Evolving concepts in defining optimal strategies for the management of patients with stable ischemic heart disease






William E. BODEN,1,2,3
MD, FACC, FAHA
Mandeep S. SIDHU,1,2,3MD, PhD
MD, MBA, FACC
Santosh K. PADALA,1,3MD
1Division of Cardiology
Department of Medicine
Albany Medical Center
Albany, NY, USA
2Albany Stratton VA Medical
Center, Albany, NY, USA
3Albany Medical College
Albany, NY, USA

Evolving concepts in defining optimal strategies for the management of patients with stable ischemic heart disease


by S. K. Padala, M. S. Sidhu,
and W. E. Boden,
USA



The optimal strategy for the management of patients with stable ischemic heart disease (SIHD) has been a matter of considerable debate over the past 2 decades. During this time period, there have been notable technological evolutions in catheter-based revascularization that include the advent of bare-metal and drug-eluting stents, the genesis of more effective antiplatelet therapy, the continued refinement of stent delivery platforms, improving operator experience, and quality improvement initiatives which have led to declining complication rates. As a result, the approach to the management of SIHD has shifted increasingly from an initial pharmacologic strategy to one that embraces an initial percutaneous coronary intervention (PCI) approach. However, such a management paradigm is not fully supported by robust outcomes data, which suggests the need for a critical reappraisal of contemporary clinical practice. In particular, clinical decision making is now better informed because of the results of several important randomized controlled trials that have rigorously compared “hard” clinical end points of death and myocardial infarction (MI) in patients with SIHD who have undergone PCI with contemporary, guideline-directed medical therapy combined with lifestyle intervention.

Medicographia. 2014;36:45-54 (see French abstract on page 54)



The 2012 American College of Cardiology (ACC)/American Heart Association (AHA) guidelines on management of stable ischemic heart disease (SIHD) advocate an initial management strategy of intensive medical therapy, reduction in risk factors, and lifestyle modification (best defined as optimal medical therapy [OMT]) rather than an initial percutaneous coronary intervention (PCI) strategy.1 However, a recent observational study of 467 211 SIHD patients from the National Cardiovascular Data Registry (NCDR) who underwent PCI revealed that only approximately 45% of patients initially received OMT prior to PCI.2 Importantly, this analysis demonstrated that the percentage of SIHD patients undergoing initial PCI strategy remained similar before and after the COURAGE (Clinical Outcomes Utilizing Revascularization and AGgressive drug Evaluation) study results were published in 2007. These findings are further supported by observational data in SIHD patients from the New York State PCI Registry, where Hannan and colleagues reported that only 11% of patients received routine medical therapy (which was not OMT), while 89% underwent initial PCI.3 Over the past few decades, PCI has been shown to reduce the incidence of death and myocardial infarction (MI) in patients presenting with acute coronary syndromes (ACS),4-8 with the greatest benefit in patients with ST-segment elevation MI (STEMI) and in high-risk non-ST-segment elevation MI (NSTEMI). To date, med similar clinical benefit on reducing “hard” events has not been demonstrated in randomized controlled trials (RCTs) of patients with SIHD. Over this same period of time, several randomized trials9-12 and meta-analyses13,14 have yielded remarkably consistent data supporting medical therapy as the optimal initial management strategy in patients with SIHD. However, some more indiscriminate meta-analyses have purported to show benefit of either PCI or myocardial revascularization compared with medical therapy by including either studies of patients with STEMI and/or NSTEMI or comingling the results of trials that employed PCI and coronary artery bypass graft (CABG) surgery as part of the revascularization comparison.15,16 Such pooling of disparate patient populations and revasculariza- tion approaches has created conceptual harm and has done little to clarify the true role of PCI and revascularization on cardiovascular outcomes in patients with SIHD.


Table I
Table I. Baseline and angiographic characteristics of major clinical trials comparing initial percutaneous intervention + optimal medical therapy with optimal medical therapy alone in stable ischemic heart disease patients.

Abbreviations: BARI 2D, Bypass Angioplasty Revascularization 2 Diabetes; CABG, coronary artery bypass graft; CCS, Canadian Cardiovascular Society; COURAGE, Clinical Outcomes Utilizing Revascularization and Aggressive druG Evaluation; FAME 2, Fractional Flow Reserve versus Angiography for Multivessel Evaluation 2; FFR, fractional flow reserve; JSAP, Japanese Stable Angina Pectoris; LAD, left anterior descending; MI, myocardial infarction; N, number; OMT, optimal medical therapy; PCI, percutaneous coronary intervention; T2DM, type 2 diabetes mellitus.
Based on data from references 17-20.



Table II
Table II. Outcomes in major clinical trials comparing initial percutaneous coronary intervention + optimal medical therapy with optimal
medical therapy alone in stable ischemic heart disease patients.

Abbreviations: ACS, acute coronary syndrome; BARI 2D, Bypass Angioplasty Revascularization 2 Diabetes; CABG, coronary artery bypass graft; CI, confidence interval; COURAGE, Clinical Outcomes Utilizing Revascularization and Aggressive druG Evaluation; FAME 2, Fractional Flow Reserve versus Angiography for Multivessel Evaluation 2; HR, hazard ratio; JSAP, Japanese Stable Angina Pectoris; MI, myocardial infarction; OMT, optimal medical therapy; PCI, percutaneous coronary intervention.
Based on data from references 17-20.



Evidence from contemporary randomized controlled trials and meta-analyses comparing an initial PCI strategy with an initial OMT strategy Four recently published randomized studies—the COURAGE trial,17 the BARI 2D (Bypass Angioplasty Revascularization Intervention 2 Diabetes) trial,18 the JSAP study (Japanese Stable Angina Pectoris),19 and the FAME 2 trial (Fractional Flow Reserve versus Angiography for Multivessel Evaluation 2)20— have evaluated an initial strategy of PCI combined with medical therapy compared with medical therapy alone in SIHD patients. In the aggregate, none of these studies have shown any incremental clinical benefit for PCI above and beyond OMT for the reduction in either death or nonfatal MI. The baseline demographics and outcomes of these 4 trials are outlined in Table I and Table II respectively.

The data from these randomized trials are consistent with an earlier meta-analysis by Katritsis and Ioannidis,13 which was published in 2005 prior to the COURAGE trial. That meta-analysis included 11 randomized trials comparing PCI with medical therapy, totaling only 2950 SIHD patients. Importantly, all 11 trials were designed to compare PCI alone against medical therapy, and did not compare PCI plus medical therapy with medical therapy alone. Additionally, the medical therapy employed in these earlier 11 trials antedated the use of disease-modifying therapies that have been commonly employed since 2000, namely statins, inhibitors of the renin-angiotensin system, and thienopyridines. There were no significant differences between the 2 treatment strategies with regard to mortality (odds ratio [OR], 0.94; 95% confidence interval [CI], 0.72-1.24), cardiac death or MI (OR, 1.17; 95% CI, 0.88-1.57), or PCI during follow-up (OR, 1.23; 95% CI, 0.80- 1.90). Subsequently, multiple meta-analyses of RCTs have been published that have failed to show any incremental benefit of an initial PCI strategy over an initial OMT strategy in SIHD patients.21-23

In contradistinction, a seriously flawed meta-analysis of 17 randomized trials by Schomig et al15 including 7513 patients was published in 2008 and reported a significant reduction in death (OR, 0.80; 95% CI, 0.64-0.99), and nonsignificant reductions in cardiac death (OR, 0.74; 95% CI, 0.51-1.06) and MI (OR, 0.90; 95% CI, 0.66-1.23) in the group with a strategy of initial PCI as compared with medical therapy. The authors concluded that in patients with SIHD, an initial PCI-based strategy might improve long-term survival as compared with an OMT-only strategy. The limitations of the Schomiget al meta-analysis were articulated in an in-depth review and further analysis by Wijeysundera and Ko24 published in 2009 and showed that the original meta-analysis had included 4 trials (2071 patients) that compared the invasive strategy (PCI or CABG) with medical therapy, and 5 trials (1758 patients) that included patients with recent ACS (MI <4 weeks). Therefore, the population analyzed was not homogeneous and is clearly a limitation that would make these findings less generalizable to the SIHD population at large. After excluding the CABG and recent MI studies from the overall Schomig et al data set, there were no residual benefits and no statistically significant difference between PCI and OMT as the initial strategy for managing patients with SIHD (Figure 1).24


Figure 1
Figure 1. Summary odds ratios of meta-analyses of the impact on mortality: percutaneous coronary intervention versus medical therapy
in patients with stable coronary artery disease.

Abbreviations: CABG, coronary artery bypass graft; CI, confidence interval; COURAGE, Clinical Outcomes Utilizing Revascularization and Aggressive druG Evaluation; MI, myocardial infarction; OR, odds ratio; PCI, percutaneous coronary intervention.
After reference 24: Wijeysundera and Ko. Circ Cardiovasc Qual Outcomes. 2009;2(2):123-126. © 2009, American Heart Association. All rights reserved.



Another similarly flawed meta-analysis by Jeremias et al16 of 28 studies published from 1977 to 2007 was published in 2009 comparing an initial revascularization strategy (PCI or CABG) with medical therapy. The revascularization modality was PCI in 17 studies, CABG in 6 studies, and either PCI or CABG in 5 remaining studies. There were statistically significant reductions in mortality in the revascularization strategy group (OR, 0.74; 95% CI, 0.63-0.88). A stratified analysis according to revascularization mode revealed both CABG (OR, 0.62; 95% CI, 0.50-0.77) and PCI (OR, 0.82; 95% CI, 0.68-0.99) to be superior to medical therapy with respect to mortality.





Several important points warrant comment to better understand these results of the Jeremias et al study in light of both the aforementioned RCTs and other meta-analyses. Firstly, this meta-analysis included patients with recent ACS, and the benefit of revascularization might be driven by those trials as seen with the Schomig et al15 meta-analysis. Secondly, grouping trials of both PCI and CABG likely confounded the analysis, since older studies had clearly shown the benefit of CABG surgery versus medical therapy in an earlier era of rather primitive medical therapy (aspirin, β-blockers, and nitrates only). Finally, the statistical significance for superiority in the PCI arm of this meta-analysis (upper CI of 0.99) nearly crossed the line of unity. All of the above limitations should render the findings drawn from this meta-analysis as inconclusive and not generalizable to the SIHD population.

A subsequent meta-analysis by Wijeysundera and Ko25 of 14 studies including 7818 patients was published in 2010 and demonstrated that an initial PCI strategy was associated with overall greater freedom from angina compared with medical therapy (OR, 1.69; 95% CI, 1.24-2.30). The authors also stratified the trials by year of enrollment and found that the 3 trials prior to 1994 and the 6 trials between 1995 and 1999 showed significant freedom from angina in the PCI strategy compared with medical therapy. On the contrary, the 5 trials after year 2000 showed no difference in angina relief between PCI and medical therapy groups (Figure 2).25 That finding was largely attributable to the use of robust evidence-based medical therapy attenuating the effect of PCI on angina relief in contemporary trials, which likely “leveled the playing field” in effectively reducing angina in the intensively treated patients.

These conflicting results from various meta-analyses very likely reflect the selection bias of pooling scientific data from noncontemporaneous studies differing in study design and duration, raising the concern about comparing “apples and oranges.”26

What constitutes OMT?

As previously described, while there has been sustained technological evolution of PCI since its inception, similar impressive advancements in both our understanding of the pathophysiology of coronary artery disease (CAD) and newer therapeutic agents have led to the development of an effective “disease- modifying” pharmacologic therapy with proven survival benefits.1 These agents include antiplatelet agents, statins, β-blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB), and aldosterone antagonists. Additionally, agents that provide symptomatic relief of angina and ameliorate ischemia are likewise important components of OMT and include β-blockers, calcium channel blockers, nitrates, inhibitors of late inward sodium flux such as ranolazine, the selective If current inhibitor ivabradine, the potassium channel agonist nicorandil, and the metabolic agent trimetazidine.1,27


Figure 2
Figure 2. Summary odds ratios of metaanalyses of the effect of percutaneous coronary intervention on freedom from angina, stratified by recruitment period.

Abbreviations: CI, confidence interval; n, number; OR, odds ratio; PCI, percutaneous coronary intervention.
After reference 25: Wijeysundera et al. Ann Intern Med. 2010;152(6):
370-379. © 2010, The American College of Physicians. All rights reserved.



The 2012 ACC/AHA1 and the 2013 European Society of Cardiology (ESC)27 guidelines recommend intensive lifestyle intervention combined with aggressive pharmacologic therapy for SIHD, the goal of which is to reduce cardiovascular morbidity and mortality, as well as the burden of symptoms and ischemia in these patients. The guidelines strongly emphasize that these lifestyle changes should include cessation of cigarette smoking, maintenance of a healthy weight, regular physical activity (a minimum of 30-45 minutes 4-5 times/week), and adoption of a healthy diet (a diet low in saturated fat, cholesterol, and trans-fat; high in fresh fruits, whole grains, and vegetables; and with reduced sodium intake). In the aggregate, the combination of aggressive risk factor modification and intensive medical therapy is referred to as OMT.

Trials favoring an initial strategy of OMT in SIHD patients

The COURAGE trial17 randomized 2287 patients with SIHD to an initial strategy of PCI plus OMT versus OMT alone. Patients were included in the study if they had evidence of significant coronary artery stenosis on coronary angiography and objective evidence of ischemia or classic anginal symptoms. This was at least an intermediate-risk population. During a median follow-up of 4.6 years, the primary end point of all-cause mortality or nonfatal MI occurred in 211 patients in the PCI plus OMT group and 202 patients in the OMT group (19% vs 18.5%; P=0.62) (Figure 3).17 There were no significant differences between the groups in regard to the prespecified secondary end point of composite of death, MI, and stroke, and of hospitalization for unstable angina with negative biomarkers alone as shown in Table II.


Figure 3
Figure 3. Major clinical end points in the COURAGE trial.
Kaplan-Meier survival curves.

Abbreviations: CI, confidence interval; COURAGE, Clinical Outcomes Utilizing Revascularization and Aggressive druG Evaluation; PCI, percutaneous coronary intervention.
After reference 17: Boden et al. N Engl J Med. 2007;356 (15):1503-1516.
© 2007, Massachusetts Medical Society.



In examining the COURAGE data further, in terms of symptom relief, PCI plus OMT resulted in a more rapid symptomatic relief from angina. However, after 4.6 years of follow-up, reported symptoms were no longer statistically different.28 Overall, these findings support the hypothesis that there was no clear benefit of initial PCI strategy over initial OMT alone in terms of mortality, nonfatal MI, or cumulative major cardiovascular events in SIHD patients and no long-term difference in angina relief, which has often been touted as the rationale for defaulting to an initial PCI strategy.

Subsequently, the BARI 2D trial18 randomized 2368 patients with type 2 diabetes mellitus and SIHD to initial revascularization groups, either in the form of PCI or CABG, in combination with OMT versus initial OMT alone. Patients with type 2 diabetes mellitus and evidence of documented coronary artery stenosis on coronary angiography with positive stress imaging or classic angina were included. The primary end point of all-cause mortality was not statistically significantly different, with a 5-year survival of 88.3% in the revascularization arm versus 87.8% in the OMT arm (P=0.97) (Figure 4A).18 The secondary end point of composite of death, MI, or stroke (major cardiovascular events) was also not statistically different between revascularization and OMT-alone groups (Figure 4B).18 When analyzed separately based on the type of revascularization, patients who underwent PCI plus OMT showed no significant difference versus OMT alone in terms of total mortality and major cardiovascular events (Figure 4C),18 which is also consistent with the findings of COURAGE.

In the CABG subgroup of BARI 2D, overall mortality was similar to that in the OMT-alone group, but the CABG group had significantly fewer cardiovascular events (Figure 4D),18 which was driven primarily by the reduction in number of nonfatal MIs in the CABG arm. Overall, these findings demonstrate that in diabetic patients with SIHD, an initial strategy of PCI in combination with OMT did not offer any additional, or incremental, benefits compared with OMT alone in terms of all-cause mortality or the composite major cardiovascular events. However, CABG appears to reduce the rate of nonfatal MI when compared with OMT alone in diabetic patients who exhibited more extensive CAD, generally those with 3-vessel CAD. The strategy of CABG for revascularization may be beneficial for diabetic patients with more extensive CAD.18

Trials designed to show benefit of an initial PCI
strategy in SIHD patients

The JSAP study19 randomized 384 low-risk SIHD patients to an initial strategy of PCI plus OMT versus an initial strategy of OMT alone. Patients with evidence of documented coronary stenosis in 1 or 2 vessels on coronary angiography, other than the proximal left anterior descending artery, with a positive stress test or exertional angina were included. The primary end point of cumulative death rate was not significantly differ- ent at 3.3 years in the initial PCI-plus-OMT group compared with the initial OMT-alone group (2.9% vs 3.9%; P=0.794). On the other hand, ACS occurred significantly less frequently in the initial PCI-plus-OMT group compared with the initial OMT-alone group. The reduction in this end point was driven primarily by the significantly lower rates of unstable angina in the initial PCI-plus-OMT group than in the initial OMT-alone group and not by the cumulative rates of nonfatal MI between the groups as shown in Table II. Likewise, the rates of emergency hospitalization and elective repeat revascularization were significantly lower in the initial PCI-plus-OMT group than the initial OMT-alone group. However, these “softer” end points should be viewed with caution as there is a great deal of subjective decision making both with regard to hospitalization and repeat revascularization compared with the “hard” end points of MI or death. The severity of angina symptoms was reduced in both groups. However, the severity of angina was significantly lower (P<0.05) in the initial PCI-plus-OMT group than the initial OMT-alone group at the 1-month, 6-month, 1-year, 2-year, and 3-year follow-up. In summary, these findings of the JSAP study demonstrated that in low-risk patients with SIHD, an initial strategy with PCI in combination with OMT does not offer additional benefits to OMT alone in terms of all-cause mortality or nonfatal MI. However, initial PCI plus OMT resulted in lower rates of unstable angina, emergency hospitalization, and elective repeat revascularization. Furthermore, an initial strategy with PCI appeared to provide more symptomatic angina relief at 3.3 years of follow- up compared with an initial strategy of OMT alone. Compared with contemporary randomized trials such as COURAGE and BARI 2D, it is important to recognize that JSAP included minimally symptomatic, low-risk CAD patients, who were treated with less intensive routine medical therapy in both groups at baseline and over the follow-up period, but did not receive OMT.

Figure 4
Figure 4. Major clinical end points in the BARI 2D trial.

Abbreviations: BARI 2D, Bypass Angioplasty Revascularization 2 Diabetes; CABG, coronary artery bypass graft; PCI, percutaneous coronary intervention.
After reference 18: BARI 2D Study Group et al. N Engl J Med. 2009;360 (24):2503-2515.
© 2009, Massachusetts Medical Society. All rights reserved.



Figure 5
Figure 5. Major clinical end points in FAME 2.

Abbreviations: CI, confidence interval; FAME 2, Fractional Flow Reserve versus Angiography for Multivessel Evaluation 2; PCI, percutaneous coronary intervention.
After reference 20: De Bruyne et al. N Engl J Med. 2012;367(11):991-1001. © 2012, Massachusetts Medical Society. All rights reserved.



To evaluate the efficacy of fractional flow reserve (FFR)–guided PCI, the FAME trial (Fractional Flow Reserve versus Angiography for Multivessel Evaluation)29 randomized 1005 patients with multivessel CAD to conventional angiographic-guided PCI or FFR-guided PCI (PCI performed only if FFR was ≤0.80). The composite of death, nonfatal MI, and repeat revascularization was significantly lower at 1 and 2 years in the FFRguided PCI group.29,30 Unlike COURAGE, BARI 2D, and JSAP trials, the original FAME trial did not have a medical therapy comparator arm. Thus, while the study results added to the body of literature on utility of FFR to guide PCI, it did not address the key scientific issue of which initial strategy, either OMT or FFR-guided PCI, was optimal in the management of SIHD patients. Therefore, the FAME 2 trial20 was undertaken in order to address the lack of an OMT comparator in the original FAME trial, and in this more recent study, 888 patients with SIHD were randomized to an initial strategy of FFR-guided PCI plus OMT versus an initial strategy of OMT alone. Only patients who had evidence of coronary artery stenosis on coronary angiography with an FFR ≤0.80 were included, while those with an FFR >0.80 were followed in a registry and treated medically. The Data and Safety Monitoring Board halted the recruitment prematurely owing to significant differences in the primary end points between the 2 groups. After a mean follow-up of merely 7 months, the primary end point of the composite of all-cause mortality, nonfatal MI, or unplanned hospitalization leading to urgent revascularization was significantly lower in the group with FFR-guided PCI plus OMT as compared with the initial OMT-alone group (4.3% vs 12.7%; P<0.001) (Figure 5A-D). This difference was primarily driven by significantly lower rates of urgent revascularization in the initial PCI-plus-OMT group than in the initial OMT-alone group. There were no significant differences between the groups in the prespecified secondary end point of death or nonfatal MI. The proportion of patients with angina class II to IV was reduced during follow-up in both groups, but this reduction was greater among patients randomized to initial PCI plus OMT than among those randomized to initial OMT alone. Importantly, this was likely a very low–risk group, in that there were very few cardiac events observed after 12 months (see section on limitations of FAME 2 below). The results of the FAME 2study were comparable to the JSAP study in that the initial strategy of PCI plus OMT did not reduce the rates of death or nonfatal MI in SIHD patients, but seemed to provide more symptomatic anginal relief.

Limitations of FAME 2

FAME 2 has received significant criticism primarily because the demonstrated benefit of PCI over OMT was limited to the “soft” end point of urgent revascularization without affecting the incidence of the more meaningful “hard” end points (ie, cardiovascular mortality or nonfatal MI).31 Overall, there were very few “hard” events with only 4 total deaths and 29 MIs. In the OMT-alone group, there were 3 deaths and 14 MIs compared with the PCI-plus-OMT group which had 1 death and 15 MIs. There was only 1 cardiac death in each group. After 12 months, there were just 2 MIs, both in the PCI-plus-OMT group, and no deaths in either group. The trial was designed to enroll 1632 patients, with a projected 2-year follow-up period; however, it was terminated at a mean follow-up of 7 months after enrolling only 54% of planned participants because of a highly significant treatment difference, a finding driven solely by a difference in the end point of urgent revascularization. More than half of the unplanned revascularizations (52%) were performed solely on the basis of reported clinical symptoms without supporting evidence of positive cardiac biomarkers or electrocardiographic evidence of ischemia. In the context of a nonblinded trial, there is clearly a concern that decisions regarding interventions during follow-up may have been biased by the knowledge of the previous treatment assignment. Biologically, the follow-up period was also far too short (average 7 months) for coronary restenosis to emerge. Therefore, a longer follow-up might have narrowed the difference in the rates of unplanned revascularization between the groups. Furthermore, the study population in FAME 2, when compared with COURAGE, did not appear to be at particularly high risk (as evidenced by multivessel disease 24% vs 69%, respectively). Finally, while fewer than 80 patients had 12 months of follow-up, the benefit of PCI in improving class II to IV angina symptoms was not significant beyond 6 months. In summary, while FAME 2 did show that an FFR-guided PCI strategy resulted in a lower rate of unplanned revascularization as compared with medical therapy alone, the notable limitations of the trial as highlighted above makes it difficult to justify or generalize the more widespread use of an FFR guided revascularization approach in the management of SIHD patients.31,32

The ISCHEMIA trial (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches; Clinical Trials.gov, NCT 01471522), funded by the US National Institutes of Health, is currently under way. ISCHEMIA is designed and powered to evaluate the long-term superiority of revascularization of choice combined with OMT versus a strategy with OMT alone with respect to cardiovascular death or MI (composite primary end point) in patients with stable CAD and moderate-to-severe myocardial ischemia as assessed by noninvasive stress imaging studies (myocardial perfusion imaging, stress echocardiography, or magnetic resonance imaging). The ISCHEMIA trial is projected to enroll 8000 patients from among 400 enrolling sites worldwide, with a planned average follow-up period of 4 years.

In conclusion, based on the best available data from multiple randomized trials, it would appear both reasonable and justifiable to defer an initial strategy of PCI in favor of an adequate empirical trial of OMT as a strategy that can be advocated for the majority of patients with SIHD and Canadian Cardiovascular Society (CCS) class I or II anginal symptoms. In SIHD patients with refractory and/or worsening symptoms, despite OMT (ie, “failed medical therapy”), or those with high-risk criteria on noninvasive testing, such as inducible ischemia involving a moderate or large territory of myocardium, an initial revascularization strategy with PCI could be considered appropriate until further data from the ISCHEMIA trial informs our clinical practice of how best to treat these patients.


References
1. Fihn SD, Gardin JM, Abrams J, et al; American College of Cardiology Foundation/ American Heart Association Task Force. 2012 ACCF/AHA/ACP/AATS/ PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation. 2012;126(25):e354-e471.
2. Borden WB, Redberg RF, Mushlin AI, Dai D, Kaltenbach LA, Spertus JA. Patterns and intensity of medical therapy in patients undergoing percutaneous coronary intervention. JAMA. 2011;305(18):1882-1889.
3. Hannan EL, Samadashvili Z, Cozzens K, et al. Comparative outcomes for patients who do and do not undergo percutaneous coronary intervention for stable coronary artery disease in New York. Circulation. 2012;125(15):1870-1879.
4. Anderson JL, Adams CD, Antman EM, et al. 2012 ACCF/AHA Focused update incorporated into the ACCF/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;127(23):e663-e828.
5. American College of Emergency Physicians; Society for Cardiovascular Angiography and Interventions; O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;61(4): e78-e140.
6. Cannon CP, Weintraub WS, Demopoulos LA, et al; TACTICS (Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy)— Thrombolysis in Myocardial Infarction 18 Investigators. Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban. N Engl J Med. 2001;344(25):1879-1887.
7. Mehta SR, Cannon CP, Fox KA, et al. Routine vs selective invasive strategies in patients with acute coronary syndromes: a collaborative meta-analysis of randomized trials. JAMA. 2005;293(23):2908-2917.
8. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous throm bolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials. Lancet. 2003;361(9351):13-20.
9. RITA-2 Trial Participants. Coronary angioplasty versus medical therapy for angina: the second Randomised Intervention Treatment of Angina (RITA-2). Lancet. 1997;350(9076):461-468.
10. Henderson RA, Pocock SJ, Clayton TC, et al; Second Randomized Intervention Treatment of Angina (RITA-2) Trial Participants. Seven-year outcome in the RITA-2 trial: coronary angioplasty versus medical therapy. J Am Coll Cardiol. 2003;42(7):1161-1170.
11. TIME Investigators. Trial of invasive versus medical therapy in elderly patients with chronic symptomatic coronary-artery disease (TIME): a randomised trial. Lancet. 2001;358(9286):951-957.
12. Hueb W, Soares PR, Gersh BJ, et al. The medicine, angioplasty, or surgery study (MASS-II): a randomized, controlled clinical trial of three therapeutic strategies for multivessel coronary artery disease: one-year results. J Am Coll Cardiol. 2004;43(10):1743-1751.
13. Katritsis DG, Ioannidis JP. Percutaneous coronary intervention versus conservative therapy in nonacute coronary artery disease: a meta-analysis. Circulation. 2005;111(22):2906-2912.
14. Bucher HC, Hengstler P, Schindler C, Guyatt GH. Percutaneous transluminal coronary angioplasty versus medical treatment for non-acute coronary heart disease: meta-analysis of randomised controlled trials. BMJ. 2000;321(7253): 73-77.
15. Schomig A, Mehilli J, de Waha A, Seyfarth M, Pache J, Kastrati A. A meta-analysis of 17 randomized trials of a percutaneous coronary intervention-based strategy in patients with stable coronary artery disease. J Am Coll Cardiol. 2008; 52(11):894-904.
16. Jeremias A, Kaul S, Rosengart TK, Gruberg L, Brown DL. The impact of revascularization on mortality in patients with nonacute coronary artery disease. Am J Med. 2009;122(2):152-161.
17. Boden WE, O’Rourke RA, Teo KK, et al; COURAGE Trial Research Group. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med. 2007;356(15):1503-1516.
18. BARI 2D Study Group; Frye RL, August P, Brooks MM, et al. A randomized trial of therapies for type 2 diabetes and coronary artery disease. N Engl J Med. 2009;360(24):2503-2515.
19. Nishigaki K, Yamazaki T, Kitabatake A, et al; Japanese Stable Angina Pectoris Study Investigators. Percutaneous coronary intervention plus medical therapy reduces the incidence of acute coronary syndrome more effectively than initial medical therapy only among patients with low-risk coronary artery disease: a randomized, comparative, multicenter study. JACC Cardiovasc Interv. 2008;1 (5):469-479.
20. De Bruyne B, Pijls NH, Kalesan B, et al; FAME 2 Trial Investigators. Fractional flow reserve-guided PCI versus medical therapy in stable coronary disease. N Engl J Med. 2012;367(11):991-1001.
21. Cecil WT, Kasteridis P, Barnes JW Jr, Mathis RS, Patric K, Martin S. A metaanalysis update: percutaneous coronary interventions. Am J Manag Care. 2008; 14(8):521-528.
22. Stergiopoulos K, Brown DL. Initial coronary stent implantation with medical therapy vs medical therapy alone for stable coronary artery disease: meta-analysis of randomized controlled trials. Arch Intern Med. 2012;172(4):312-319.
23. Thomas S, Gokhale R, Boden WE, Devereaux PJ. A meta-analysis of randomized controlled trials comparing percutaneous coronary intervention with medical therapy in stable angina pectoris. Can J Cardiol. 2013;29(4):472-482.
24. Wijeysundera HC, Ko DT. Does percutaneous coronary intervention reduce mortality in patients with stable chronic angina: are we talking about apples and oranges? Circ Cardiovasc Qual Outcomes. 2009;2(2):123-126.
25. Wijeysundera HC, Nallamothu BK, Krumholz HM, Tu JV, Ko DT. Meta-analysis: effects of percutaneous coronary intervention versus medical therapy on angina relief. Ann Intern Med. 2010;152(6):370-379.
26. Boden WE. Meta-analysis in clinical trials reporting: has a tool become a weapon? Am J Cardiol. 1992;69(6):681-686.
27. Montalescot G, Achenbach S, Andreotti F, et al. 2013 ESC guidelines on the management of stable coronary artery disease: The Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J. 2013;34(38):2949-3003.
28. Maron DJ, Spertus JA, Mancini GB, et al; COURAGE Trial Research Group. Impact of an initial strategy of medical therapy without percutaneous coronary intervention in high-risk patients from the Clinical Outcomes Utilizing Revascularization and Aggressive DruG Evaluation (COURAGE) trial. Am J Cardiol. 2009;104(8):1055-1062.
29. Pijls NH, Fearon WF, Tonino PA, et al; FAME Study Investigators. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention in patients with multivessel coronary artery disease: 2-year follow-up of the FAME (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation) study. J Am Coll Cardiol. 2010;56(3):177-184.
30. Tonino PA, De Bruyne B, Pijls NH, et al; FAME Study Investigators. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med. 2009;360(3):213-224.
31. Boden WE. Which is more enduring—FAME or COURAGE? N Engl J Med. 2012;367(11):1059-1061.
32. Sidhu MS, Boden WE. Does revascularization work? Heart Metab. 2013;58: 10-14.


Keywords: coronary artery disease; myocardial ischemia; optimal medical therapy; revascularization; stable ischemic heart disease