American College of Cardiology

A. Experience With New Technologies

The introduction of coronary stents and atherectomy devices has broadened the scope of patients that can be approached by PCI beyond those that could be safely treated by PTCA alone. Directional coronary atherectomy successfully treats eccentric, ostial and proximal left anterior descending lesions or bifurcation lesions ⁽⁴⁴³⁾. Rotational atherectomy successfully treats calcific and diffusely diseased coronary vessels ⁽⁴⁴⁴⁾ and ostial stenoses ^(445,446). Excimer laser can be used successfully to treat diffuse diseases and fibrotic coronary stenoses ⁽⁴⁴⁷⁾. All atherectomy devices successfully remove or “debulk” plaque, allowing for improved acute angiographic results when followed by balloon angioplasty or stenting ⁽⁴⁴⁸⁾. Whether debulking before stenting reduces restenosis is currently under investigation.

Stenting has been successful in the initial treatment of SVGs previously not suitable for balloon angioplasty ⁽¹³⁹⁾. For total occlusions, excimer laser has not been shown to be significantly better than balloon angioplasty in terms of acute success or late outcomes ⁽⁴⁴⁹⁾.

1. Acute Results. Historically, one of the important limitations of balloon angioplasty has been its high rate of abrupt closure (4 to 7%) and less than optimal acute angiographic result (30% residual diameter stenosis with frequent evidence of dissections). Significant reduction in the acute complication rate for PTCA has resulted from the adjunctive use of glycoprotein receptor IIb/IIIa blockers, which have been shown to reduce abrupt closure and periprocedural MI rates compared to placebo. Improved acute outcomes (in terms of abrupt closure rates and reduced target lesion residual diameter stenosis) have also been seen with the use of coronary stents, DCA, and adjunctive rotational atherectomy ^{(31,32,34,450)}.

2. Late-Term Results. PCI devices offer the possibility of lower restenosis compared to PTCA in the native coronary circulation. Lower restenosis rates have been demonstrated for balloon-expandable slotted tubular stents in large (3 mm) native coronary arteries ^(31,32) but are variable depending on lesion length for SVG lesions ⁽¹³⁹⁾. Initial trials of DCA showed no benefit compared to balloon angioplasty for elective single lesion treatment ^(58,59). However, a trial using DCA in a more aggressive fashion to produce larger acute coronary lumens was associated with a lower angiographic restenosis rate, but did not show any significant improvement in clinical outcomes ⁽³⁴⁾.

Despite the improvement in acute results seen for rotational atherectomy and excimer laser, there is no evidence that these devices improve the late outcomes in lesions than can be feasibly treated by balloon angioplasty or stenting alone ^(450-452).

B. Antiplatelet and Antithrombotic Therapies and Coronary Angioplasty (Table 31)

1. Aspirin, Ticlopidine, Clopidogrel. Aspirin reduces the frequency of ischemic complications after coronary angioplasty. Although the minimum effective aspirin dosage in the setting of coronary angioplasty has not been established, an empiric dose of aspirin, 80-325 mg, given at least 2 h before the PCI procedure is generally recommended ⁽⁴⁵³⁾. While other antiplatelet agents have similar antiplatelet effects to aspirin ⁽⁴⁵⁴⁾, only the thienopyridine derivatives ⁽⁴⁵⁵⁾ ticlopidine and clopidogrel have been routinely used as alternative antiplatelet agents in aspirin-sensitive patients during coronary angioplasty. In elective settings, ideally ticlopidine and clopidogrel should be given for at least 72 h prior to the procedure in order to achieve maximum platelet inhibition ^(456,457).

Prior to the advent of potent combination antiplatelet therapy in recent years, enthusiasm for stenting during acute MI or unstable angina use was tempered by the sudden, and often unpredictable, occurrence of subacute stent thrombosis, which developed in 3.5 to 8.6% of stent-treated patients ^{(25,31,32,458)}. Anatomic factors (e.g., underdilation of the stent, proximal and distal dissections, poor inflow or outflow obstruction, <3 mm vessel diameter) were felt to predispose to the occurrence of subacute stent thrombosis in some patients ^{(423, 459, 460)}.

Several randomized trials have evaluated the efficacy of combination antiplatelet therapy in patients undergoing urgent and elective stent implantation. In the ISAR trial of 517 patients treated with Palmaz-Schatz (PS) stents for acute MI, suboptimal angioplasty, or other “high-risk” clinical and anatomic features, patients were randomly assigned to treatment with aspirin + ticlopidine or aspirin, intravenous heparin, and phenprocoumon after successful stent placement ⁽⁴⁶¹⁾. The primary endpoint of cardiac death, MI, coronary bypass surgery, or repeat angioplasty occurred in 1.5% of patients assigned to antiplatelet therapy and 6.2% of those assigned to anticoagulant therapy (relative risk, 0.25; 95% confidence interval, 0.06 to 0.77) ⁽⁴⁶¹⁾. In another randomized trial of antiplatelet (aspirin + ticlopidine) versus anticoagulant (aspirin + warfarin) therapy in high-risk patients (suboptimal or multiple stent deployment), antiplatelet therapy was again associated with a reduction in the composite occurrence of death, MI, and urgent repeat revascularization (5.6% vs. 11%; p = 0.07) and in major bleeding or vascular complications (1.7% vs. 6.9%) compared with anticoagulation therapy respectively ⁽⁴⁶²⁾.

In the STARS trial ⁽³⁰⁾, the efficacy of aspirin (325 mg daily), the combination of aspirin (325 mg daily) + ticlopidine (500 mg daily for 1 month), and aspirin (325 mg daily) + warfarin on ischemic endpoints at 30 days in 1653 in “low-risk” patients after “optimal” PS stent placement demonstrated more adverse events in patients not receiving ticlopidine as part of the therapeutic regimen. The primary 30-day composite endpoint of death, target lesion revascularization, subacute thrombosis, or MI was 3.6% in patients only assigned to aspirin, 2.7% assigned to aspirin + warfarin, compared to 0.5% in those assigned to aspirin + ticlopidine (aspirin + ticlopidine vs. aspirin alone; p < 0.001; aspirin + ticlopidine vs. aspirin + warfarin; p = 0.014) ⁽³⁰⁾. Pretreatment with ticlopidine for more than 24 h may allow more effective inhibition of platelet activation than shorter durations of therapy ^(456,463).

Ticlopidine has a number of important side effects, including gastrointestinal distress (20%) ⁽⁴⁶⁴⁾, cutaneous rashes (4.8 to 15%) ⁽⁴⁶⁴⁾, and abnormal liver function tests ⁽⁴⁶⁴⁾. The most severe side effect is severe neutropenia, occurring in approximately 1% of patients ^(464,465). Ticlopidine-induced neutropenia is generally reversible after its discontinuation ⁽⁴⁶⁶⁾, although infrequent episodes of sepsis and death have been reported. Rare (< 1:1000), but fatal, episodes of thrombotic thrombocytopenic purpura have also been reported ^(467-469), and patients receiving ticlopidine should be monitored for the occurrence of this untoward sequelae. Shorter durations (10-14 days) of ticlopidine therapy may reduce untoward side effects of therapy while maintaining therapeutic efficacy ^(470,471).

Clopidogrel, 300 mg loading dose followed by 75 mg daily, may be used as an alternative to ticlopidine in patients undergoing stent placement. A number of nonrandomized trials ^(472-474) and a randomized trial ⁽⁴⁷⁵⁾ have failed to show a difference in the clinical outcomes among patients treated with ticlopidine and clopidogrel after stent placement. A small number of cases of thrombocytopenia purpura have been reported in patients treated with clopidogrel; therefore, patients should be monitored during treatment for occurrence of this untoward effect ⁽⁴⁶⁹⁾.

The routine use of warfarin is no longer recommended after stent implantation, unless there are other indications for its use, such as a poor LV function, atrial fibrillation, or mechanical heart valves.

2. Glycoprotein IIb/IIIa Inhibitors. Aspirin is only a partial inhibitor of platelet aggregation ^(476,477), as it affects only cycloxygenase, thereby preventing the formation of thromboxane A2. Functionally active glycoprotein (GP IIb/IIIa) receptors aggregate platelets through fibrin bound at the receptor sites. These receptors are activated by a variety of agonists, including thromboxane A², serotonin, ADP, and collagen, among others. The binding of fibrinogen and other adhesive proteins to adjacent platelets by means of the GP IIb/IIIa receptor serves as the “final common pathway” of platelet-thrombus formation and can be effectively attenuated by GP IIb/IIIa antagonists. These agents have reduced the frequency of ischemic complications after coronary angioplasty.

a. Abciximab. The clinical safety and efficacy of abciximab was evaluated in the Evaluation of 7E3 for the Prevention of Ischemic Complications (EPIC) Trial, which included 2099 patients with acute MI, refractory unstable angina, or “high-risk” clinical or anatomic features ⁽⁴⁷⁸⁾. Patients were randomly assigned to treatment with aspirin and fixed-dose heparin alone, aspirin, fixed-dose heparin, and a bolus of abciximab (0.25 mg per kg), or aspirin, fixed dose heparin, and a bolus of abciximab (0.25 mg per kg) + a 12-h abciximab infusion (10 µg per min). A 35% reduction in the frequency of the primary composite endpoint of death, nonfatal MI, repeat revascularization, and procedural failure resulting in stent or intra-aortic balloon pump placement was found in the patients given both the bolus + infusion abciximab compared with placebo-treated patients; (8.3% vs. 12.8%, p = 0.008) ⁽⁴⁷⁸⁾. The bolus of abciximab alone did not produce a significant reduction in ischemic events. The major effect of abciximab was a reduction in nonfatal MI (5.2% vs. 8.6% in placebo-treated patients; p = 0.013) and in the need for repeat coronary angioplasty (0.8% vs. 4.5% in placebo-treated patients; p < 0.001); these benefits were maintained for at least 3 years following the procedure ⁽⁴⁷⁹⁾. It should be noted that the reduction in ischemic complications in EPIC was offset by a doubling of the bleeding complication rate associated with non-weight-adjusted heparin use (14% vs. 7% in placebo-treated patients; p = 0.001), likely due to the fixed-dose heparin regimen used for the procedure.

The value of abciximab in patients undergoing primary angioplasty for acute MI was prospectively evaluated in a trial of 483 patients who were randomly assigned to therapy with abciximab or placebo ⁽⁴⁸⁰⁾. The 30-day composite endpoint of death, reinfarction, or urgent revascularization was reduced in patients treated with abciximab (5.8% vs. 11.2% in placebo-treated patients; p = 0.03), mostly due to a reduction in the need for urgent revascularization in patients treated with abciximab (1.8% vs. 5.6% in placebo-treated patients; p = 0.03) ⁽⁴⁸⁰⁾. There was also a reduction in the need for a “bailout” stent with abciximab (11.9% vs. 20.4% in placebo-treated patients; p = 0.031) ⁽⁴⁸⁰⁾.

The strategy of low-dose heparin and early sheath removal in conjunction with abciximab therapy in relatively “low-risk” patients undergoing coronary angioplasty was evaluated in the EPILOG Trial ⁽²⁷⁾. In this study, 2792 patients were randomly assigned to therapy with aspirin plus standard-dose weight-adjusted heparin and abciximab, or aspirin plus low-dose weight-adjusted heparin and abciximab, or aspirin plus standard-dose weight-adjusted heparin alone ⁽²⁷⁾. The 30-day major event rate was 11.7% in the placebo with standard-dose heparin group; 5.2% in the abciximab with low-dose heparin group (hazard ratio, 0.43; p < 0.001); and 5.4% in the abciximab with standard-dose heparin group (hazard ratio, 0.45; p < 0.001) ⁽²⁷⁾. The need for unplanned coronary stent use was also reduced in patients treated with abciximab ^(480,481). In EPILOG, there were no differences in major bleeding rates among the 3 groups although minor bleeding was more frequent among patients receiving abciximab with standard-dose heparin ⁽²⁷⁾.

To assess the role of GP IIb/IIIa blockade in the setting of elective stenting, the Evaluation of Platelet IIb/IIIa Inhibition in STENTing (EPISTENT) trial evaluated the effect of abciximab therapy among patients undergoing stenting or balloon angioplasty relative to the strategy of stenting alone. A total of 2399 patients were randomized to stenting plus placebo, balloon angioplasty plus abciximab, or the combination of stenting and abciximab. Stenting was performed using contemporary high-pressure implantation techniques, with ticlopidine administered for 4 weeks after the procedure. The primary endpoint of death, MI, or urgent repeat revascularization at 30 days was 10.8% in the stented plus placebo group, 6.9% in the angioplasty plus abciximab group (p = 0.007), and 5.1% in the stent plus abciximab group (p < 0.001) ⁽²⁸⁾. By 6 months, rates of repeat target-vessel revascularization were 10.6% in the stent plus placebo, 8.7% in the stent plus abciximab group (p = 0.22), and 15.4% in the angioplasty plus abciximab group (p = 0.005) ⁽⁸⁹⁾. In the predefined subgroup of patients with diabetes mellitus undergoing stenting, treatment with abciximab diminished rates of repeat target vessel revascularization by 51% compared with placebo (8.1% vs. 16.6%, p = 0.021). Angiographic results among diabetics enrolled in an angiographic substudy were concordant with the clinical outcome: minimal luminal diameters (MLDs) and net gain at 6-months follow-up were improved by abciximab with stenting compared with stenting alone. EPISTENT 1-year follow-up demonstrated a survival advantage in favor of abciximab in stented patients. Mortality at 1 year was 2.4% in stent and placebo patients and 1.0% in stent and abciximab patients (p = 0.037) ⁽⁴⁸²⁾.

Heeschen et al. ⁽⁴⁸³⁾, for the CAPTURE investigators, demonstrated that troponin-T but not C-reactive protein, was predictive of cardiac risk during the initial 72-h period when treating unstable angina patients with standard therapy or with abciximab. C-reactive protein was an independent predictor of both cardiac risk and repeated coronary revascularization during the 6-month follow-up. In a similar study, Hamm et al. ⁽⁴⁸⁴⁾, for the CAPTURE investigators, also reported that among the 1265 patients with unstable angina enrolled in the CAPTURE trial, troponin-T and CK-MB from 890 patients correlated with subsequent 6-month adverse cardiac risk. In patients without elevated troponin-T levels, there was no benefit of treatment with respect to the relative risk of death or myocardial infarction at 6 months (odds ratio 1.26, CI 95%, 0.74 to 2.31; p = 0.47). This study indicated that serum troponin-T level, which is considered to be a surrogate marker for thrombus formation, identified a high-risk subgroup of patients with refractory unstable angina suitable for coronary intervention who would particularly benefit from antiplatelet treatment with abciximab.

Patients requiring unplanned or “bailout” coronary stent deployment appear to be at especially high risk for the development of ischemic events early following stent deployment. In patients who required unplanned stent deployment in the EPILOG trial, the prophylactic administration of abciximab was associated with a reduction in the composite endpoint of death, MI, or urgent revascularization at 30 days (p < 0.001) and 6 months (p < 0.001) ⁽⁴⁸¹⁾. A subsequent analysis of 529 patients having unplanned coronary stent deployment in the EPILOG, EPIC, and CAPTURE trials demonstrated a reduction in mortality at 30 days (p = 0.04) ⁽⁴⁸¹⁾ in addition to reduction in the composite endpoint of death, MI, or urgent intervention at 30 days (p < 0.001) at 6 months (p = 0.002), in patients who had received prophylactic therapy with abciximab. These data suggest that prophylactic adjunctive platelet GP IIb/IIIa blockade improves the clinical outcomes of patients who require unplanned coronary stent deployment.

One putative limitation of abciximab is the potential for immune-mediated hypersensitivity reactions following subsequent readministration. With the first administration, human antichimeric antibodies (HACA) form in approximately 6% of patients ⁽⁴⁷⁸⁾. The implications of HACA, however, are unclear. Among 500 patients enrolled in the ReoPro Readministration Registry (R³), there were no cases of anaphylaxis or other allergic manifestations whether or not HACA was present, and HACA was not predictive of any other measure of complication or success. From the R³ Study, HACA has been shown to be an IgG (not IgE) immunoglobulin that does not neutralize abciximab. The more worrisome clinical phenomenon associated with readministration is the potential for increased rates of thrombocytopenia. In the 500-patient Registry, a 4.4% incidence in thrombocytopenia (to a platelet count of <100 X 10⁹/L) was observed, with half of the patients developing acute profound thrombocytopenia (to a platelet count of <20 X 10⁹/L). This potential complication should always be monitored when treating a patient with abciximab ^(485-488).

b. Eptifibatide. The clinical utility of eptifibatide, a short-acting cyclic heptapeptide that also inhibits the GP IIb/IIIa receptor, was evaluated in the Integrilin to Manage Platelet Aggregation to prevent Coronary Thrombosis-II (IMPACT-II) trial, a double-blind, randomized, placebo-controlled multicenter trial that enrolled 4010 patients undergoing coronary angioplasty ⁽⁴⁸⁹⁾. Patients were assigned to treatment with aspirin, heparin and placebo, aspirin, heparin and eptifibatide bolus (135 µg per kg) followed by a low-dose eptifibatide infusion (0.5 µg per kg per min for 20-24 h), or aspirin, heparin, and eptifibatide bolus (135 µg per kg) and higher dose infusion (0.75 µg per kg per min for 20-24 h) ⁽⁴⁸⁹⁾. The 30-day composite primary endpoint of death, MI, unplanned surgical or repeat percutaneous revascularization, or coronary stent implantation for abrupt closure occurred in 11.4% of placebo-treated patients compared with 9.2% in the 135/0.5 eptifibatide group (p = 0.063) and 9.9% in the 135/0.75 eptifibatide group (p = 0.22) ⁽⁴⁸⁹⁾. The frequency of major bleeding events and transfusions was similar among the three groups.

A higher bolus and infusion of eptifibatide was evaluated in 10,948 patients with unstable angina who were assigned to treatment with placebo or 1 of 2 doses of eptifibatide: 180 µg per kg bolus + 1.3 µg per kg per minute infusion (180/1.3) or 180 µg per kg bolus + 2.0 µg per kg per minute infusion (180/2.0) ⁽⁴⁹⁰⁾. Compared with placebo, patients receiving 180/2.0 eptifibatide had a lower frequency of 30-day death or MI (15.7% vs. 14.2%; p = 0.042). In patients undergoing early (<72 hrs) coronary intervention, 30-day composite events occurred less often in patients receiving 180/2.0 eptifibatide (11.6% and 16.7% in placebo-treated patients; p = 0.01) ^(491,492).

The ESPRIT (Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy) Trial evaluated the efficacy and safety of eptifibatide treatment as adjunctive therapy during nonemergency coronary stent implantation. A total of 2064 patients were enrolled from June 1999 to February 2000 in this multicenter, randomized, double-blind, parallel-group, placebo-controlled (crossover-permitted) clinical trial. A double-bolus regimen of eptifibatide (180 µg/kg bolus followed by a 2.0 µg/kg-min infusion, with a second 180 µg/kg bolus given 10 min after the first bolus) was compared to placebo treatment. The 48-h primary composite endpoint of death, MI, urgent target-vessel revascularization, or bailout treatment with open-label GP IIb/IIIa inhibitor therapy was reduced 37% from 10.5 to 6.6% (p = 0.0015). There was a consistent treatment benefit across all components of the endpoint as well as across all subgroups of patients. At 30 days, the key secondary composite endpoint of death, MI, and urgent large-vessel revascularization was also improved 35% from 10.4 to 6.8% (p=0.0034) ^(491,492).

c. Tirofiban. Tirofiban is a nonpeptidyl tyrosine derivative that produces a dose-dependent inhibition of GP IIb/IIIa mediated platelet aggregation ⁽⁴⁹³⁾. The clinical effect of tirofiban during coronary angioplasty was evaluated in the Randomized Efficacy Study of Tirofiban for Outcomes and Restenosis (RESTORE) Trial, a double-blind, placebo-controlled trial of 2139 patients with unstable angina pectoris or acute MI ⁽⁴⁹⁴⁾. Patients were randomly assigned to aspirin, heparin and a tirofiban bolus (10 µg per kg over 3 min) + infusion (0.15 µg per kg per minute), or to aspirin, heparin, and a placebo bolus + infusion for 36 h. The primary endpoint of the trial was the occurrence of major 30-day events, including death from any cause, MI, coronary bypass surgery due to angioplasty failure or recurrent ischemia, repeat target-vessel angioplasty for recurrent ischemia, or insertion of a stent due to threatened abrupt closure ⁽⁴⁹⁴⁾. The primary 30-day endpoint was reduced from 12.2% in the placebo group to 10.3% in the tirofiban group (p = 0.160). Patients treated with tirofiban had a 38% relative reduction in the composite end point at 48 h (p < 0.005), and a 27% relative reduction at 7 days (p = 0.022). The incidence of major bleeding was similar in the 2 groups using the Thrombolysis In Myocardial Infarction (TIMI) criteria (2.4% in tirofiban-treated patients and 2.1% in the placebo-treated patients; p = 0.662) ⁽⁴⁹⁴⁾, although major bleeding tended to be higher in tirofiban-treated patients (5.3% vs. 3.7% in the placebo-treated patients; p = 0.096), Thrombocytopenia was similar in both groups (0.9% for the placebo group vs. 1.1% for the tirofiban group; p = 0.709) ⁽⁴⁹⁴⁾. A larger clinical benefit with tirofiban was seen in patients with unstable angina undergoing coronary angioplasty in the PRISM-PLUS Study, a randomized trial of 1570 patients with unstable angina or non-Q-wave MI assigned to 48 to 108-h treatment with heparin + tirofiban or heparin alone ⁽⁴⁹⁵⁾. Coronary angioplasty was performed in 30.5% of patients between 49-96 h after randomization ⁽⁴⁹⁵⁾. The composite endpoint of death, MI, or refractory ischemia was significantly reduced in the heparin + tirofiban group or compared to the heparin alone group (10.0% vs. 15.7%; p < 0.01) ⁽⁴⁹⁵⁾.

Based on the numerous trials to date (Figure 4), intravenous GP IIb/IIIa receptor inhibitors should be considered in patients undergoing coronary angioplasty, particularly in those with unstable angina or with other clinical characteristics of high-risk. There is no consistent evidence that the GP IIb/IIIa inhibitors reduce the frequency of late restenosis in the non-diabetic patient. In EPISTENT (as noted previously), diabetic patients who received abciximab therapy in conjunction with stent deployment had a 51% reduction in target-vessel revascularization at 6 months ^{(133, 496)}. This trial is the only one that has shown a reduction in target-vessel revascularization in the diabetic group. It will be important to determine if supporting evidence is found from other trials using this agent and other GP IIb/IIIa antagonists.

3. Heparin. Intravenous unfractionated heparin prevents clot formation at the site of arterial injury ⁽⁴⁹⁸⁾ and on coronary guidewires and catheters used for coronary angioplasty ⁽⁴⁹⁹⁾. While the intensity of anticoagulation with unfractionated heparin is generally determined using activated partial thromoboplastin times (aPTTs), these values are less useful for monitoring anticoagulation during coronary angioplasty because higher levels of anticoagulation are needed than can be discriminated with the aPTT alone. Instead, the activated clotting time (ACT) has been more useful to follow heparin therapy during coronary angioplasty ⁽⁵⁰⁰⁾. The Hemochron and HemoTec devices are commonly used to measure ACT values during coronary angioplasty ^(500-502). The Hemochron ACT generally exceeds the Hemotech ACT by 30-50 s, although considerable measurement variability exists.

Empiric recommendations regarding heparin dosage during coronary angioplasty have been proposed ^(503,504), but ACT levels after a fixed dose of unfractionated heparin may vary substantially due to differences in body size ⁽⁵⁰⁵⁾, concomitant use of other medications, including intravenous nitroglycerin ^(506,507), and in the presence of acute coronary syndromes that increase heparin resistance.

The relationship between the level of the ACT and development of ischemic complications during coronary angioplasty has been controversial. Whereas some studies have identified an inverse relationship between the initial ACT and the risk of ischemic events ^(508,509), others found either no relationship or a direct relationship between the degree of anticoagulation and occurrence of complications ⁽⁵¹⁰⁾. It is generally felt that very high levels (ACTs >400 to 600 s) of periprocedural anticoagulation are associated with an increased risk for bleeding complications ⁽⁵¹¹⁾.

The safety of low-dose heparin during coronary angioplasty has also been shown in a recent study. Fatal complications (0.3%), emergency bypass surgery (1.7%), MI (3.3%), or repeat angioplasty within 48 h (0.7%) were uncommon after an empiric bolus of heparin 5,000 U at the beginning of the procedure ⁽⁵¹²⁾. In a smaller randomized study of 400 patients assigned to fixed-dose heparin (15,000 IU) or weight-adjusted heparin (100 IU per kg), there were no differences in procedural success or bleeding complications between the two groups ⁽⁵¹³⁾, although use of the weight-adjusted heparin resulted in earlier sheath removal and more rapid transfer to a stepdown unit ⁽⁵¹³⁾. Another advantage of weight-adjusted heparin dosing is that “overshooting” the ACT value can be avoided.

The results of these limited studies suggests that heparin is an important component for PCI, despite dosing uncertainties and an unpredictable therapeutic response with the unfractionated preparation. Higher levels of anticoagulation with heparin are roughly correlated with therapeutic efficacy in the reduction of complications during coronary angioplasty, albeit at the expense of bleeding complications at very high levels of heparin dosing. It appears that weight-adjusted heparin dosing may provide a clinically superior anticoagulation method over fixed heparin dosing, although definitive studies are lacking.

Routine use of unfractionated heparin after an uncomplicated coronary angioplasty is no longer recommended ^(53,514-517), and may be associated with more frequent bleeding events ^{(53, 514)}, particularly when platelet GP IIb/IIIa inhibitors are used ^{(53, 514)}. Subcutaneous administration of unfractionated heparin ⁽⁵¹⁵⁾ may provide a safer and less costly means of extending antithrombin therapy than intravenous unfractionated heparin, if there are clinical reasons to continue anticoagulation, such as residual thrombus or significant residual dissections.

Some patients with unstable angina are treated with low-molecular-weight heparin (LMWH) prior to coronary angioplasty ⁽⁵¹⁸⁾. Anticoagulation monitoring is not routinely possible with LMWH, and conventional dosages of unfractionated heparin are currently recommended. Conventional ACT monitoring methods may underestimate the true degree of periprocedural anticoagulation with LMWH. Use of LMWH as the sole anticoagulant during PCI is not supported at this time in the absence of absolute or relative contraindications to unfractionated heparin, although data from clinical trials of these agents administered alone or in conjunction with GP IIb/IIIa blockade are forthcoming.

a. Heparin Dosing Guidelines. In those patients who do not receive GP IIb/IIIa inhibitors, sufficient unfractionated heparin should be given during coronary angioplasty to achieve an ACT of 250 to 300 s with the HemoTec device and 300 to 350 s ^(491,492) with the Hemochron device. Weight-adjusted bolus heparin (70-100 IU per kg) can be used to avoid excess anticoagulation. If the target values for ACT are not achieved after a bolus of heparin, additional heparin boluses (2000-5000 IU) can be given. Early sheath removal should be performed when the ACT falls to less than 150-180 s.

The unfractionated heparin bolus should be reduced to 50-70 IU per kg when GP IIb/IIIa inhibitors are given in order to achieve a target ACT of 200 s using either the HemoTec or Hemochron device. Currently recommended Target ACT for eptifibatide and tirofiban is <300 s during coronary angioplasty. Postprocedural heparin infusions are not recommended during GP IIb/IIIa therapy ^(519-521).

C. Post-PCI Management

Following PCI, in-hospital care should focus on monitoring the patient for recurrent myocardial ischemia, achieving hemostasis at the catheter insertion site, and detecting and preventing contrast-induced renal failure. Attention should also be directed toward implementing appropriate secondary atherosclerosis prevention programs. The patient should understand and adhere to recommended medical therapies and behavior modifications known to reduce subsequent morbidity and mortality from coronary heart disease.

Most patients can be safely discharged from the hospital within 24 h after an uncomplicated elective PCI. Special skilled nursing units have been developed by many institutions to facilitate post-PCI management. Specific protocols for sheath removal, continuation of anticoagulation or antiplatelet therapies, and observation for recurrent myocardial ischemia/infarction and contrast-induced renal failure are of particular assistance in ensuring appropriate outcomes during this period. Pilot studies suggest that selected patients may be discharged on the same day after PCI ^(522,523) especially when the procedure is performed by the percutaneous radial or brachial approach. However, confirmation by larger studies is necessary prior to widespread endorsement of this strategy.

In the prior setting of aggressive systemic anticoagulation, vascular complications may occur in as many as 14% of patients after PCI, but those requiring surgical repair occur in 3.5% ⁽⁵¹¹⁾ of patients, although lower rates of vascular complications can now be expected with reduced anticoagulation and smaller sheath sizes ^(524-529). Major factors associated with vascular complications include use of thrombolytic or platelet inhibitor therapy, coexisting peripheral vascular disease, female gender, prolonged heparin use with delayed sheath removal, and older age ^{(511,525,527-531)}. Although most bleeding complications at the vascular access site are obvious and readily managed, physicians and nurses should remain alert for retroperitoneal hematoma, the signs and symptoms of which may include hypotension, marked suprainguinal tenderness, and severe back or lower quadrant abdominal pain ⁽⁵³²⁾. Post-PCI hematocrit should be monitored for a decrease >5 to 6%. Computed tomography can confirm the diagnosis of retroperitoneal hematoma, and >80% of patients can be treated conservatively using transfusions without surgery ⁽⁵³¹⁾. Pseudoaneurysms may be treated effectively with ultrasound-directed compression in the majority of patients who are not bleeding and do not require continued anticoagulation ^{(530,533,534)}. Arteriovenous fistulas, generally occurring late after a procedure, are detected by a continuous murmur over the puncture site and, in rare cases, may be associated with high output failure. Both pseudoaneurysm and arteriovenous fistula can occur secondary to cannulation of the superficial rather than the common femoral artery ⁽⁵³⁵⁾. Newer arterial compression systems and percutaneous vascular closure devices hold promise to reduce the incidence of vascular complications. However, the degree to which these technologies reduce length of hospital stay, and cost remains to be determined ^{(531,536-538)}.

1. Post-Procedure Evaluation of Ischemia. After PCI, chest pain may occur in as many as 50% of patients. ECG evidence of ischemia identifies those with significant risk for acute vessel closure ^{(5,93,96,97,539-541)}. When angina pectoris or ischemic ECG changes occur after PCI, the decision to proceed with further interventional procedures, CABG surgery, or medical therapy should be individualized based on factors such as hemodynamic stability, amount of myocardium at risk and the likelihood that the treatment will be successful.

A 12-lead ECG should be obtained before and immediately after PCI, and again if symptoms should occur. Angina-like symptoms with ECG changes will assist in deciding upon the need for repeat angiography and for additional therapy.

As discussed elsewhere in this document, coronary stents and platelet glycoprotein receptor inhibitors have significantly reduced the incidence of acute closure. Factors that correlate with a poor outcome after acute coronary closure include age 70 years, large ischemic burden, presentation with ACS, and LV ejection fraction 30% ^(539-541).

Elevated levels of CK or the MB subfraction (CK-MB), or ECG abnormalities are reported to occur in 5 to 30% of patients after PCI ⁽²⁰⁾. The mechanisms associated with CK release include side branch occlusion, distal embolization, intimal dissection, and coronary spasm ⁽⁵⁴²⁾. A more frequent requirement for revascularization procedures and a higher risk of death or subsequent MI are associated with elevated cardiac enzymes, increasing as a continuous function with no obvious threshold effect. Both acute and chronic complications are higher among patients with elevated enzymes. Even in patients with low-level elevations of CK-MB where the in-hospital risk is low, the intermediate- and long-term risks are also increased. Post-procedural increases in CK and CK-MB are not specific for a particular technique and have been reported after balloon angioplasty, directional and rotablator atherectomy, excimer laser angioplasty, and stent placement. Kong et al. ⁽⁵⁴³⁾ found increased levels of CK are a significant independent predictor of cardiac mortality and subsequent MI ⁽³⁶³⁾. Cardiac mortality after elective PCI was significantly higher for patients with high (>3.0 times normal) and intermediate CK (1.5 to 3.0 times normal) compared with low CK (>1.0 to <1.5 times normal) elevations and control patients (p = 0.007).

CK and CK-MB should be obtained in patients with suspected ischemia (prolonged chest pain, side branch occlusion, recurrent ischemia, hemodynamic instability) during PCI. Ideally, the ESC/ACC recommends that small infarcts may and should be detected by serial blood sampling and analysis before and after the procedure (6 to 8 h and 24 h, respectively) ⁽⁵⁴⁴⁾. In patients in whom a clinically-driven CK-MB determination is made, a CK-MB index increase of >3 times the upper limit of normal should be treated as having a MI and be recommended for further observation. The results of CK-MB should be considered for the discharge management strategies for these patients.

The Troponin isoforms TnI and TnT have a high level of sensitivity and specificity for the diagnosis of acute MI. However, the clinical significance of elevated TnT or TnI after PCI procedures has not been widely investigated, and further studies are necessary to establish the clinical utility of these MI markers.

Patients with renal dysfunction and diabetes should be monitored for contrast-induced nephropathy. In addition, those patients receiving higher contrast loads or a second contrast load within 72 h should have renal function assessed. Whenever possible, nephrotoxic drugs (certain antibiotics, nonsteroidal anti-inflammatory agents, and cyclosporine) and metformin (especially in those with pre-existing renal dysfunction) should be withheld for 24 to 48 h prior to performing PCI and for 48 h afterwards ⁽⁵⁴⁵⁾.

2. Risk-Factor Modifications. All patients should be instructed about necessary behavior and risk-factor modification and the appropriate medical therapies for the secondary prevention of atherosclerosis prior to leaving the hospital. The interventional cardiologist should emphasize the importance of these measures directly to the patient as failure to do so may suggest that secondary prevention therapies are not necessary. The interventional cardiologist should interact with the primary care physician to assure that necessary secondary prevention therapies are initiated and maintained. Secondary prevention measures are an essential part of long-term therapy because they can reduce future morbidity and mortality associated with the atherosclerotic process.

Depending on the risk factors and contraindications present, advice should include aspirin therapy, hypertensive control, diabetic management, aggressive control of serum lipids to a target LDL goal <100 mgm/dL following AHA guidelines, abstinence from tobacco use, weight control, regular exercise, and ACE Inhibitor therapy for those with LV dysfunction (LVEF <0.40) as recommended in the AHA/ACC consensus statement on secondary prevention (Figure 5). Given the nature and natural history of CAD among patients undergoing PCI, with the exception of those patients intolerant to the agents, the clinically indicated secondary prevention measures which usually include ASA, statin therapy, and ACE inhibitors, should be continued indefinitely ^(546-548). Patients should receive instructions on the timing of return to full activities and be informed to contact their physician or seek immediate medical attention if symptoms recur.

3. Exercise Testing After PCI. The published ACC/AHA practice guidelines for exercise testing ⁽⁵⁴⁹⁾ provide an excellent summary of the available information on exercise testing after PTCA. Although restenosis remains the major limitation of PCI, symptom status is an unreliable index to development of restenosis with 25% of asymptomatic patients documented as having ischemia on exercise testing ⁽⁵⁵⁰⁾.

To identify restenosis rather than predict the probability of its occurrence, patients may be tested later (3 to 6 months after PCI). Table 32 reviews the predictive value of exercise testing for restenosis ^(551-558). Variability is attributed predominantly to differences in the populations studied and criteria for restenosis.

Because myocardial ischemia, whether painful or silent, worsens prognosis ⁽⁵⁵⁹⁾, some authorities have advocated routine testing. However, the ACC/AHA practice guidelines for exercise testing favor selective evaluation in patients considered to be at particularly high risk (e.g., patients with decreased LV function, multivessel CAD, proximal left anterior descending disease, previous sudden death, diabetes mellitus, hazardous occupations, and suboptimal PCI results). The exercise ECG is an insensitive predictor of restenosis, with sensitivities ranging from 40 to 55%, significantly less than those obtainable with SPECT ^(560,561) or exercise echocardiography ^(562,563). This lower sensitivity of the exercise ECG and its inability to localize disease limits its usefulness in patient management both before and after PCI ^{(552,564,565)}. For those reasons, stress imaging is preferred to evaluate symptomatic patients after PCI. If the patient's exertional capacity is significantly limited, coronary angiography may be more expeditious to evaluate symptoms of typical angina. Exercise testing after discharge is helpful for activity counseling and/or exercise training as part of cardiac rehabilitation. Neither exercise testing nor radionuclide imaging is indicated for the routine, periodic monitoring of asymptomatic patients after PCI without specific indications.