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The Effect of Routine, Early Invasive Management on Outcome for Elderly Patients with Non–ST-Segment Elevation Acute Coronary Syndromes

Richard G. Bach, MD; Christopher P. Cannon, MD; William S. Weintraub, MD; Peter M. DiBattiste, MD; Laura A. Demopoulos, MD; H. Vernon Anderson, MD; Paul T. DeLucca, PhD; Elizabeth M. Mahoney, ScD; Sabina A. Murphy, MPH; and Eugene Braunwald, MD
[+] Article and Author Information

From Washington University Medical Center, St. Louis, Missouri; Brigham and Women's Hospital, Boston, Massachusetts; Emory University, Atlanta, Georgia; Merck & Co., West Point, Pennsylvania; University of Texas Health Sciences Center, Houston, Texas; and New England Research Institutes, Watertown, Massachusetts.


Note: A list of investigators and research coordinators participating in the TACTICS–TIMI 18 study is provided in an appendix to reference 2 and is available at http://www.timi.org.

Grant Support: By Merck & Co.

Potential Financial Conflicts of Interest:Employment: P.M. DiBattiste (Merck & Co.), L.A. Demopoulos (Merck & Co.), P.T. DeLucca (Merck & Co.); Consultancies: C.P. Cannon (GlaxoSmithKline, Vertex Pharmaceuticals, Guilford Pharmaceuticals); Honoraria: W.S. Weintraub (Merck & Co.); Stock ownership or options (other than mutual funds): P.M. DiBattiste (Merck & Co.), L.A. Demopoulos (Merck & Co.), P.T. DeLucca (Merck & Co.); Grants received: R.G. Bach (Bristol-Myers Squibb, Eli Lilly & Co., Merck & Co.), C.P. Cannon (Bristol-Myers Squibb, Sanofi, Merck & Co., AstraZeneca), W.S. Weintraub (Merck & Co.), S.A. Murphy (Merck & Co.), E. Braunwald (Merck & Co.).

Requests for Single Reprints: Richard G. Bach, MD, Cardiovascular Division, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110; e-mail, rbach@im.wustl.edu.

Current Author Addresses: Dr. Bach: Cardiovascular Division, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110.

Dr. Cannon: Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02482.

Dr. Weintraub: Emory University, Briarcliff Campus, Atlanta, GA 30322.

Dr. DiBattiste: AstraZeneca, 1800 Concord Pike, FOC W1-373, Wilmington, DE 19803.

Dr. Demopoulos: University of Pennsylvania Health System, Penn Medicine at Radnor, 250 King of Prussia Road, Radnor, PA 19087.

Dr. Anderson: University of Texas Health Sciences Center, 6431 Fannin Street, Houston, TX 77030.

Dr. DeLucca: Merck & Co., HM-209, PO Box 4, West Point, PA 19486.

Dr. Mahoney: New England Research Institutes, 9 Galen Street, Watertown, MA 02472.

Ms. Murphy: TIMI Study Group, 350 Longwood Avenue, Boston, MA 02115.

Dr. Braunwald: Brigham and Women's Hospital, 350 Longwood Avenue, Boston, MA 02115.

Author Contributions: Conception and design: R.G. Bach, C.P. Cannon, W.S. Weintraub, P.M. DiBattiste, L.A. Demopoulos, H.V. Anderson, S.A. Murphy, E. Braunwald.

Analysis and interpretation of the data: R.G. Bach, C.P. Cannon, W.S. Weintraub, P.M. DiBattiste, L.A. Demopoulos, H.V. Anderson, P.T. DeLucca, E.M. Mahoney, S.A. Murphy, E. Braunwald.

Drafting of the article: R.G. Bach, C.P. Cannon, W.S. Weintraub.

Critical revision of the article for important intellectual content: R.G. Bach, C.P. Cannon, W.S. Weintraub, H.V. Anderson, E.M. Mahoney, S.A. Murphy, E. Braunwald.

Final approval of the article: R.G. Bach, C.P. Cannon, W.S. Weintraub, H.V. Anderson, P.T. DeLucca, S.A. Murphy, E. Braunwald.

Provision of study materials or patients: R.G. Bach, C.P. Cannon.

Statistical expertise: C.P. Cannon, W.S. Weintraub, P.T. DeLucca, E.M. Mahoney, S.A. Murphy.

Obtaining of funding: C.P. Cannon, W.S. Weintraub, P.M. DiBattiste, L.A. Demopoulos, E. Braunwald.

Administrative, technical, or logistic support: C.P. Cannon, W.S. Weintraub, P.M. DiBattiste, E. Braunwald.

Collection and assembly of data: R.G. Bach, C.P. Cannon, W.S. Weintraub, S.A. Murphy.


Ann Intern Med. 2004;141(3):186-195. doi:10.7326/0003-4819-141-3-200408030-00007
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Among the 2220 patients enrolled in TACTICS–TIMI 18, 962 (43%) were 65 years of age or older. All but 27 patients (1.2%) completed 6 months of follow-up. Table 1 shows the baseline characteristics of patients younger than 65 years of age and those 65 years of age or older. Compared with younger patients, patients 65 years of age or older were more often women and more often white. Certain characteristics traditionally associated with higher risk among patients with acute coronary syndromes, including diabetes mellitus and congestive heart failure, ST-segment changes on electrocardiography, and elevated levels of serum troponin T, were more common among patients 65 years of age or older. The proportion of patients enrolled with a diagnosis of non–ST-segment elevation MI did not differ between the 2 groups. Cigarette smoking was less common among elderly persons. The distribution of TIMI risk score among patients 65 years of age or older differed significantly from that among younger patients. Intermediate to high TIMI risk scores (scores ≥ 3) characterized 90.6% of the elderly patients, whereas only 63.0% of patients younger than 65 years of age had similar scores (P < 0.001).

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Figures

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Figure 2.
Kaplan–Meier curves for 6-month death or nonfatal myocardial infarction (MI) according to age and treatment strategy among patients with unstable angina and non–ST-segment elevation MI.

*  = 0.02 for early invasive management vs. conservative management among patients ≥ 65 years of age. †  < 0.001 for conservative management and  = 0.09 for invasive management among patients <65 years of age vs. those ≥ 65 years of age;  > 0.2 for early invasive management vs. conservative management among patients <65 years of age.

Grahic Jump Location
Grahic Jump Location
Figure 3.
Odds ratios (ORs) for death; nonfatal myocardial infarction (MI); death or nonfatal MI; and death, MI, or rehospitalization for acute coronary syndromes at 6 months in patients with unstable angina and non–ST-segment elevation MI.

Data are stratified by age group: ≤ 55 years ( = 716), >55–65 years ( = 614), >65–75 years ( = 612), and >75 years ( = 278). The dotted line indicates the point estimate for the primary end point among all patients in the Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy–Thrombolysis in Myocardial Infarction (TACTICS–TIMI) 18 trial. *  = 0.010. †  = 0.016. ‡  = 0.05.

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Comments

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Cognition and functional status
Posted on August 7, 2004
Nasseer A Masoodi
None
Conflict of Interest: None Declared

In this article, the authors have made no mention in baseline characteristics about the Cognitive status of the patients especially those above the age of 75. Cognitive impairment plays a vital role in charting the plan of care, more so when invasive procedures are considered. It will be more convincing if authors can mention how many patients were above the age of 75 in both the groups. Age of 65 is no more considered elderly in practical life except for research purposes. Since there is no startling difference in the mortality between two groups, it would have been more prudent if morbidities compared included delerium and functional status between the two groups.

Nasseer A Masoodi MD

Conflict of Interest:

None declared

Invasive strategies in the "old old"?
Posted on August 29, 2004
Roy E Fried
none
Conflict of Interest: None Declared

Bach et. al. found an early invasive strategy superior in the elderly with acute coronary syndromes, including their 278 subjects older than 75 years. This age stratum contains both old and "old old" patients, with distinct levels of frailty, physiologic reserve and possibly, distinct levels of potential net benefit from invasive strategies, particularly those that can cause bleeding or adverse CNS events. It would be helpful to know the authors' point estimates and confidence intervals for major outcomes for subjects grouped into 5 year age groups beginning at age 75.

Conflict of Interest:

None declared

A routine invasive management strategy for elderly patients with unstable angina?
Posted on September 9, 2004
Armin Arbab-Zadeh
Univ. Texas Southwestern Medical Center at Dallas
Conflict of Interest: None Declared

TO THE EDITOR: In their subgroup analysis of the TACTICS-TIMI 18 trial, the authors concluded a routine early invasive management strategy is superior to a more conservative one in elderly patients with unstable angina or non-ST-elevation myocardial infarction (1). However, the high incidence of major bleeding in patients in these elderly patients managed invasively should raise caution regarding such a management strategy in this population, particularly since the proposed benefit of such a treatment strategy is an improvement in morbidity, not mortality. Furthermore, since the publication of the original TACTICS trial (2), new data have emerged which question some of the benefits of routine invasive management in subjects with acute coronary syndromes. The difference in the incidence of myocardial infarction favoring a routine early invasive approach may be based on differences in the criteria used for diagnosing myocardial infarction: while an elevation of creatine kinase more than twice the upper limit of normal was sufficient for the diagnosis of "spontaneous" myocardial infarction in TACTICS and FRISC II (3), an elevation more than three times the upper limit of normal was required for the diagnosis of myocardial infarction in association with percutaneous intervention. It is now clear that periprocedural enzyme elevations are associated with a similar prognosis as are "spontaneous" myocardial infarctions (4). Therefore, the consensus statement of the European Society of Cardiology and the American College of Cardiology defines any cardiac marker elevation in association with percutaneous intervention as myocardial infarction (5). Furthermore, although 94% of interventions in the invasive arm of TACTICS were performed with a concomitant 2b/3a inhibitor, only 59% of these performed in the conservatively managed subjects had the benefit of 2b/3a inhibition, which likely further favored the invasive management strategy. When similar criteria were applied, as was done in RITA III, the most recent trial comparing a routine invasive with a routine conservative approach in patients with unstable angina, no difference in the incidence of myocardial infarction was detected (6). The most consistent benefit of a routine early invasive strategy in acute coronary syndromes is freedom from recurrent ischemic events. In the subgroup analysis by Bach et al, it was rehospitalization for acute coronary syndrome within 30 days, an advantage which was no longer present at 6 months. Whether this benefit outweighs the dramatic increase in major bleeding in patients > 75 years of age is questionable, particularly since contemporary aggressive lipid lowering management has likewise been shown to reduce ischemic events after coronary syndromes (7). In summary, currently available data are insufficient to support a routine early invasive strategy in elderly patients with non-ST-segment elevation acute coronary syndromes. Until new data emerge, a management guided by risk stratification appears to be most reasonable in this population.

References: 1.Bach RG, Cannon CP, Weintraub WS, DiBattiste PM, Demopoulos LA, Anderson HV, DeLucca PT, Mahoney EM, Murphy SA, Braunwald E. The effect of routine, early invasive management on outcome for elderly patients with non-ST- segment elevation acute coronary syndromes. Ann Intern Med. 2004;141:186- 195. 2.Cannon CP, Weintraub WS, Demopoulos LA, Vicari R, Frey MJ, Lakkis N, Neumann F-J, Robertson DH, DeLucca PT, DiBattiste PM, Gibson M, Braunwald E. 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;344:1879-1887. 3.Invasive compared with non-invasive treatment in unstable coronary- artery disease: FRISC II prospective randomised multicentre study. FRISC II Investigators. Lancet. 1999;354:708-715. 4.Ioannidis JPA, Karvouni E, Katritis DG. Mortality risk conferred by small elevations of creatinine kinase-MB isoenzyme after percutaneous intervention. J Am Coll Cardiol. 2003;42:1406-1411. 5.Joint European Society of Cardiology/American College of Cardiology Committee. Myocardial infarction redefined - A consensus document of the Joint European Society of Cardiology/American College of Cardiology Committee for the Redefinition of Myocardial Infarction. J Am Coll Cardiol. 2000;36:959-969. 6.Fox KAA, Poole-Wilson PA, Henderson RA, Clayton TC, Chamberlain DA, Shaw TRD, Wheatley DJ, Pocock SJ. Interventional versus conservative treatment for patients with unstable angina or non-ST-elevation myocardial infarction: the British Heart Foundation RITA 3 randomised trial. Lancet. 2002;360:743-751. 7.Intensive versus moderate lipid lowering with statins after coronary syndromes. Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, Joyal SV, Hill KA, Pfeffer MA, Skene AM. N Engl J Med. 2004;350:495- 504.

Armin Arbab-Zadeh MD University of Texas Southwestern Medical Center Dallas, TX 75390-9047

Conflict of Interest:

None declared

Age and Routine Invasive Management of Acute Coronary Syndromes
Posted on October 15, 2004
Richard G Bach
Washington University School of Medicine
Conflict of Interest: None Declared

Dr. Masoodi raises two points regarding our analysis of outcome according to age among patients with non-ST-segment elevation acute coronary syndromes randomized to early invasive versus conservative management strategy. The first pertains to the lack of data on cognitive status of trial participants. While cognitive status was not specifically quantified among the baseline patient characteristics, it should be noted that to be included in the trial, the protocol dictated patients needed to be considered candidates for coronary angiography and revascularization, and patients were excluded who had any "clinically important neurological disorder" or who were unable to provide informed consent. It is thus likely that patients with significant cognitive impairment would have been excluded, appropriately, from the trial. We agree that cognitive status should be an important consideration when recommending management for any patient with a coronary syndrome, but would caution that degrees of cognitive impairment vary across a wide spectrum and the related management decisions remain largely subjective and challenging.

The second observation is that age 65 is not considered elderly "in practical life except for research purposes." While it is hard to argue with that perspective, age 65 has served as a milestone for many previous studies of age-related outcomes, and this can allow for comparison of treatment effects across trials. For example, by combining our results [1], with those from TIMI IIIB [2] and FRISC II [3], there is available data from 2724 patients of age >= 65 and 3422 patients of age < 65 randomized to a management strategy. Compared to conservative management, the invasive strategy resulted in a relative reduction of 6 to 12 month death or myocardial infarction of 37.5% (10.7% vs. 16.8%, p < 0.0001) for the older patients yet only 1.4% (8.2% vs. 8.4%, p = 0.90) for the younger patients. With respect to 6 to 12 month mortality among the 2249 patients of age >= 65 from FRISC II and TACTICS-TIMI 18 combined, allocation to the early invasive rather than conservative arm was associated with 27.5% fewer deaths at 6 to 12 months (4.2% vs. 5.8%, p = 0.099). We recognize that in an era of increasing life expectancy, to call a specific age "elderly" is arbitrary and non-physiologic. For that reason, we extended previous observations by including an analysis of age ranges from < 55 to > 75 years and showed that among the 278 patients in our trial over age 75, randomization to a routine early invasive rather than conservative strategy resulted in 42% fewer (20.1% vs. 30.2%, p = 0.05) occurrences of death, myocardial infarction or re- hospitalization for acute coronary syndrome, and a 33% lower "“ albeit non- significant "“ mortality rate (7.9% vs. 10.1%, p = 0.53) at 6 months. While we would expect that fewer of the most common morbid events for these elderly patients, recurrent myocardial infarctions and re- hospitalizations for unstable ischemia, should translate into an improved quality of life, a more detailed assessment of the effect of management strategy on functional status in the elderly awaits further study.

Conflict of Interest:

None declared

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Summary for Patients

Invasive versus Conventional Management of Elderly Patients with Acute Coronary Artery Disease: Which Is Better?

The summary below is from the full report titled “The Effect of Management Strategy on Clinical Outcome for Elderly Patients with Non–ST-Segment Elevation Acute Coronary Syndromes.” It is in the 3 August 2004 issue of Annals of Internal Medicine (volume 141, pages 186-195). The authors are R.G. Bach, C.P. Cannon, W.S. Weintraub, P.M. DiBattiste, L.A. Demopoulos, H.V. Anderson, P.T. DeLucca, E.M. Mahoney, S.A. Murphy, and E. Braunwald.

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