This Article Extract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Killip, T. Search for Related Content PubMed PubMed Citation Articles by Killip, T.

(Circulation. 1997;95:1992-1993.)
© 1997 American Heart Association, Inc.

Articles

Silent Myocardial Ischemia: Some Good News

Thomas Killip, MD

From the Albert Einstein College of Medicine and Beth Israel Medical Center, New York, NY.

Correspondence to Thomas Killip, MD, Beth Israel Medical Center, 16th St @ 1st Ave, New York, NY 10003. E-mail: tkillip{at}bethisraelny.org

Key Words: Editorials • revascularization • ischemia

	Introduction

Top Introduction References

 
In patients with coronary artery disease, silent myocardial ischemia is a troublesome problem for the clinician.¹ It is an iceberg: a small amount is readily visible, but much more remains hidden from view. In the absence of evidence-based guidelines for treatment, many questions arise, including how assiduously should it be sought and what should be done about it when found?

Estimated to occur in 4% to 5% of an asymptomatic male population in their fifth decade² but far more common in patients with angina pectoris, silent ischemia is most often recognized during exercise testing or fortuitously with ambulatory electrocardiography. A number of studies have now clearly demonstrated that patients with silent ischemia have increased risk for coronary events: sudden death or myocardial infarction.^{3 4 5 6} Reasoning that if silent ischemia is bad, then amelioration with revascularization must be good, investigators have reported nonrandomized observational data to support an aggressive therapeutic approach.^{7 8 9} These anecdotal reports cannot be evaluated, however, because careful studies comparing revascularization with state-of-the-art medical treatments have heretofore been lacking.

In the current issue of Circulation, Davies et al⁹ report on the Asymptomatic Cardiac Ischemia Pilot (ACIP) Study 2-year follow-up, a randomized trial designed to determine whether the prognosis of patients with silent ischemia is improved by aggressive treatment with anti-ischemic drugs or revascularization. Because concern has been expressed about the quality of many reported randomized clinical trials,¹⁰ it is worthwhile to review the ACIP study on the basis of the CONSORT (CONsolidated Standards Of Reporting Trials) statement, which provides a checklist and a flow diagram as a standard for quality of a randomized clinical trial.¹¹ CONSORT emphasizes the need for an optimal design and an optimal format for reporting the results. CONSORT identifies some 21 items on a proposed checklist (q.v. Reference 11¹¹ ).

ACIP performs very well against the CONSORT standard. Randomization was blocked and balanced against treatment assignment. Random, preassigned allocation was recorded by telephone call to the coordinating center when eligibility criteria were confirmed. Protocol deviations, an important aspect to consider in any randomized trial, are carefully described in the text. Power calculations are reported. Criteria for statistical significance were determined before the trial. Impressive indeed is the correction notice¹² issued after a preliminary report when the investigators recognized inconsistencies in the reporting of baseline characteristics at 1 of the 11 original clinical units. After an extensive audit, the records from 60 patients enrolled at this clinical site were deemed not acceptable and were eliminated from the original and all subsequent analyses, including the present report. My conclusion after applying the CONSORT criteria for quality of this clinical trial: excellent design, well performed, and carefully and reasonably reported.

ACIP randomized 558 patients with asymptomatic ischemia during stress testing and ambulatory ECG monitoring who had coronary anatomy suitable for revascularization to three treatment strategies: angina-guided medical therapy, guided medical therapy or revascularization by angioplasty, or bypass surgery. Predetermined end points were total mortality, the combined rate of death or myocardial infarction, or cardiac hospitalization plus death or myocardial infarction. Two medical anti-ischemic protocols were used: atenolol and controlled-release nifedipine or sustained-release diltiazem with sustained-release isosorbide dinitrate. Dosages were increased if needed. All patients received aspirin unless contraindicated. Assigned treatments were maintained for 1 year. Analysis was by the intention-to-treat principle. Baseline characteristics were comparable among the three randomized groups of treatment.

After 2 years of follow-up, mortality was significantly lower in the revascularization group (1.1%) than in the ischemia-guided (4.4%) or angina-guided treatment groups (6.6%). Although patients were withdrawn from the protocol at 1 year with subsequent treatment adjusted according to need, mortality in the ischemia and angina groups continued to diverge from the revascularization group, suggesting a long-term advantage from the invasive treatment arm. For the end points of death or myocardial infarction, the incidence after 2 years in the three treatment groups was 4.7% for revascularization, 8.8% for ischemia-guided treatment, and 12.1% for angina-guided treatment. When cardiac hospitalization was added to myocardial infarction or death as an end point, after 2 years the angina and ischemia-guided incidence results were similar (41.8% and 38.5%, respectively), but revascularization retained an advantage at 23.1%.

These are exciting findings. In a carefully constructed and well-performed study in a well-described group of patients with silent ischemia, revascularization appears to offer a significant prognostic advantage. Medical therapy designed to reduce or avert ischemia appears to be prognostically better than symptomatic therapy but is not as effective as revascularization.

As the authors correctly point out, there are a number of limitations to the study. The number of patients randomized is small but the probability values favoring revascularization are impressive. Comparisons of medical and revascularization treatment in patients with coronary artery disease are confounded by crossovers to nonprotocol revascularization driven by medical necessity. In the present study, 29% of the patients in the medical treatment strategies had nonprotocol revascularization, a high figure indeed. Because analysis was by intention-to-treat, these crossovers may well have improved the medical group outcome in selected subjects, thus decreasing the differences among groups, yet revascularization had a significantly better prognosis in the three end points prospectively defined for analysis.

Randomized trials can only incorporate treatments available at the time of design, but their generalizability at completion is hostage to the whims of progress. No less with ACIP. The medical therapies chosen are reasonable and would be used currently. It could be argued that a different ß-blocker, calcium channel blocker, or nitrate might be more effective than those chosen, but the evidence to substantiate such modifications is limited.

As the authors comment, however, information about the effectiveness of the HMG-CoA reductase inhibitors both in secondary and primary prevention was not available when the trial was designed.¹³ Future patients with silent ischemia might well receive aggressive statin therapy to modify blood lipids to currently accepted minimum risk standards and also influence coronary vascular reactivity. It could be argued that this treatment might improve the effectiveness of medical therapy and possibly narrow or erase the prognostic advantage afforded by revascularization. On the other hand, many of the postrevascularization subjects should probably also receive statin therapy, which might enhance even further the revascularization advantage. The possible effect of these and other drugs cannot be answered without another, larger trial. Such a trial might also identify subgroups defined by extent of coronary vessel disease or left ventricular function or other factors with special advantage or risk depending on treatment.

However, the design of further trials is going to be problematic because of the convincing evidence of an advantage for revascularization in the present report. The hierarchy of graded increased risk in the ischemia and angina subgroups is strongly supportive of the conclusion favorable to revascularization. Thus, the ethical justification for a nonrevascularization control group in further trials may well be difficult to defend.

In the meantime, the reader, recognizing that no trial is perfect and that improvements in treatment are inevitable, may rejoice in the good news from a convincing, if preliminary, answer to a difficult question: what to do about silent myocardial ischemia in certain cases. Revascularization appears to offer a distinct prognostic advantage compared with medical therapy as reported by Davies et al in selected patients with angina pectoris and silent ischemia. However, the cost-effectiveness of revascularization, longer-term results, and the influence of new forms of medical treatment on outcome in silent myocardial ischemia must await further investigation.

	Footnotes

 
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

	References

Top Introduction References

 

1. Parmley WW. Prevalence and clinical significance of silent myocardial ischemia. Circulation. 1989;80(suppl IV):IV-68-IV-73.
   
2. Erikssen J, Enge I, Forfang J, Shorstein O. False-positive diagnostic tests and coronary angiographic findings in 105 presumably healthy males. Circulation. 1976;54:371-376. [Abstract/Free Full Text]
   
3. Bugiardini R, Borghi A, Pozzati A, Ruggeri A, Puddu P, Maseri A. Relation of severity of symptoms to transient myocardial ischemia and prognosis in unstable angina. J Am Coll Cardiol. 1995;25:597-604. [Abstract]
   
4. Deedwania PC, Carbajal EV. Silent ischemia during daily life is an independent predictor of mortality in stable angina. Circulation. 1990;81:748-756. [Abstract/Free Full Text]
   
5. Ruberman W, Crow R, Rosenberg CR, Rautaharju PM, Shore RE, Pasternack BS. Intermittent ST depression and mortality after myocardial infarction. Circulation. 1992;85:1440-1446. [Abstract/Free Full Text]
   
6. Yeung AC, Barry J, Selwyn AP. Silent ischemia after myocardial infarction: prognosis, mechanism, and intervention. Circulation. 1990;82(suppl II):II-143-II-148.
   
7. Finci L, Chatelain P, Meier B, Steffenino G, Favre J, Righetti A, Rutishauser W. Coronary angioplasty in silent and painful myocardial ischemia. Adv Cardiol. 1990;37:278-287. [Medline] [Order article via Infotrieve]
   
8. Tuzcu EM, Nisanci Y, Simpfendorfer C, Dorosti K, Franco I, Hollman J, Whitlow P. Percutaneous transluminal coronary angioplasty in silent ischemia. Am Heart J. 1990;119:797-801.[Medline] [Order article via Infotrieve]
   
9. Davies RF, Goldberg AD, Forman S, Pepine CJ, Knatterud GL, Geller N, Sopko G, Pratt C, Deanfield J, Conti CR, for the ACIP Investigators. Asymptomatic Cardiac Ischemia Pilot (ACIP) Study two-year follow-up: outcomes of patients randomized to initial strategies of medical therapy versus revascularization. Circulation. 1997;95:2037-2043. [Abstract/Free Full Text]
   
10. Moher D, Dulberg CS, Wells GA. Statistical power, sample size, and their reporting in randomized controlled trials. JAMA. 1994;272:122-124. [Abstract]
    
11. Begg C, Cho M, Eastwood S, Horton R, Moher D, Olkin I, Pitkin R, Rennie D, Schultz KF, Simel D, Stroup DF. Improving the quality of reporting of randomized controlled trials. JAMA. 1996;276:637-639. [Medline] [Order article via Infotrieve]
    
12. Conti CR, Knatterud GL, Sopko G. Correction. J Am Coll Cardiol. 1995;26:842.
    
13. Scandinavian Simvastatin Survival Study Group. Randomized trial of cholesterol lowering in 444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383-1390. [Medline] [Order article via Infotrieve]
    

This article has been cited by other articles:

				R. J. Adams, M. I. Chimowitz, J. S. Alpert, I. A. Awad, M. D. Cerqueria, P. Fayad, and K. A. Taubert Coronary Risk Evaluation in Patients With Transient Ischemic Attack and Ischemic Stroke: A Scientific Statement for Healthcare Professionals From the Stroke Council and the Council on Clinical Cardiology of the American Heart Association/American Stroke Association Circulation, September 9, 2003; 108(10): 1278 - 1290. [Full Text] [PDF]

				R. J. Adams, M. I. Chimowitz, J. S. Alpert, I. A. Awad, M. D. Cerqueria, P. Fayad, and K. A. Taubert Coronary Risk Evaluation in Patients With Transient Ischemic Attack and Ischemic Stroke: A Scientific Statement for Healthcare Professionals From the Stroke Council and the Council on Clinical Cardiology of the American Heart Association/American Stroke Association Stroke, September 1, 2003; 34(9): 2310 - 2322. [Full Text] [PDF]

				Revascularization Best for Silent Ischemia Journal Watch Cardiology, May 19, 1997; 1997(519): 1 - 1. [Full Text]

This Article Extract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Killip, T. Search for Related Content PubMed PubMed Citation Articles by Killip, T.