in Myocardial Infarction Regarding Acute and Long-term follow-up) trial, the stent plus abciximab group had higher end-of-procedure TIMI 3 flow (95.1% versus 86.7%; P = 0.03) and 49% reduction in the primary endpoint (death, recurrent MI, and urgent TVR) at 30 days (7.4% versus 14.6%; P = 0.04%) when compared with stent plus placebo. ⁴⁸ In the CADILLAC (Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications) trial, however, abciximab failed to show incremental benefit to PCI in AMI patient. ⁴⁹ Additional studies are indicated to resolve these differences.

Despite the superior results of primary PCI, it is available only in certain referral centers. For many AMI patients, thrombolytic therapy is the only other alternative for revascularization.

Facilitated percutaneous coronary intervention

The availability of around-the-clock AMI angioplasty is limited. Transfer of patients from community hospitals to referral centers for primary PCI adds delay to the definitive treatment. The delay, due mainly to the initiation of transfer (51 ± 37 minutes) and transport time (34 ± 30 minutes), could add more than 2 hours (120 ± 69 minutes) to the process, as seen in the AIR-PAMI trial. ⁵⁰ Facilitated PCI (FPCI) strategy attempts to combine the commonly available pharmacologic agents at the peripheral hospitals with PCI at the referral centers. Improved pharmacologic regimen could stabilize AMI patients and increase the vessel patency. Furthermore, having some flow before PCI permits visualization of the distal vessel, making the procedure easier.

More recent data has alleviated the concern of SWIFT (Should We Intervene Following Thrombolysis) trial, TAMI (Thrombolysis and Angioplasty in Myocardial Infarction), and TIMI IIA trials, which demonstrated no benefit or worse outcomes with immediate/early PCI after thrombolysis. ^51-53 For totally occluded vessels post-thrombolysis, the RESCUE I (Randomized Evaluation of Rescue PCI with Combined Utilization Endpoints) trial found lower incidence of death and severe congestive heart failure at 30 days with rescue PCI compared with conservative management (6.4% versus 16.6%; P = 0.5). ⁵⁴ Pooled data from the RESCUE I and Canadian trial demonstrated lower mortality with rescue PCI ( P = 0.001). ^55,56 Reduction in 30-day mortality was also demonstrated in the GUSTO III trial where abciximab was added to the rescue strategy (37% versus 9.8%; P = 0.04). ⁵⁷ For the partially occluded vessel post-thrombolysis, the nonrandomized TIMI 9B trial showed significantly ( P <0.05) lower readmission rate (14% versus 28%), less angina (18% versus 29%), and repeat MI (4% versus 9%), with a trend towards lower 60-day mortality rate (0.5% versus 2.8%; P = 0.12) with PCI during the index hospitalization compared to medical therapy. ⁵⁸

Many combinations of pharmacologic agents were studied as part of the FPCI strategy. The PACT trial, using
t-PA, 50 mg followed by PCI, showed patency (TIMI 2 or 3 flow) rate on arrival to the catheterization laboratory of 61% in the t-PA group compared with 34% with placebo. ⁵⁹ In the SPEED (Strategies for Patency Enhancement in the Emergency Department) study, half-dose reteplase (r-PA) given in two divided doses of 5 units in combination with abciximab achieved higher TIMI 3 flow (54%) than r-PA alone (47%) at 60- to 90-minute intervals. ⁶⁰ The TIMI 14 trial achieved 77% TIMI 3 flow rate at 90 minutes with half-dose t-PA plus abciximab. ⁶¹

The FPCI strategy has yet to be proved superior to transporting patients directly for primary PCI without giving prior thrombolytics. In the PRAGUE study, direct transportation group had lower primary endpoint (death, reinfarction, and stroke) at 30 days than thrombolytic therapy during transportation group or thrombolytic therapy in the community hospital group (8%, 15%, and 23%, respectively; P <0.02). ⁶² The study suggested that there might be more ventricular fibrillation during transportation of thrombolysed patients. FPCI is a promising revascularization strategy for AMI, but more support from clinical studies is needed.

Conclusion

ACS intervention continues to improve with innovative pharmacologic and mechanical approaches. Thienopyridine derivatives, GP IIb/IIIa antagonists, and LMWH can lower the incidence of adverse events and have become an integral part of ACS management. Early intervention in combination with these pharmacologic adjuvants and stenting leads to better outcomes, although the GP IIb/IIIa antagonist of choice remains a matter of debate.