DESARROLLO ÁGIL

An important advance in the treatment of patients with UA/NSTEMI who are undergoing PCI was the introduc- tion of platelet GP IIb/IIIa receptor inhibitors in the 1990s (see Section 3.2) (126,128,130,510 –512,604 – 606). This therapy takes advantage of the fact that platelets play an important role in the development of ischemic complica- tions that can occur in patients with UA/NSTEMI or during coronary revascularization procedures. Currently, 3 platelet GP IIb/IIIa inhibitors are approved by the Food and Drug Administration on the basis of the outcomes of a variety of placebo-controlled clinical trials: abciximab, tiro- fiban, and eptifibatide. The EPIC (510), EPILOG (511), CAPTURE (372), and EPISTENT (512) trials investi- gated the use of abciximab; the PRISM (374), PRISM- PLUS (130), and Randomized Efficacy Study of Tirofiban for Outcomes and REstenosis (RESTORE) (518) trials evaluated tirofiban; and the Integrilin to Minimize Platelet

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Aggregation and Coronary Thrombosis (IMPACT) (517), PURSUIT (128), and Enhanced Suppression of Platelet Receptor GP IIb/IIIa using Integrilin Therapy (ESPRIT) (519) trials studied the use of eptifibatide (Table 18). All 3 of these agents interfere with the final common pathway for platelet aggregation. All have shown efficacy in reducing the incidence of ischemic complications in patients with UA/ NSTEMI (Fig. 16).

In the only head-to-head comparison of 2 GP IIb/IIIa inhibitors, the TARGET trial randomized 5,308 patients to tirofiban or abciximab before undergoing PCI with the intent to perform stenting (515). The primary end point, a composite of death, nonfatal MI, or urgent target-vessel revascularization at 30 d, occurred less frequently in those receiving abciximab than in those given tirofiban (6.0% vs. 7.6%, p ⫽ 0.038). There was a similar direction and magnitude for each component of the end point. Differ- ences in outcome between the 2 randomized treatment groups were particularly marked among patients with UA/ NSTEMI (63% of patients), in whom 30-d composite end point event rates were 9.3% with tirofiban versus 6.3% with abciximab (p⫽0.002). Although this finding is subject to the limitations of subgroup analysis, it suggests that any differences in efficacy between GP IIb/IIIa inhibitors might be most apparent among patients undergoing PCI in the setting of UA/NSTEMI. Inferior efficacy observed with tirofiban in this trial might have been related to inadequate initial (loading) dosing, which was subsequently demon- strated to result in platelet inhibition that was inadequate (only 28% to 33% early platelet inhibition) and less than that achieved with abciximab (65% to 81%) (516). A subsequent study evaluating a higher bolus dose of tirofiban (25 mcg per kg) during PCI was unfortunately discontinued prematurely because of funding issues. Eptifibatide has not been compared directly to either abciximab or tirofiban.

The question of whether GP IIb/IIIa inhibition is still useful in UA/NSTEMI patients undergoing PCI who have received a high loading dose (600 mg) of clopidogrel was raised by a study in CAD patients treated in an elective setting (607). To address this, 2,022 patients with UA/ NSTEMI undergoing PCI were loaded with clopidogrel, 600 mg, at least 2 h before the procedure and then randomized to receive either abciximab or placebo (ISAR- REACT 2) (244). The primary end point of death, nonfatal reinfarction, or urgent target-vessel revascularization within 30 d was reached in 8.9% of patients assigned to abciximab versus 11.9% assigned to placebo, a 25% difference, and was limited entirely to patients with an elevated troponin level, in whom the incidence of a primary event was 13.1% in the abciximab group compared with 18.3% in the placebo group (p ⫽ 0.02). Bleeding risks were similar in the 2 groups. Thus, GP IIb/IIIa inhibition provides incremental benefit beyond high-oral-dose clopidogrel loading for NSTEMI patients with elevated cardiac biomarker levels but not for UA patients with normal levels who are undergoing PCI.

In summary, data from both retrospective observations and randomized clinical trials indicate that PCI can lead to angiographic success in most patients with UA/NSTEMI (Table 18). The safety of these procedures in these patients is enhanced by the addition of intravenous platelet GP IIb/IIIa receptor inhibitors to the standard regimen of ASA, anticoagulants, clopidogrel, and anti-ischemic medications.

4.4. Surgical Revascularization

A meta-analysis of 6 trials conducted during the early years of CABG (between 1972 and 1978) documented a clear survival advantage for CABG over medical therapy in symptomatic patients with left main and 3-vessel coronary

disease that was independent of LV function (322). No

survival difference was documented between the 2 therapies for patients with 1- or 2-vessel coronary disease. However, dramatic changes in both surgical technique (including internal thoracic artery grafting to the LAD) and in medical therapy (e.g., potent anticoagulant and antiplatelet thera- pies) have subsequently occurred. Pocock et al. (608) per- formed a meta-analysis on the results of 8 randomized trials completed between 1986 and 1993 and compared the outcomes of CABG and PTCA in 3,371 patients with multivessel CAD before widespread stent use. Many of these patients presented with UA. At 1-year follow-up, no difference was documented between the 2 therapies in cardiac death or MI, but a lower incidence of angina and need for revascularization was associated with CABG.

The Bypass Angioplasty Revascularization Investigation (BARI) trial, the largest randomized comparison of CABG and PTCA, was performed in 1,829 patients with 2- or 3-vessel CAD (609,610). Unstable angina was the admit- ting diagnosis in 64% of these patients, and 19% had treated diabetes mellitus. A statistically significant advantage in survival without MI independent of the severity of present- ing symptoms was observed for CABG over PCI at 7 years (84.4% vs. 80.9%, p ⫽ 0.04) (611). Subgroup analysis demonstrated that the survival benefit was confined to patients with treated diabetes mellitus (76.4% with CABG compared with 55.7% for patients treated with PTCA,p⫽ 0.001). The Coronary Angioplasty versus Bypass Revascu- larization Investigation (CABRI) trial also showed a sur- vival benefit for CABG in patients with diabetes mellitus with multivessel CAD (612). A confirmatory study from Emory University showed that with correction for baseline differences, patients requiring insulin with multivessel dis- ease had improved survival with CABG versus PTCA (613) (see Section 6.2).

A large patient registry of consecutive CAD compared the 5-year survival rates for medical treatment, PTCA, and CABG between 1984 and 1990 (584). Patients with 3- or 2-vessel disease with a proximal severe (greater than or equal to 95%) LAD stenosis treated with CABG had significantly better 5-year survival rates than did those who received medical treatment or PTCA. In patients with less severe 2-vessel CAD or with 1-vessel CAD, either form of

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revascularization improved survival relative to medical ther- apy. The 2 revascularization treatments were equivalent for patients with nonsevere 2-vessel disease. Percutaneous transluminal coronary angioplasty provided better survival rates than CABG in patients with 1-vessel disease, except for those with severe proximal LAD stenosis, for whom the 2 revascularization strategies were equivalent. However, in patients with single-vessel disease, all therapies were asso- ciated with high 5-year survival rates, and the differences among the treatment groups were very small.

Hannan et al. (585) compared 3-year risk-adjusted sur-

vival rates in 29,646 CABG patients and 29,930 PTCA patients undergoing revascularization in the state of New York in 1993, adjusted for differences in baseline and angiographic characteristics. The anatomic extent of disease was the only variable that interacted with the specific revascularization therapy that influenced long-term survival. Unstable angina or diabetes mellitus did not result in treatment-related differences in long-term survival rates. Patients with single-vessel disease not involving the LAD or with less than 70% LAD stenosis had higher adjusted 3-year survival rates with PTCA (95.3%) than with CABG (92.4%). Patients with proximal LAD stenosis of at least 70% had higher adjusted 3-year survival rates with CABG than with PTCA regardless of the number of diseased coronary vessels. Patients with 3-vessel disease had higher adjusted 3-year survival rates with CABG regardless of proximal LAD disease. Patients with other 1- or 2-vessel disease had no treatment-related difference in survival rates. The 3-year reintervention rate was significantly higher in the PCI group than in the CABG group both for subse- quent CABG (10.4% vs. 0.5%) and for subsequent PCI (26.6% vs. 2.8%).

Hannan et al. performed a follow-up study using the same New York State cardiac registries to compare the outcomes of 37,212 patients who underwent CABG with 22,102 patients who underwent PCI using stents (614). The maximum follow-up was more than 3 years in each group. Patients were divided into 5 anatomic groups; 2-vessel disease without LAD disease; 2-vessel disease with proximal LAD disease; 2-vessel disease with nonproximal LAD disease; 3-vessel disease with proximal LAD disease; and 3-vessel disease with nonproximal LAD disease. Patients with single-vessel disease were generally treated with PCI. The unanticipated finding was that the risk-adjusted long- term mortality of patients in all 5 subsets was lower in the CABG group. The HR for death after CABG compared with stent implantation ranged from a low of 0.64 (95% CI 0.56 to 0.74) for patients with 3-vessel disease and proximal LAD disease to a high of 0.76 (95% CI 0.60 to 0.96) for patients with 2-vessel disease with involvement of the nonproximal LAD. The risk of long-term mortality also was lower with CABG for patients with diabetes in each of these anatomic subsets, with HRs ranging from 0.59 to 0.69. In all but the subset of patients with 2-vessel disease without LAD disease, the increase in mortality associated

with PCI compared with CABG was significant for patients with diabetes. The lack of significance in this subset likely reflected smaller numbers of patients (CABG plus PCI combined). In this study (614), as in the earlier study by Hannan et al. (585), the 3-year reintervention rate was significantly higher in the PCI group than in the CABG group for both subsequent CABG (7.8% vs. 0.3%) and subsequent PCI (27.3% vs. 4.6%). In contrast, the random- ized trials of multivessel disease have shown no differences in patients without diabetes. These disparate results could be due to adverse selection biases for PCI. On the other hand, the registry is very large and included a broad range of angiographic characteristics not included in the randomized trials. Consistently, however, the location of a coronary stenosis in the LAD, especially if severe and proximal, is a characteristic associated with higher mortality rates and with a favorable outcome with CABG.

The BARI and CABRI randomized trials appeared to identify a subset of diabetic patients who had a better outcome with CABG than with PTCA, a finding not observed in earlier cohort studies (609,610,612) but con- firmed in a more recent cohort study that exclusively used stents in the PCI group (614). Analysis of the subgroup with diabetes was retrospective in both the BARI and CABRI trials. Moreover, the treatment-related effect was not reproduced in the BARI registry population (615). A reasonable explanation for these inconsistent results is that physicians might be able to recognize characteristics of CAD in diabetic patients that permit patients to more safely undergo one or the other revascularization therapy. How- ever, when all patients with diabetes are randomly assigned to therapies without the added insight of clinical judgment, a treatment advantage is apparent for CABG. Given the combination of data derived from randomized trials and more recent cohort studies comparing PCI using stents with CABG, it is reasonable to consider CABG as the preferred revascularization strategy for most patients with 3-vessel disease, especially if it involves the proximal LAD, and for patients with multivessel disease and treated diabetes mel- litus or LV dysfunction. Alternatively, it would be unwise to deny the advantages of PCI to a patient with diabetes and less severe coronary disease on the basis of the current information. In addition, the use of GP IIb/IIIa inhibitors together with PCI for UA/NSTEMI in recent years appears to have resulted in more favorable outcomes (133,616).

An important consideration in a comparison of different revascularization strategies is that none of the large random- ized trials reflect the current practice of interventional cardiology that includes the routine use of stents, with an increasing use of DES, and the increasing use of platelet receptor inhibitors. Coronary stenting improves procedural safety, and DES reduce restenosis compared with PTCA or bare-metal stents. The adjuvant use of platelet inhibitors, particularly in high-risk patients, is also associated with improved short- and intermediate-term outcomes. Al- though the effects of DES and platelet GP IIb/IIIa inhib-

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itors could have improved the PCI results observed, their added benefit relative to CABG cannot be assumed or assessed on the basis of the previously reported randomized trials or large registries. Meanwhile, refinement of surgical management with right internal mammary artery grafts, radial artery grafts, improved myocardial protection strate- gies, and less invasive methodology could have reduced the morbidity and mortality rates for CABG. In fact, the risk-adjusted mortality for CABG has declined progres- sively during the last decade based on data derived from the

STS National Adult Cardiac Database (617).

The most recent comparisons of PCI and CABG surgery, relevant to current medical practice, can be summarized as follows: In a randomized study of patients with medically refractory myocardial ischemia at high risk of adverse outcomes of CABG surgery (the Angina With Extremely Serious Operative Mortality Evaluation [AWESOME] trial), there was comparable survival with traditional CABG surgery and PCI, which included stenting or atherectomy (618). A meta-analysis of CABG versus stenting for the treatment of multivessel disease (619) included patients in the randomized trials Arterial Revascularization Therapy Study (ARTS), Stent or Surgery (SoS), Estudio Random- izado Argentino de Angioplastia vs. CIrugia-II (ERACI- II), and Multicenter Anti Atherosclerotic Study-II (MASS- II) (620 – 624). ERACI-II included a cohort in which 92% of the patients had UA; patients in the SoS study did not have apparent recent acute events; patients in MASS-II had stable angina and preserved ventricular function; and those in ARTS (with 5-year follow-up data) were not specifically described. However, these trials, which enrolled patients between 1995 and 2000 and primarily used traditional on-pump CABG surgery and PCI with bare-metal stents, showed no difference in the primary composite end point of death, MI, and stroke and no difference in mortality between the CABG and the stent groups. The ARTS trial, which included but was not limited to patients with UA, randomized patients with multivessel disease to coronary stenting versus CABG. Three-year survival rates without stroke and MI were identical in both groups.

Nevertheless, evolutionary changes in revascularization therapy require randomized trials that incorporate the most contemporary therapies. Off-pump CABG and PCI with DES are 2 examples. Indeed, not all evolutionary changes in therapy have shown net incremental clinical benefits. Ran- domized trial data suggest that coronary graft patency rates are somewhat lower with off-pump CABG (625). The use of DES has not decreased the occurrence of death or MI compared with bare-metal stents, and DES are subject to a small increase in the rate of late (greater than 6-month, off-dual-platelet antagonism) stent thrombotic complica- tions and thrombosis-related clinical events (399,400,402, 403,411,626). Further complicating the picture, ASA and clopidogrel and other medical therapies are increasingly utilized in patients after CABG (627), which makes com- parisons of medical, PCI, and surgical therapy challenging.

The requirement for long-term follow-up and the need for adequate statistical power add to the difficulty in defining the unique benefits of each of the available forms of therapy separately. In summary, it cannot be assumed that all evolutionary changes in these therapies will have a beneficial impact on long-term outcomes, and clinical judgment in treatment selection for individual patients and a conserva- tive approach to new therapies are indicated.

4.5. Conclusions

In general, the indications for PCI and CABG in UA/

NSTEMI are similar to those for stable angina (628–633).

High-risk patients with LV systolic dysfunction, patients with diabetes mellitus, and those with 2-vessel disease with severe proximal LAD involvement or severe 3-vessel or left main disease should be considered for CABG (Fig. 20). Many other patients will have less severe CAD that does not put them at high risk for cardiac death. However, even less severe disease can have a substantial negative impact on the quality of life. Compared with high-risk patients, low-risk patients will have negligibly increased chances of long-term survival with CABG (or PCI) and therefore should be managed medically. How- ever, in low-risk patients, quality of life and patient preferences may be considered in addition to strict clinical outcomes in the selection of a treatment strategy. Low-risk patients whose symptoms do not respond well to maximal medical therapy and who experience a significant negative impact on their quality of life and functional status should be considered for revascularization. Patients in this group who are unwilling to accept the increased short-term procedural risks to gain long- term benefits or who are satisfied with their existing capabilities should be managed medically at first and followed up carefully as outpatients. Other patients who are willing to accept the risks of revascularization and who want to improve their functional status or to decrease symptoms may be considered appropriate candidates for early revascularization.

5. Late Hospital Care, Hospital Discharge, and Post-Hospital Discharge Care

The acute phase of UA/NSTEMI is usually over within 2 months. The risk of progression to MI or the development of recurrent MI or death is highest during that period. At 1 to 3 months after the acute phase, most patients resume a clinical course similar to that in patients with chronic stable coronary disease.

The broad goals during the hospital discharge phase are 2-fold: 1) to prepare the patient for normal activities to the extent possible and 2) to use the acute event as an opportunity to reevaluate the plan of care, particularly lifestyle and risk factor modification. Aggressive risk factor modifications that can prolong survival should be the main goals of long-term management of stable CAD. Patients who have undergone successful PCI with an uncomplicated course are usually discharged the next day,

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and patients who undergo uncomplicated CABG are generally discharged 4 to 7 d after CABG. Medical management of low-risk patients after noninvasive stress testing and coronary angiography can typically be accom- plished rapidly, with discharge soon after testing. Med- ical management of a high-risk group of patients who are unsuitable for or unwilling to undergo revascularization could require vigilant inpatient monitoring in order to achieve adequate ischemic symptom control with medical therapy that will minimize future morbidity and mortality and improve quality of life.

5.1. Medical Regimen and Use of Medications

RECOMMENDATIONS

CLASS I

1. Medications required in the hospital to control ischemia should be continued after hospital discharge in patients with UA/NSTEMI who do not undergo coronary revascularization, patients with unsuccess- ful revascularization, and patients with recurrent symptoms after