VIEWPOINT AND COMMENTARY
Clinical Guidelines and Practice
In Search of the Truth
Dean J. Kereiakes, MD, FACC1,*,* and
Elliott M. Antman, MD, FACC
* Heart Center of Greater Cincinnati and the Lindner Center at the Christ Hospital, Cincinnati, Ohio
Brigham and Women’s Hospital, Boston, Massachusetts
Manuscript received January 18, 2006;
revised manuscript received March 23, 2006,
accepted March 30, 2006.
* Reprint requests and correspondence: Dr. Dean J. Kereiakes, The Lindner Center, 2123 Auburn Avenue, Suite 424, Cincinnati, Ohio 45219. (Email: lindner{at}fuse.net).
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Abstract
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Data from randomized clinical trials, non-randomized studies, and registries, as well as expert panel consensus are appropriately weighted and woven into the context of clinical practice guidelines. Recent guidelines for the care of patients with ischemic heart disease have emphasized both risk stratification and early coronary angiography with revascularization of patients with high-risk indicators. Advances in our understanding of the pathogenesis of acute coronary syndromes and the dynamics of therapeutic innovation (improvement in catheter-based technologies and adjunctive pharmacotherapy) mandate the timely update and revision of practice guidelines. We believe that the weight of evidence remains clearly in support of an early invasive treatment strategy based on risk stratification. Arguments regarding treatment strategy (invasive vs. conservative) are misguided, and greater focus should be placed on improving the treatment-risk paradox demonstrated in clinical practice as well as on strategies to enhance current guideline compliance and utilization. Interest exists in establishing regional centers of excellence for care of patients with acute ischemic heart disease, analogous to the regionalized approach already established for patients with trauma or stroke. This approach is supported by data that demonstrate an inverse relationship between both institutional and operator procedural volumes and mortality, as well as by existing constraints in resources such as specialized nurses and subspecialty-trained physicians. It is appropriate at this time to briefly review specific aspects of the American College of Cardiology/American Heart Association practice guidelines and the current process of care for acute ischemic heart disease.
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Abbreviations and Acronyms
| | ACC = American College of Cardiology | | ACS = acute coronary syndrome | | AHA = American Heart Association | | CPG = clinical practice guideline | | DES = drug-eluting stents | | ECG = electrocardiogram | | GPI = glycoprotein IIb/IIIa inhibitor | | MI = myocardial infarction | | NSTEACS = non–ST-segment elevation acute coronary syndrome | | RCT = randomized clinical trial | | STEMI = ST-segment elevation myocardial infarction | | TIMI = Thrombolysis In Myocardial Infarction |
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The number of deaths in the U.S. from acute coronary syndrome (ACS) exceeds by 7-fold that for all-cause trauma in the general population, and for persons  65 years of age the number is 20-fold higher (1). Based on theory developed from discovery science and clinical observations, controlled clinical trials evaluate new therapies and strategies for treatment of specific patient populations. Clinical trial evidence drives the development of clinical practice guidelines (CPGs), which provide recommendations to define standards of care (2,3). Adherence to these standards may then be used to estimate quality as part of a systematic approach to the measurement of the process of care and outcomes.
In light of the rapidly evolving understanding of the pathogenesis of ACS, as well as the parallel evolution in catheter-based technology and adjunctive pharmacotherapy, it is appropriate to review the current CPGs that govern clinical practice for acute ischemic heart disease.
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Non–ST-segment elevation acute coronary syndrome (NSTEACS)
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Despite therapy with aspirin, unfractionated or low-molecular-weight heparin, nitrates, and beta-blockers, patients with NSTEACS remain at appreciable risk for death ( 6%), recurrent myocardial infarction (MI) (11%), or need for coronary revascularization (50% to 60%) for up to 1 year following diagnosis (4). In the era before coronary stenting and advances in adjunctive pharmacotherapy, CPGs promoted "conservatism" to avoid the "hazard" (periprocedural infarction, abrupt coronary closure) associated with early coronary revascularization. With procedural adjunctive platelet glycoprotein IIb/IIIa inhibitor (GPI) therapy to reduce periprocedural complications and coronary stents to minimize coronary occlusion, the benefit (vs. risk) of early percutaneous coronary intervention (PCI) was enhanced (5). Further benefit for reduction in periprocedural myocardial injury has been demonstrated following loading with oral clopidogrel (6) or preprocedural treatment with atorvastatin (7). The introduction of drug-eluting stents (DES) reduced angiographic and clinical restenosis following PCI in patients with ACS (8). Thus, the dynamics of therapeutic innovation make CPG recommendations a "moving target." Indeed, since publication of the most recent CPG for NSTEACS, considerable data have been presented on the prevalence, pathogenesis, and clinical relevance of clopidogrel non-responsiveness. Hypo- or non-responsiveness to clopidogrel has been demonstrated in 15% to 31% of patients undergoing PCI who receive the standard 300 mg oral loading dose (9,10) and has been correlated with the occurrence of adverse clinical events (11,12). Acceleration in the time course and extent of platelet inhibition and reduction in the prevalence of non-responsiveness accompany an increase in clopidogrel oral loading dose from 300 to 600 mg (13–15). Preliminary but as yet inconclusive data suggest that better clinical outcomes are also seen with higher oral loading doses of clopidogrel (6). In NSTEACS patients with an elevated troponin level (>0.03 µg/l) who received preprocedural clopidogrel 600 mg oral load, the addition of GP IIb/IIIa inhibition with abciximab was demonstrated to reduce periprocedural adverse outcomes (25% reduction in death, MI, and urgent target vessel revascularization to 30 days) (16). In addition, some data support the benefit of "upstream" initiation of platelet GPI therapy before PCI in NSTEACS (17,18). The earlier initiation of GPI therapy (upstream vs. in-cath lab) was associated with improvement in angiographic parameters of coronary flow and myocardial perfusion. Optimal cost efficacy (lowest cost per life-year gained) was observed for those patients at highest clinical risk, which suggests that the decision to use upstream GPI may need to be based on clinical risk stratification. Concomitant with technological advances, there have been improvements in the ability to assign risk to patients presenting with NSTEACS. The 2002 American College of Cardiology/American Heart Association (ACC/AHA) CPG update places considerable focus on risk stratification using a constellation of clinical, biochemical, and inflammatory markers to facilitate triage of appropriate patients to an optimal treatment strategy. The ACC/AHA CPG does not recommend indiscriminate utilization of invasive early revascularization therapy for NSTEACS, as the relative benefit of such treatment (vs. conservative evaluation) is directly proportional to patient risk profile. This benefit-risk relationship has been demonstrated for the Thrombolysis in Myocardial Infarction (TIMI) Study Group, PURSUIT (Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin), and GRACE (Global Registry of Acute Coronary Events) risk stratification schemes (19). However, both the ICTUS (Invasive versus Conservative Treatment in Unstable Coronary Syndromes) trial (20), which demonstrated no apparent benefit of a "routine" early invasive (vs. selectively invasive) treatment strategy in NSTEACS patients for reducing the composite clinical end point of death, non-fatal MI, or rehospitalization for angina to 1 year; as well as a meta-analysis of 7 randomized clinical trials (RCTs) (11), have questioned the advisability of an "early invasive" treatment strategy. We believe that the cumulative weight of data from RCTs continues to favor the invasive (vs. conservative) treatment strategy (Fig. 1). Furthermore, the ACC/AHA CPG clearly recommends risk assessment before triage for invasive treatment rather than a systematic or indiscriminate approach. Clearly, close scrutiny of the data is warranted.
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Figure 1 Randomized controlled trials of invasive versus conservative treatment strategies for unstable angina and non–ST-segment elevation myocardial infarction. The "weight" of evidence favors the invasive strategy. (Adapted from Cannon CP, et al. Circulation 2003;107:2640.)
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For example, despite the inclusion of trials performed with antiquated technology (Veterans Affairs Non-Q Wave Infarction Strategies In-Hospital, TIMI-IIIb), the meta-analysis of Mehta et al. (21) still demonstrates a highly significant (p < 0.001) reduction in the composite occurrence of death or MI following a routine (vs. selective) invasive treatment strategy for NSTEACS. In addition, questions have been raised regarding patient risk profile and study methodology in the ICTUS trial (22,23). The contention that a "high-risk population" was studied does not appear to be supported by the fact that <50% of patients were 65 years old, <15% had diabetes, <50% had ST-segment deviation of 0.1 mV on electrocardiogram (ECG), and 20% had troponin levels <0.10. Indeed, despite the fact that ischemia-driven revascularization was performed in 54% of the conservative-strategy patients, the cumulative 1-year rate of death or non-fatal MI was <9% using the definition for MI employed in the TACTICS–TIMI-18 (Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy–Thrombolysis In Myocardial Infarction-18) trial. In addition, DES technologies were not employed in the ICTUS trial, and data on statin or clopidogrel pretreatment before PCI are not available (23). The ICTUS trial was also underpowered to show a mortality difference owing to its short duration of follow-up. In contrast, the 5-year follow-up of the RITA (Randomized Intervention Treatment of Angina)-3 trial showed a 24% reduction in the odds of dying in the early intervention arm (odds ratio 0.76; 95% confidence interval 0.58 to 1.00; p = 0.054), which did not become apparent until 2 years post randomization (24).
The importance of late clinical follow-up is underscored by a meta-analysis of multiple trials with at least 6 to 12 months follow-up, which demonstrates a significant reduction in the composite end point of death or recurrent MI as well as improved survival in favor of the invasive (vs. conservative) treatment strategy for NSTEACS (25). Some authors who have included older trials and trials with shorter term follow-up for analysis have questioned the magnitude of benefit attributable to an invasive (vs. conservative) treatment strategy (odds ratios for reduction in death or MI 0.85; 95% confidence interval 0.69 to 1.06) (26). We believe the weight of evidence remains in support of early invasive treatment based on risk stratification. The relative magnitude of clinical benefit observed for the invasive (vs. conservative) strategy is directly proportional to the clinical risk strata (TIMI, PURSUIT, GRACE) (19), serum troponin elevation (27), magnitude of ST-segment shift (28), and age (29,30) of the patient.
We believe that arguments regarding strategy (invasive vs. conservative) are misguided and that more focus should be placed on the treatment-risk paradox which has been demonstrated in practice for the early invasive treatment strategy. Although the benefit of an early invasive strategy is proportional to patient risk, the propensity to receive such treatment appears greater in patients at lower risk. This observation may be due to physician misconceptions regarding benefit-harm tradeoffs or concerns about treatment complications. Nevertheless, compliance with the current ACC/AHA CPG, including early (<48 h) angiography (hospital compliance guideline adherence quartile), is inversely correlated with in-hospital mortality for ACS (Fig. 2) (31). Every 10% increment in CPG adherence is associated with a 10% reduction in hospital mortality. Furthermore, evidence-based therapies (antiplatelet agents, beta-adrenergic blockers, lipid-lowering agents, angiotensin-converting enzymic inhibitors) initiated before hospital discharge are associated with an incremental survival advantage in follow-up (32). The fact that performance measures (CPG compliance) relate process of care to mortality presents an opportunity to define strategies that enhance current CPG compliance and utilization.
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Figure 2 Link between American College of Cardiology/American Heart Association guideline adherence (hospital composite quality quartiles) and in-hospital mortality. Every 10% increase in guideline adherence was associated with a 10% reduction in in-hospital mortality (adapted from Peterson et al. [31]). *Adjusted for age, gender, body mass index, race, insurance status, family history of coronary disease, hypertension, diabetes, smoking, hypercholesterolemia, prior myocardial infarction/percutaneous coronary intervention/coronary bypass surgery/congestive heart failure/stroke, renal insufficiency, blood pressure, heart rate, ST-segment shift, and positive cardiac biomarkers.
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ST-segment elevation myocardial infarction (STEMI)
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The rapid restoration of normal coronary blood flow via pharmacologic or mechanical recanalization of an occluded infarct-related artery limits myocardial necrosis and reduces subsequent morbidity and mortality. The ACC/AHA CPG for STEMI promotes reperfusion therapy (both fibrinolysis and PCI) and bases the choice of strategy on both resource availability and the anticipated time course for implementing treatment (2). The relative advantage of PCI versus fibrinolytic therapy is dependent on several factors. As the strategy of primary PCI usually entails an obligate additional time delay for implementation, the advantage of PCI (vs. fibrinolysis) depends on the relative time delay to definitive treatment (balloon inflation). Pooled analyses of RCTs suggest that the relative survival advantage demonstrated in favor of PCI may be lost if the PCI-related time delay (door-to-balloon minus door-to-needle time) exceeds either 60 or 110 min (33,34). Differences between these analyses may be explained by differences in patient risk profile. Indeed, the absolute mortality benefit of PCI versus fibrinolysis from these pooled analyses is dependent upon mortality risk in the fibrinolytic treated patient cohorts. A survival advantage in favor of PCI is evident only when the risk of death to 30 days following fibrinolysis exceeds 4% (35,36). One analysis suggests that even longer PCI-related time delays (exceeding 60 to 110 min) may still be associated with a PCI survival advantage in patients at highest risk for death following fibrinolysis (21). Thus, accurate risk assessment should be incorporated into any STEMI treatment triage algorithm.
The relative survival advantage of PCI versus fibrinolysis is also dependent on the case volume experience of both the operator (cardiologist) and the hospital facility (37–40). The best clinical outcomes, and hence the greatest relative advantage of PCI, are obtained by the highest volume operators and institutions. No "advantage" of PCI may be evident in low-volume institutions. Indeed, an increase in mortality and major adverse cardiovascular events in low-volume ( 400 cases/year) PCI centers has prompted some experts to conclude that "tolerance of low-volume thresholds for angioplasty centers with the purpose of providing primary PCI in acute MI should not be recommended, even in underserved areas" (41). Transport to a center capable of performing PCI yields superior clinical outcomes when compared with onsite (community hospital) fibrinolytic therapy when the randomization (treatment decision)-to-balloon time approximates 90 min (42,43). Importantly, no adverse outcomes related to transport have been observed in thousands of patients included in these analyses. Remarkably, the vast majority of individuals in the U.S. who experience STEMI live within a 60-min prehospital commute from an established PCI center (44). Following DES deployment during primary PCI for STEMI, there is a marked reduction in angiographic and clinical restenosis, further enhancing the relative benefit of PCI, as optimal late outcomes are linked to durable coronary patency. Finally, although RCTs performed before the era of coronary stenting and modern antiplatelet therapy demonstrated no benefit for the strategy of coronary angiography and PCI following fibrinolysis (45), more recent observations (46) and randomized trials have consistently demonstrated improved clinical outcomes with this pharmacoinvasive approach (47–49). In both the GRACIA (Routine Invasive Strategy within 24 Hours of Thrombolysis versus Ischemia Guided Conservative Approach for Acute Myocardial Infarction with ST-Segment Elevation)-I and the SIAM (Southwest German Interventional Study in Acute Myocardial Infarction)-III RCTs, the composite occurrence of death, recurrent MI, or revascularization was reduced by an early invasive strategy with coronary stenting (47,48). Similarly, the REACT (Rescue Angioplasty versus Conservative Treatment or Repeat Thrombolysis) trial demonstrated that rescue angioplasty (70% stent) after failed fibrinolytic treatment was associated with a significant reduction in the composite end point occurrence of death, recurrent infarction, severe heart failure, or stroke within 6 months as compared with either repeated fibrinolysis or conservative management (50). Again, one would expect these results to be further enhanced if DES (now available) had been used in the REACT trial. Furthermore, the benefit of oral clopidogrel therapy as an adjunct to fibrinolysis appears especially noteworthy when patients undergo catheter-based intervention after initial fibrinolysis (51). Finally, a meta-analysis of multiple randomized controlled trials evaluating rescue PCI (vs. conservative management) demonstrates a reduction in mortality to 30 days (odds ratio 0.64; 95% confidence interval 0.41 to 1.00; p = 0.048) (52).
Some authors have questioned the benefit of pharmacologically "facilitated" PCI for STEMI when GPI, fibrinolytics, or their combination are used in comparison with primary PCI alone (53). Subgroup analysis and pooled trial results suggest that earlier administration of abciximab "upstream" in the ambulance or emergency room is associated with improved pre-PCI TIMI flow grades as well as post-PCI TIMI myocardial blush grades and >70% ST-segment resolution when compared with later, in-cath lab abciximab administration at the time of PCI (54,55). Earlier abciximab administration was accompanied by greater improvement in global and regional infarct zone left ventricular function as well as a trend toward improved survival (53–55). Ongoing trials evaluating upstream use of abciximab should provide much needed insight into the potential benefits of facilitated PCI.
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The greater truth
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Despite the preeminence of coronary disease as a public health concern, treatment for ACS in the U.S. remains highly fragmented. In considering a more global approach to ACS care, several "truths" have become self-evident:
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Volume drives proficiency
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A direct relationship has been demonstrated between both operator and facility procedural volumes and optimal outcomes for both elective and primary PCI, as well as for coronary bypass surgery. Those doctors and hospitals performing the highest volume of procedures demonstrate the best outcomes, including survival. Regional centers of excellence for care of ACS should provide procedural volumes that are both commensurate with optimal outcomes and adequate to allow meaningful measurements and comparisons between centers (56,57). Such comparisons of quality and process measures are difficult among low-volume institutions.
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Resources are limited
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We currently face a critical shortage of both specialized nurses and cardiovascular specialists (56). Patients with more complex cardiovascular illness (congestive heart failure, MI) fare better with subspecialty (cardiologist) than with generalist care (57). One strategy for dealing with the mismatch between emerging evidence in favor of an interventional approach and the ability to deliver such care routinely is to construct centers for ACS care. Centers for care of ACS would provide state-of-the-art digital radiographic equipment, a broad inventory of PCI supplies, and intra-aortic balloon pumps and ancillary staff well versed in their use and maintenance. Indeed, institutional intra-aortic balloon pump procedural volume is inversely linked to mortality of patients who present with STEMI complicated by cardiogenic shock (58). For bypass surgery, the removal of the requirement for a certificate of need was associated with proliferation of low-volume centers and a corresponding increase in mortality rate compared with states maintaining a certificate of need program (59). Finally, the majority (>80%) of the adult population in the U.S. are estimated to live within a 60-min commute from an existing PCI center (44,60). Thus, the proliferation of multiple small programs with reduplication of services will further tax these limited resource pools. However, it is important to evaluate the implications for community healthcare delivery if regional ACS centers "siphon" ACS patients from local hospitals.
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The prehospital care phase for ACS, especially STEMI, is critically important
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Earlier STEMI diagnosis via the prehospital 12-lead ECG can facilitate in-hospital STEMI treatment with either fibrinolysis or PCI. In fact, those hospitals with the shortest door-to-balloon times incorporate prehospital diagnosis (transmitted ECG) with a multidisciplinary "team" approach in which the emergency physician activates the catheterization laboratory before cardiology consultation (61).
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The establishment of "ACS Centers of Excellence" should facilitate CPG adherence (56)
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Data suggest our current system of non-regionalized care is suboptimal in dispensing guideline adherent care, even to high-risk NSTEACS patients. Data suggest that combinations of evidence-based therapies (antiplatelet agents, beta-blockers, lipid-lowering agents, angiotensin-converting enzyme inhibitors) provide incremental survival advantage to 1 year following STEMI (Fig. 3) (62). The comparisons of CPG adherence and clinical outcomes among regional facilities can contribute to the "continuous cycle" for quality improvement and therapeutic development. Greater adherence to CPGs has been observed in those hospitals with higher STEMI volumes (63). Small centers are unlikely to allocate the resources required to optimally track, audit and report these measures.
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Figure 3 Combination evidence-based therapies reduce mortality to 1 year following myocardial infarction independent of renal function. Patients receiving multiple clinical practice guideline-adherent medications (antiplatelet agents, beta-blockers, lipid-lowering agents, angiotensin-converting enzyme inhibitors) enjoy incremental survival benefit. Adapted from Tay et al. (62). GFR = glomerular filtration rate; CI = confidence interval.
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A specialized center approach has already been validated in the U.S. for improving clinical outcomes for trauma
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The lack of specialized centers for acute ischemic heart disease is not commensurate with the magnitude of this public health problem. A similar approach has been developed for establishing regional centers of care for stroke, and a credentialing process for such centers has been proposed by the AHA. The time dependency of successful reperfusion in stroke creates an even more limited window of opportunity for brain salvage and clinical recovery. The collaborative spirit among community hospitals participating in integrated systems for trauma or stroke care may be facilitated by the stark reality that both trauma and stroke patients are frequently not profitable. Stroke patients generate few high-profit margin procedures and often have complicated, protracted hospital stays. The current scheme for disproportionate cardiovascular procedural reimbursement likely constrains the evolution of an optimal care process for ACS, similar to those for trauma or stroke (64–66).
In the context of rapid evolution in technology, all guidelines must be dynamic and require more frequent update/revision. Current "problems" or controversies should not focus on the current evidence-based CPG recommendations themselves, but rather on the fact that the present system is inefficient in CPG implementation and adherence. Furthermore, adherence to currently available CPGs has been correlated with improved survival. We should focus our efforts on mechanisms for improving and measuring system performance for the implementation and adherence to existing evidence-based guidelines that have been shown to improve clinical outcomes (67). Only by doing so will we provide appropriate, quality assured care to the greatest number of our patients.
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Footnotes
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1 Dr. Kereiakes serves as a consultant for Boston Scientific, Cordis Corporation, and Conor Medsystems, and as a member of the speaker bureau for Eli Lilly and Company. Dr. Antman has research grant relationships with Aventis, Bayer, Biosite, Boehringer Mannheim, Bristol-Myers Squibb, British Biotech, Centocor, Cor/Millennium, Corvas, Dade, Genentech, Lilly, Merck, Pfizer, and Sunol via the TIMI study group, of which he is a member. 
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Abstract
Non-ST-segment elevation acute...