Are the current American College of Cardiology/American Heart Association stable ischemic heart disease guidelines too conservative?

Abstract

The American College of Cardiology/American Heart Association stable ischemic heart disease (SIHD) practice guidelines, published in 2012, represent a tremendous collaborative effort to synthesize the existing literature and evidence base for patients with SIHD. Notably, the guidelines focus not only upon the appropriate identification of patients with SIHD, but also upon the comprehensive treatment of SIHD patients. In doing so, these guidelines have no doubt already helped numerous practicing physicians who have referenced them; however, the goal of guideline documents is not for the included recommendations to be static, but instead to dynamically adapt over time. In this editorial, we discuss three potential areas of improvement in the guidelines, ranging from the use of specific diagnostic testing and risk-stratification modalities to the preferred treatment approach for symptomatic patients with SIHD.

Keywords::

• angina
• angiography
• coronary disease

Coronary heart disease (CHD) is one of the leading causes of death and morbidity in most developed countries, including the US. Therefore, it is of great importance to be able to identify individuals at risk for future cardiovascular events in order to implement therapies with the potential to avert these events. While CHD patients with acute coronary syndromes represent some of the highest risk/acuity patients with coronary disease, patients with ‘stable’ ischemic heart disease (SIHD) also represent a potentially high-risk subset of patients with CHD. Several US professional societies (including the American College of Cardiology and the American Heart Association) have developed clinical practice guidelines for SIHD in order to provide clinicians with an evidence-based construct in which to practice. The most recent comprehensive revision of these guidelines was released in 2012 [1], updating a set of guidelines whose origin dates back to 1999, with focused updates in 2002 and 2007.

The American College of Cardiology/American Heart Association SIHD guidelines represent a tremendous collaborative effort to synthesize the existing literature and evidence base for patients with SIHD. Notably, the guidelines focus not only upon the appropriate identification of patients with SIHD, but also upon the comprehensive treatment of SIHD patients. Therapeutic options addressed within the guidelines range from those aiming to improve the quality of life of symptomatic SIHD patients to those with the potential to improve hard clinical outcomes among appropriately selected patients. Besides pharmacologic and procedural strategies, oft-neglected non-pharmacologic approaches to coronary disease management (e.g., lifestyle modification, exercise therapy) are also well described within the guidelines document. All in all, these guidelines represent an effort to comprehensively and thematically address the treatment of patients with SIHD, providing detailed treatment algorithms that many treating physicians will find very useful in day-to-day practice.

Nonetheless, there are several areas of the guidelines that are perhaps more controversial and merit further discussion. In the remainder of this brief editorial, the authors will discuss three specific areas of possible improvement within the current guidelines, ranging from the preferred modality of diagnostic testing for many SIHD patients to the most appropriate therapies for symptomatic patients (Box 1).

Box 1. Potential areas of improvement within the stable ischemic heart disease guidelines.

• 1. Preference of routine exercise treadmill testing in the majority of SIHD patients

• Problem as currently formulated: By recommending this as the first test for patients across a broad range of pre-test probabilities (10–90%), the guidelines run the risk of missing a significant number of patients with prognostically important CHD due to the limited sensitivity of the test.

• Solution: Consider testing with greater accuracy for intermediate risk patients, and narrow the range of ‘intermediate risk’.

• 2. Omission of coronary angiography as a diagnostic and/or risk-stratification test for SIHD

• Problem as currently formulated: Coronary angiography as a diagnostic test is conspicuously missing from the guidelines. Notably, in randomized trials of medical therapy versus revascularization, diagnostic angiography was performed on all patients as part of the screening process prior to randomization.

• Solution: Coronary angiography should be considered as both a diagnostic and risk-stratification test within the guidelines, and not only for patients with high-risk findings on non-invasive testing. Patients with high pre-test probability should likely also undergo anatomic delineation of CHD in conjunction with GDMT to ensure that they do not have prognostically important left main and/or severe multivessel CHD.

• 3. Equating anti-anginal therapies with prognostically-altering medical therapy under the ‘GDMT umbrella’

• Problem as currently formulated: Anti-anginal therapies that have not been shown to alter prognosis are recommended under the overall package of GDMT. Failure of anti-anginal therapy is a prerequisite in the guidelines prior to consideration of revascularization.

• Solution: Further differentiation of prognostically altering GDMT from solely symptom-relieving GDMT is required. Given that revascularization is associated with more rapid and effective relief of symptoms than anti-anginal therapy, guidelines ought to allow and/or encourage up-front discussions of the benefits/risks of revascularization therapies in patients with significant symptoms.

Preference of routine exercise treadmill testing in the majority of SIHD patients

The guidelines endorse standard exercise ECG testing as the preferred test for patients able to exercise, with an interpretable ECG with a broadly defined ‘intermediate’ (10–90%) pretest probability of ischemic heart disease. The use of conventional treadmill ECG testing has been a cornerstone of cardiovascular care for decades, and can be a very useful test to rule out prognostically important SIHD provided the tested patient has an interpretable study a normal age-appropriate workload. However, while this test is an indispensable tool for the assessment of sufficiently low-risk (and even high-risk) patients, the diagnostic accuracy of the test is limited, with a reported sensitivity of approximately 60% and a specificity of approximately 75% [1]. As such, for patients within the broad range of intermediate risk proposed by the guidelines (no doubt the vast majority of patients presenting for CHD evaluation), this test has a markedly limited ability to sufficiently alter the post-test probability of disease. Notwithstanding the results of one randomized trial in women suggesting that this test could be an appropriate triage test [2], the risk of using routine treadmill ECG testing in patients with pre-test probabilities ranging from 10 to 90% is significant. For example, a patient with an 80% pre-test probability of disease and unknown multivessel disease could be mistakenly diagnosed as having no significant disease by a falsely negative routine ECG test, particularly if a negative test is not followed up by other confirmatory testing.

It should also be stressed that the actual way in which stress testing is performed is vitally important. Particularly for the diagnosis of CHD, an adequate treadmill ECG test should be symptom limited rather than solely heart rate limited. While achievement of an age-appropriate workload is important, exercise tolerance tests are too often terminated prior to the onset of symptoms, thereby limiting the overall accuracy of the test for the diagnosis of CHD. In addition, the exercise tolerance test should be administered using validated protocols, rather than rapidly escalating stages of the test in order to achieve maximal predicted heart rate. Anecdotally, the authors have observed, not infrequently, treadmill tests that have been of overall limited diagnostic value because of rapid protocol escalation and test termination in order to increase testing throughput within physician offices.

Omission of coronary angiography as a diagnostic &/or risk-stratification test for SIHD

The recent update to the SIHD guidelines is heavily influenced by two randomized trials conducted nearly a decade ago: Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) and the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D). Both trials demonstrated that for lower risk patients with SIHD, revascularization along with optimal medical therapy did not reduce death or myocardial infarction compared to optimal medical therapy alone [3,4]. A unique attribute of both these trials was that all randomized patients underwent coronary angiography prior to randomization. In these trials, diagnostic angiography during the screening process prior to randomization served two purposes: first, to clearly make the diagnosis of obstructive CHD and second, to rule out prognostically important (life-threatening) left main and/or severe multivessel disease, as randomization for these patients would likely be unethical.

The most current iteration of the SIHD guidelines appears to have neglected this most important operational attribute of COURAGE and BARI 2D. The guidelines recommend guideline-directed medical therapy (GDMT) without angiography for the majority of patients with SIHD, reserving angiography only for the highest risk patients (either those with high-risk stress testing or a limited number of additional scenarios discussed below). By limiting the use of diagnostic coronary angiography only to patients with high-risk stress testing, the guidelines make the following two critical assumptions that are currently unproven: first, high-risk stress testing (independent of clinical risk characteristics) is the most appropriate ‘upstream’ triage strategy in all patients with SIHD and second, the results of trials that randomized patients after angiography can be safely extrapolated to the much greater population of patients presenting prior to angiography. Both these assumptions are far from proven in the current literature. In fact, both these assumptions are encompassed in the primary study hypothesis of the International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial. The National Institutes of Health-funded ISCHEMIA trial is designed to study whether an invasive management strategy combined with GDMT for patients with moderate-severe ischemia on non-invasive testing is superior to a strategy of GDMT alone. In a sense, by recommending the approach encompassed within the control arm of the ISCHEMIA trial, the SIHD guidelines presuppose that the results of this trial will demonstrate no difference in an angiography-guided versus a conservatively guided management strategy for high-risk patients with SIHD. Furthermore, the design of the ISCHEMIA trial additionally incorporates a blinded computed tomography angiogram prior to randomization, both to ensure that randomized patients have obstructive disease and, more importantly, in order to avoid enrolling patients with prognostically important left main coronary artery disease, which can occur in approximately 10% of patients upon diagnostic coronary angiography [5]. If the trial itself mandates this test, then why do the guidelines allow clinicians to take the risk of medically treating undiagnosed left main disease?

In the opinion of the authors, diagnostic coronary angiography should be considered as the definitive (and often first) diagnostic test in patients with sufficiently high pre-test probability of CHD (i.e., those patients for whom negative non-invasive testing would not sufficiently alter post-test probability of prognostically significant CHD). In this setting, the use of non-invasive testing can be misleading (and even with adjunctive imaging cannot sufficiently lower the post-test probability of prognostically important left main and/or severe multivessel disease). This view is supported by the current American College of Cardiology/American Heart Association Appropriate Use Criteria for Diagnostic Catheterization, which rate diagnostic catheterization without non-invasive testing in high-risk symptomatic patients as ‘appropriate’ [6]. This rating is quite discordant with the current SIHD guidelines, which restrict up-front coronary angiography as a diagnostic test only to patients who have survived sudden cardiac death or life-threatening ventricular arrhythmias, and possibly for patients with symptomatic heart failure.

Equating anti-anginal therapies with prognostically altering medical therapy under the ‘GDMT umbrella’

A final area of ‘conservatism’ within the SIHD guidelines relates to the preferential position held by the anti-anginal medications within the guidelines. The SIHD guidelines appropriately endorse the administration of GDMT for all patients with SIHD. But what specifically are encompassed within the umbrella of GDMT are heterogeneous groups of therapies, some of which have been demonstrated to reduce overall CHD risk (e.g., lifestyle modification, smoking cessation), some have been demonstrated to improve survival and/or subsequent myocardial infarction (e.g., statins) and some only reduce the anginal symptoms without having other prognostic effects (e.g., nitrates, ranolazine). Although the guideline document does categorize these types of GDMT separately within its text, all these therapies are equally favored over any form of coronary revascularization. Furthermore, although the guidelines do endorse coronary angiography among persons who continue to have symptoms despite receiving optimal medical therapy, some patients are likely to have an improvement in their ischemic symptoms but may still have significant and life-threatening disease (i.e., severe left main disease). Thus, by delaying invasive testing and treating symptoms without knowledge of the underlying anatomy, we may miss the opportunity to diagnose prognostically important CHD.

According to the guidelines document, a symptomatic patient would have to be unsuccessfully treated by three to four different classes of anti-anginal medications before being considered for a coronary revascularization procedure. This is despite the fact that coronary revascularization has been demonstrated to have greater (and more rapid) effectiveness at treating symptoms of SIHD and improving the quality of life, compared with anti-anginal medical therapies [7–9]. Although randomized trials like COURAGE demonstrated similar long-term effects of optimal medical therapy to a strategy of up-front revascularization plus optimal medical therapy, the most symptomatic patients in this trial crossed over to revascularization (the more immediately effective therapy). A sub-analysis of COURAGE that focused upon patients who crossed over to revascularization demonstrated that not crossing over to revascularization within the first year following randomization was associated with an increased incidence of unstable angina and worsened health status [10]. Thus, for patients who are very symptomatic and are good candidates for revascularization, it is the opinion of the authors that a discussion of revascularization options is warranted up-front, in order to allow the patient to choose whether he/she prefers gradual uptitration of anti-anginal medications or more rapid relief of symptoms through a definitive revascularization procedure. As long as revascularization is feasible and the risk/benefit ratio is favorable, one could argue that this could be the preferred strategy for amenable patients with lifestyle-limiting symptoms.

This belief stems from a pragmatic and patient-centered view regarding medical therapy that sometimes goes missing within guidelines documents. Anti-anginal medications (none of which have been demonstrated to improve prognosis in the vast majority of SIHD patients) are often the fourth, fifth and/or sixth cardiac medications given to patients with CHD – after aspirin, statins and either hypertensive or diabetic medications. The burden of these medications (in addition to medications for any other medical conditions a patient may have) is substantial and adherence to them may be imperfect due to patient preference, medication side effects and cost. Furthermore, the effectiveness of GDMT in clinical practice differs from that observed in clinical trials. In a recent publication from a national prospective cohort study of CHD patients in a ‘real-world setting’, on average, only four out of seven optimal treatment goals were met and less than 25% of patients met five or more of the seven goals of therapy [11].

Conclusions

In light of these data, more work is clearly needed to educate and empower patients to make choices that can more effectively treat underlying CHD. In this regard, the updated SIHD guidelines represent a remarkable effort to synthesize an evolving evidence base. In doing so, clinicians are offered the opportunity to reassess their practice patterns and potentially improve outcomes for the millions of patients with CHD. The goal of guidelines documents is not for the included recommendations to be static, but instead to dynamically adapt over time. The authors hope that several of the issues raised above will be taken into further consideration, so that the next version of the SIHD guidelines can be much improved going forward.

Financial & competing interests disclosure

AJ Kirtane has declared institutional research grants to Columbia University from Medtronic CardioVascular, Boston Scientific, Abiomed, St. Jude Medical, Abbott Vascular, Vascular Dynamics and Eli Lilly. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Notes

CHD: Coronary heart disease; GDMT: Guideline-directed medical therapy; SIHD: Stable ischemic heart disease.