Unstable angina non ST elevation myocardial infarction initial conservative versus initial invasive strategies

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Smita Kohli, M.D.

Overview

Two approaches to the use of cardiac catheterization and revascularization in UA/NSTEMI include:

Clinical practice guidelines[1] and systematic reviews[2][3] state:

  • “Early angiography and coronary intervention have been more effective in reducing ischemic complications than delayed interventions, particularly in patients at high risk (defined by a GRACE score >140)”[1].
  • “An early invasive strategy within 24 h is recommended for high-risk patients with positive cardiac biomarkers, dynamic ST-T changes, or a GRACE risk score more than 140 points” (28778541).
  • “Subgroup analysis demonstrated a significant reduction in recurrent MI amongst patients treated <24 hours”[3].
  • “Patients with unstable features, such as hemodynamic instability or major arrhythmias, should still receive intervention within two hours as per the European Society of Cardiology (ESC) guidelines”[3].

For the efficacy of early, versus late intervention, the number needed to treat (NNT) are:

  • Major cardiovascular events (MACE) such as death, myocardial infarction, or stroke[4]:
    • NNT for early vs late intervention to avoid MACE in GRACE score 0-140 = -111 (Not clinically nor statistically significant)
    • NNT for early vs late intervention to avoid MACE in GRACE score ≥141 = 14.1 & P-Value = 0.01 (Clinically and statistically significant)
  • Recurrent ischemia[3]:
    • NNT for early vs late intervention to avoid recurrent ischemia = 28.4 & P-Value = 0.004 (Clinically and statistically significant)

Trials Supporting Initial Invasive Strategy

More recently conducted randomized trials have shown benefit of early invasive strategy.

  • FRISC II[5] was a prospective randomized multicenter study conducted in 58 Scandinivian hospitals involving of 2457 patients with unstable angina. Patients were assigned in an early invasive or non-invasive treatment strategy with placebo-controlled long-term low-molecular-mass heparin (dalteparin) for 3 months. Coronary angiography was done within the first 7 days in 96% and 10%, and revascularization within the first 10 days in 71% and 9% of patients in the invasive and non-invasive groups, respectively. Patients were followed up at 6 months for composite endpoint of death or myocardial infarction. There was a significant decrease in myocardial infarction alone and non-significant reduction in mortality, independent of dalteparin treatment. Additional analyses showed greater benefit of the invasive strategy in higher risk groups identified by ST segment depression on the admission ECG or troponin elevation.
  • TACTICS-TIMI 18 trial[6] enrolled 2220 patients with unstable angina and myocardial infarction without ST-segment elevation who had electrocardiographic evidence of changes in the ST segment or T wave, elevated levels of cardiac markers, a history of coronary artery disease, or all three findings. During follow up, the rate of death, MI, or rehospitalization for ACS at 6 months fell from 19.4 percent in the conservative group to 15.9 percent in the early invasive group. Death or nonfatal MI was significantly reduced at 30 days and at 6 months. Using the TIMI risk score, there was significant benefit of the early invasive strategy in intermediate (score 3 to 4) and high-risk patients (5 to 7); whereas low-risk (0 to 2) patients had similar outcomes when managed with either strategy. Interestingly, this study also showed that invasive approach was cost effective as well.
  • The Randomized Intervention Trial of Unstable Angina (RITA-3 trial)[7], a randomised multicentre trial of 1810 patients with non-ST-elevation acute coronary syndromes, an interventional strategy was found to be beneficial when compared to a conservative strategy, mainly because of the halving of refractory or severe angina, and with no increased risk of death or myocardial infarction.
  • ISAR-COOL trial[8] also demonstrated benefit of early intervention. In this study, patients with UA/NSTEMI were randomly allocated to antithrombotic pretreatment for 3 to 5 days or to early intervention after pretreatment for less than 6 hours. Both groups received antithrombotic pretreatment with intravenous unfractionated heparin, aspirin, oral clopidogrel, and intravenous tirofiban. Patients were followed for composite 30-day incidence of large nonfatal myocardial infarction or death from any cause. The study concluded that in patients with unstable angina, deferral of intervention for prolonged antithrombotic pretreatment does not improve the outcome compared with immediate intervention accompanied by intense antiplatelet treatment.

Trials Supporting Initial Conservative Strategy

  • Delaying intervention till after neurologic recovery is not harmful according to the COACT trial[10].
  • TIMI IIIB trial[11] studied 1473 patients with unstable angina or non q wave MI were assigned to either tPA versus placebo and early invasive strategy versus conservative approach. The end point for the comparison of the two strategies (death, myocardial infarction, or an unsatisfactory symptom-limited exercise stress test at 6 weeks) occurred in 18.1% of patients assigned to the early conservative strategy and 16.2% of patients assigned to the early invasive strategy (P = NS). It concluded that both strategies can be used to achieve similar low mortality at the end of 6 weeks. However, it did show reduced incidence of days of hospitalization and of rehospitalization and in the use of antianginal drugs in early invasive strategy group.
  • VANQWISH trial[12] randomly assigned 920 patients to either invasive management or conservative management, defined as medical therapy and noninvasive testing, with subsequent invasive management if indicated by the development of spontaneous or inducible ischemia, within 72 hours of the onset of a non q wave MI. Overall mortality during follow-up (one month and one year) did not differ significantly between patients assigned to the conservative-strategy group and those assigned to the invasive-strategy group.

Indications

Initial Invasive strategy:

  • Based on multiple randomized trials, an early invasive strategy is now recommended in patients with UA/NSTEMI with ST segment changes and/or positive troponin on admission or that evolves over the next 24 hours.
  • Some patients may also require urgent catheterization and revascularization in the absence of ST deviation because of ongoing ischemic symptoms or hemodynamic or rhythm instability. Such patients are not candidates for conservative strategy.
  • In patients with other high-risk indicators, such as recurrent ischemia or evidence of congestive heart failure, cardiogenic shock, prior PCI within past 6 months and prior CABG; an early invasive approach is indicated.

Initial Conservative strategy:

  • Patients for whom a conservative approach is chosen should undergo a stress test (e.g., exercise or pharmacological stress) for the assessment of ischemia is recommended before discharge or shortly thereafter to identify patients who may also benefit from revascularization. Hence, a plan for noninvasive evaluation is required to detect severe ischemia that occurs spontaneously or at a low threshold of stress and to promptly refer these patients for coronary angiography and revascularization when possible.
  • Also, early assessment of left ventricular function is recommended with an echocardiogram.
  • In recent times, the use of aggressive anticoagulant and antiplatelet agents has reduced the incidence of adverse outcomes in patients managed conservatively.

Timing of an Invasive Strategy

There has been an ongoing debate about what should be the timing for an invasive strategy, once it is decided that the patient will be managed with this strategy.

  • Based on previous trials, patients treated with an invasive strategy generally undergo coronary angiography as early as 2 hrs to as late as 48hrs of admission with variable outcomes.
  • However, based on the recent trial results, it is reasonable for high risk patients to undergo early invasive strategy within 12-24 hours of admission.
    • Recent 2009 update of PCI guidelines by ACC/AHA was based on a large multicenter randomized trial by the TIMACS investigators[4]. This trial randomly assigned 3031 patients with acute coronary syndromes to undergo either routine early intervention (coronary angiography < or = 24 hours after randomization) or delayed intervention (coronary angiography > or = 36 hours after randomization). The primary outcome was the composite of death, MI, or stroke at 6 months, and a prespecified secondary outcome was death, MI, or refractory ischemia. Coronary angiography was performed at a median of 14 hours in the early-intervention group and 50 hours in the delayed intervention group. At 6 months, 9.7% of patients in the early-intervention group experienced a primary outcome versus 11.4% in the delayed-intervention group. Death, MI, or refractory ischemia was reduced by 28% in favor of early intervention. Prespecified analyses showed that early intervention improved the primary outcome in the third of patients who were at highest risk but not in the two thirds at low-to-intermediate risk. Early intervention did not differ greatly from delayed intervention in preventing the primary outcome, but it did reduce the rate of the composite secondary outcome of death, myocardial infarction, or refractory ischemia and was superior to delayed intervention in high-risk patients (GRACE risk score greater than 140).
    • In patients without ST-segment elevation on the electrocardiogram, urgent angioplasty may occur anytime within the first 24 hours according to the ABOARD randomized controlled trial[13].

2014 AHA/ACC Guideline for the Management of Patients With Non–ST-Elevation Acute Coronary Syndromes (DO NOT EDIT) [14]

Early Invasive and Ischemia-Guided Strategies

Class I
"1. An urgent/immediate invasive strategy (diagnostic angiography with intent to perform revascularization if appropriate based on coronary anatomy) is indicated in patients (men and women) with NSTE-ACS who have refractory angina or hemodynamic or electrical instability (without serious comorbidities or contraindications to such procedures). (Level of Evidence: A)"
"2. An early invasive strategy (diagnostic angiography with intent to perform revascularization if appropriate based on coronary anatomy) is indicated in initially stabilized patients with NSTEACS (without serious comorbidities or contraindications to such procedures) who have an elevated risk for clinical events. (Level of Evidence: B)"
Class III (No Benefit)
"1. An early invasive strategy (i.e., diagnostic angiography with intent to perform revascularization) is not recommended in patients with:

a. Extensive comorbidities (e.g., hepatic, renal, pulmonary failure, cancer), in whom the risks of revascularization and comorbid conditions are likely to outweigh the benefits of revascularization. (Level of Evidence: C)
b. Acute chest pain and a low likelihood of ACS (Level of Evidence: C) who are troponin negative, especially women. (Level of Evidence: B) "

Class IIa
"1. It is reasonable to choose an early invasive strategy (within 24 hours of admission) over a delayed invasive strategy (within 25 to 72 hours) for initially stabilized high-risk patients with NSTE-ACS. For those not at high/intermediate risk, a delayed invasive approach is reasonable. (Level of Evidence: B)"
Class IIb
"1. In initially stabilized patients, an ischemia-guided strategy may be considered for patients with NSTE-ACS (without serious comorbidities or contraindications to this approach) who have an elevated risk for clinical events. (Level of Evidence: B)"
"2. The decision to implement an ischemia-guided strategy in initially stabilized patients (without serious comorbidities or contraindications to this approach) may be reasonable after considering clinician and patient preference. (Level of Evidence: C)"

Cardiogenic Sock

Class I
"1. Early revascularization is recommended in suitable patients with cardiogenic shock due to cardiac pump failure after NSTE-ACS. (Level of Evidence: B)"

2012 ACCF/AHA Focused Update of the Guideline for the Management of Patients With Unstable Angina/Non–ST-Elevation Myocardial Infarction (Updating the 2007 Guideline and Replacing the 2011 Focused Update) (DO NOT EDIT)[15]

Initial Invasive Versus Initial Conservative Strategies (DO NOT EDIT)[15]

Class I
"1. An early invasive strategy (i.e., diagnostic coronary angiography with intent to perform percutaneous coronary revascularization or CABG) is indicated in UA / NSTEMI patients who have refractory angina or hemodynamic or electrical instability (without serious comorbidities or contraindications to such procedures). (Level of Evidence: B)"
"2. An early invasive strategy (i.e., diagnostic angiography with intent to perform percutaneous coronary revascularization or CABG) is indicated in initially stabilized UA / NSTEMI patients (without serious comorbidities or contraindications to such procedures) who have an elevated risk for clinical events (Level of Evidence: A)"
Class III (No Benefit)
"1. An early invasive strategy (i.e., diagnostic angiography with intent to perform coronary artery revascularization) is not recommended in patients with extensive comorbidities (e.g., liver failure or pulmonary failure, cancer), in whom the risks of revascularization and comorbid conditions are likely to outweigh the benefits of revascularization. (Level of Evidence: C)"
"2. An early invasive strategy (i.e., diagnostic angiography with intent to perform coronary artery revascularization) is not recommended in patients with acute chest pain and a low likelihood of Acute coronary syndromes. (Level of Evidence: C)"
"3. An early invasive strategy (i.e., diagnostic angiography with intent to perform coronary artery revascularization) should not be performed in patients who will not consent to revascularization regardless of the findings. (Level of Evidence: C)"
Class IIa
"1. It is reasonable to choose an early invasive strategy (within 12 to 24 hours of admission) over a delayed invasive strategy for initially stabilized high-risk patients with UA / NSTEMI*. For patients not at high risk, a delayed invasive approach is also reasonable. (Level of Evidence: B)"
Class IIb
"1. In initially stabilized patients, an initially conservative (i.e., a selectively invasive) strategy may be considered as a treatment strategy for UA / NSTEMI patients (without serious comorbidities or contraindications to such procedures) who have an elevated risk for clinical events including those who are troponin positive. (Level of Evidence: B). The decision to implement an initial conservative (vs. initial invasive) strategy in these patients may be made by considering physician and patient preference. (Level of Evidence: C)"

* Immediate catheterization/angiography is recommended for unstable patients.

2007 ACC/AHA Guidelines for the Management of Patients With Unstable Angina/Non–ST-Elevation Myocardial Infarction (DO NOT EDIT) [16]

The Timing of Angiography and Antiplatelet Therapy (DO NOT EDIT) [16]

Class I

"1. Patients with definite or likely UA/NSTEMI selected for an invasive approach should receive dual-antiplatelet therapy (Level of Evidence: A). Aspirin should be initiated on presentation (Level of Evidence: A), clopidogrel (before or at the time of PCI) (Level of Evidence: A) or prasugrel (at the time of PCI) (Level of Evidence: B) is recommended as a second antiplatelet agent."

Class IIa

"1. It is reasonable for initially stabilized high-risk patients with UA/NSTEMI (GRACE i.e. Global Registry of Acute Coronary Events, risk score greater than 140) to undergo an early invasive strategy within 12 to 24 hours of admission. For patients not at high risk, an early invasive approach is also reasonable. (Level of Evidence: B)"

References

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  2. Jobs A, Mehta SR, Montalescot G, Vicaut E, Van't Hof AWJ, Badings EA; et al. (2017). "Optimal timing of an invasive strategy in patients with non-ST-elevation acute coronary syndrome: a meta-analysis of randomised trials". Lancet. 390 (10096): 737–746. doi:10.1016/S0140-6736(17)31490-3. PMID 28778541. Review in: Evid Based Med. 2017 Dec;22(6):227
  3. 3.0 3.1 3.2 3.3 Javat D, Heal C, Buchholz S, Zhang Z (2017). "Early Versus Delayed Invasive Strategies in High-Risk Non-ST Elevation Acute Coronary Syndrome Patients - A Systematic Literature Review and Meta-Analysis of Randomised Controlled Trials". Heart Lung Circ. 26 (11): 1142–1159. doi:10.1016/j.hlc.2017.02.031. PMID 28515027.
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  7. Fox KA, Poole-Wilson PA, Henderson RA, Clayton TC, Chamberlain DA, Shaw TR, Wheatley DJ, Pocock SJ (2002). "Interventional versus conservative treatment for patients with unstable angina or non-ST-elevation myocardial infarction: the British Heart Foundation RITA 3 randomised trial. Randomized Intervention Trial of unstable Angina". Lancet. 360 (9335): 743–51. PMID 12241831. Retrieved 2011-04-13. Unknown parameter |month= ignored (help)
  8. Neumann FJ, Kastrati A, Pogatsa-Murray G, Mehilli J, Bollwein H, Bestehorn HP, Schmitt C, Seyfarth M, Dirschinger J, Schömig A (2003). "Evaluation of prolonged antithrombotic pretreatment ("cooling-off" strategy) before intervention in patients with unstable coronary syndromes: a randomized controlled trial". JAMA : the Journal of the American Medical Association. 290 (12): 1593–9. doi:10.1001/jama.290.12.1593. PMID 14506118. Retrieved 2011-04-13. Unknown parameter |month= ignored (help)
  9. Bavry AA, Kumbhani DJ, Rassi AN, Bhatt DL, Askari AT (2006). "Benefit of early invasive therapy in acute coronary syndromes: a meta-analysis of contemporary randomized clinical trials". Journal of the American College of Cardiology. 48 (7): 1319–25. doi:10.1016/j.jacc.2006.06.050. PMID 17010789. Retrieved 2011-04-13. Unknown parameter |month= ignored (help)
  10. Lemkes JS, Janssens GN, van der Hoeven NW, Jewbali LSD, Dubois EA, Meuwissen M; et al. (2019). "Coronary Angiography after Cardiac Arrest without ST-Segment Elevation". N Engl J Med. 380 (15): 1397–1407. doi:10.1056/NEJMoa1816897. PMID 30883057. Review in: Ann Intern Med. 2019 Jul 16;171(2):JC4
  11. "Effects of tissue plasminogen activator and a comparison of early invasive and conservative strategies in unstable angina and non-Q-wave myocardial infarction. Results of the TIMI IIIB Trial. Thrombolysis in Myocardial Ischemia". Circulation. 89 (4): 1545–56. 1994. PMID 8149520. Retrieved 2011-04-13. Unknown parameter |month= ignored (help)
  12. Boden WE, O'Rourke RA, Crawford MH, Blaustein AS, Deedwania PC, Zoble RG, Wexler LF, Kleiger RE, Pepine CJ, Ferry DR, Chow BK, Lavori PW (1998). "Outcomes in patients with acute non-Q-wave myocardial infarction randomly assigned to an invasive as compared with a conservative management strategy. Veterans Affairs Non-Q-Wave Infarction Strategies in Hospital (VANQWISH) Trial Investigators". The New England Journal of Medicine. 338 (25): 1785–92. doi:10.1056/NEJM199806183382501. PMID 9632444. Retrieved 2011-04-13. Unknown parameter |month= ignored (help)
  13. Montalescot G, Cayla G, Collet JP, Elhadad S, Beygui F, Le Breton H, Choussat R, Leclercq F, Silvain J, Duclos F, Aout M, Dubois-Randé JL, Barthélémy O, Ducrocq G, Bellemain-Appaix A, Payot L, Steg PG, Henry P, Spaulding C, Vicaut E (2009). "Immediate vs delayed intervention for acute coronary syndromes: a randomized clinical trial". JAMA : the Journal of the American Medical Association. 302 (9): 947–54. doi:10.1001/jama.2009.1267. PMID 19724041. Retrieved 2011-04-13. Unknown parameter |month= ignored (help)
  14. Ezra A. Amsterdam, MD, FACC; Nanette K. Wenger, MD et al.2014 AHA/ACC Guideline for the Management of Patients With Non–ST-Elevation Acute Coronary Syndromes. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. JACC. September 2014 (ahead of print)
  15. 15.0 15.1 2012 Writing Committee Members. Jneid H, Anderson JL, Wright RS, Adams CD, Bridges CR; et al. (2012). "2012 ACCF/AHA Focused Update of the Guideline for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction (Updating the 2007 Guideline and Replacing the 2011 Focused Update): A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines". Circulation. 126 (7): 875–910. doi:10.1161/CIR.0b013e318256f1e0. PMID 22800849.
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