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European Heart Journal – Cardiovascular Pharmacotherapy (2015) 1, 179–181
doi:10.1093/ehjcvp/pvv017
EDITORIAL
Acute coronary syndromes
Medical management: the dark side of acute
coronary syndromes
He´ctor Bueno*
Department of Cardiology, Hospital General Universitario Gregorio Maran˜o´n, Madrid, Spain
Online publish-ahead-of-print 27 March 2015
In this issue of European Heart Journal Cardiovascular Pharmacology a
substudy of the Italian EYESHOT Registry focused on medically
managed patients is published.1 In it, the authors describe the antithrombotic therapy employed in hospital in the roughly 30% of patients
with acute coronary syndromes (ACS) who did not undergo coronary
revascularization during index hospitalization, that is, who were
medically managed.
Guidelines recommend an invasive strategy for a majority of
patients with ACS.2 – 5 However, still a substantial proportion of
ACS patients are currently medically managed,6,7 as shown again in
this 2585 patient cohort study. This is particularly true for patients
with non-ST-segment elevation ACS (NSTEACS) in whom the rate
of medical management (MM) was more than three times higher
than for ST-segment elevation myocardial infarction (STEMI)
patients (42.7 vs. 12.6%). The reasons for MM are varied (Figure 1).
The first reason is the decision not to send the patient for coronary
angiography. That would be expected in low-risk patients, in whom
coronary angiography is not initially recommended. However, the
current study shows that patients who did not undergo coronary
angiography were older, had a greater cardiovascular burden,
presented more comorbidities, and developed more complications
in hospital. These findings are consistent with several other registries
from all over the world.6,8 – 12 What is the reason for this risk
paradox? It is understandable that MM may be preferred in a minority
of patients, such as those of very advanced age with dementia or
severe dependence, or those with heavy comorbidity, particularly
with severe renal dysfunction or malignancy at an advanced stage in
whom prognosis, risk, or quality of life may be conditioned by noncardiac conditions. And this is, in fact, part of the picture in this
study. However, the most important determinant of MM is the lack
of a catheterization laboratory in the hospital, something that is not
related to the patient’s risk. It is a shame that in the era in which networks for STEMI care have become the standard of care, high-risk
patients with NSTEACS are not transferred to centres with catheterization laboratory for reasons different from potential futility or patient
preference. Unfortunately, the current study shows again that having
a catheterization laboratory in hospital remains the main determinant
of receiving coronary angiography in these patients as in the past
years.8,11,13 Moreover, the majority of independent predictors of
not receiving coronary angiography during hospitalization and of
not undergoing coronary revascularization after coronary angiography are known to be associated with a worse prognosis. In addition
to the evidences from clinical trials,14 several studies have shown that
medical management is an independent predictor of an increased
long-term mortality risk in real life.11,15,16 For this reason, there is
an obvious need to improve compliance with guidelines, particularly
in NSTEACS patients, and advance in reinforcing the use of risk stratification and effective hospital networking for non-emergent transfers, which currently show a highly variable pattern.17
There is large room for improvement in risk stratification and
putting into practice risk-driven therapies for ACS patients. While
overcoming the risk paradox for NSTEACS patients has revealed
to be a Herculean labour in the last years, a second approach to
reduce the disadvantage of medically managed patients was
attempted. The TRILOGY-ACS trial tested the intensification of
dual antiplatelet therapy with prasugrel instead of clopidogrel for a
median follow-up of 17 months in 9326 medically managed
NSTEACS patients to reduce cardiovascular outcomes. Contrary
to what might have been expected according to observations from
subgroups of the CURE and PLATO trials comparing clopidogrel
with placebo18 and ticagrelor with clopidogrel,19,20 respectively, on
top of aspirin, increasing antiplatelet potency with prasugrel failed
to show a beneficial effect in medically managed patients as it did
not translate into any significant benefit.21 Interestingly, patients
who underwent coronary angiography did seem to have some
benefit with prasugrel compared with those who did not.22 The
EYESHOT registry found that medically managed patients not only
did not undergo coronary revascularization but received a different
antithrombotic therapy during hospitalization compared with those
who were revascularized, including a higher use of low molecular
weight heparin and lower use of newer P2Y12 inhibitors, prasugrel
and ticagrelor, as recommended by current guidelines. However,
baseline risk differences instead of treatment most likely explain
the large increase in hospital mortality found in these patients. Postdischarge events may have been influenced by the different treatment.
Unfortunately, follow-up results were not provided in EYESHOT.
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal – Cardiovascular Pharmacotherapy or of the European Society of Cardiology.
* Corresponding author: [email protected]
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2015. For permissions please email: [email protected]
180
Editorial
Figure 1 Reasons for and average frequencies of medical management for patients presenting with non-ST-segment elevation acute coronary
syndromes. ACS, acute coronary syndrome; CABG, coronary artery bypass grafting; CAD, significant coronary artery disease; CAG, coronary angiography; PCI, percutaneous coronary intervention; Revasc, coronary revascularization.
Although there are basically no exceptions to prioritizing reperfusion therapy in the early treatment of STEMI, and this is universally
accepted, that is not the case for patients with NSTEACS in whom
a risk paradox for an invasive strategy is frequently found. The high
short- and long-term event rate of medically managed patients pinpoints the clinical challenge. For this reason, there are a number of
urgent needs to improve the management of these patients. First,
to understand better the key factors leading physicians to decide to
not indicate an invasive strategy for moderate- to high-risk patients
and/or, later on, coronary revascularization in those with severe coronary artery disease. Second, to develop better tools to identify
which patients would benefit from an invasive strategy even in the
case of advanced age or important comorbidity or, alternatively,
those who will not. Current information about the benefit/risk
ratios in NSTEACS patients in whom decisions are difficult to be
made is very limited. We need to define the role of advanced
age, geriatric syndromes23—frailty in particular24—and severe comorbidity25 in clinical decision-making. The development of risk
models to identify patients unlikely to benefit from an invasive strategy,
as done for other interventions,26 will also facilitate defining the highrisk patients in whom medical management may be the preferred
option in terms of risk improvement. Multicentre randomized controlled trials enrolling older patients,27 and patients with comorbidities,
especially those with moderate to advanced renal dysfunction are challenging but strongly needed. Third, more research is needed on
effective interventions to optimize patient care and facilitate changing practices to avoid patients with potential gain being deprived of
the opportunity of coronary revascularization. Finally, although it is
very unlikely that a good drug therapy may overcome the consequences of a wrong strategy, there will be a substantial proportion
of patients with NSTEACS who will receive medical management
for different reasons, appropriately or inappropriately. Defining
the optimal medical therapy for these patients, including antithrombotic therapies and other drugs with different mechanisms, is still an
unmet need.
The high short- and long-term event rate of medically managed
patients with ACS, the uncertainties about the reasons for the risk
paradox in selecting an invasive strategy, the chronic difficulties to
correct this anomaly, and the shortness of evidences about the
best treatment for these patients explain why medical management
can be defined as the dark side of ACS.
References
1. De Luca l, Leonardi S, Smecca IM, Formigli D, Lucci D, Gonzini L, Tuccillo B, Olivari Z,
Gulizia MM, Bovenzi FM, De Servi S, on behalf of the EYESHOT Investigators. Contemporary antithrombotic strategies in patients with acute coronary syndromes
managed without revascularization: insights from the EYESHOT study. Eur Heart J
Cardiovasc Pharmacother 2015;1:doi.org/10.1093/ehjcvp/pvv006.
2. Hamm CW, Bassand JP, Agewall S, Bax J, Boersma E, Bueno H, Caso P, Dudek D,
Gielen S, Huber K, Ohman M, Petrie MC, Sonntag F, Uva MS, Storey RF, Wijns W,
Zahger D; ESC Committee for Practice Guidelines. ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent
ST-segment elevation: The Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the
European Society of Cardiology (ESC). Eur Heart J 2011;32:2999 –3054.
3. Anderson JL, Adams CD, Antman EM, Bridges CR, Califf RM, Casey DE Jr.,
Chavey WE, Fesmire FM, Hochman JS, Levin TN, Lincoff AM, Peterson ED,
Theroux P, Wenger NK, Wright RS, Jneid H, Ettinger SM, Ganiats TG, Lincoff AM,
Philippides GJ, Zidar JP. 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:e663–e828.
4. Task Force on the management of ST-segment elevation acute myocardial infarction
of the European Society of Cardiology (ESC), Steg PG, James SK, Atar D, Badano LP,
Blo¨mstrom-Lundqvist C, Borger MA, Di Mario C, Dickstein K, Ducrocq G,
Fernandez-Aviles F, Gershlick AH, Giannuzzi P, Halvorsen S, Huber K, Juni P,
Kastrati A, Knuuti J, Lenzen MJ, Mahaffey KW, Valgimigli M, van’t Hof A,
Widimsky P, Zahger D. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J 2012;33:
2569 –2619.
Editorial
5. American College of Emergency Physicians; Society for Cardiovascular Angiography
and Interventions, O’Gara PT, Kushner FG, Ascheim DD, Casey DE Jr, Chung MK, de
Lemos JA, Ettinger SM, Fang JC, Fesmire FM, Franklin BA, Granger CB, Krumholz HM,
Linderbaum JA, Morrow DA, Newby LK, Ornato JP, Ou N, Radford MJ,
Tamis-Holland JE, Tommaso CL, Tracy CM, Woo YJ, Zhao DX, Anderson JL,
Jacobs AK, Halperin JL, Albert NM, Brindis RG, Creager MA, DeMets D,
Guyton RA, Hochman JS, Kovacs RJ, Kushner FG, Ohman EM, Stevenson WG,
Yancy CW. 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:e78– e140.
6. Bueno H, Sinnaeve P, Annemans L, Danchin N, Licour L, Medina J, Pocock S,
Sa´nchez-Covisa J, Storey RF, Jukema JW, Zeymer W, Van de Werf F. Opportunities
for improvement in anti-thrombotic therapy and other strategies for the management of acute coronary syndromes: insights from EPICOR, an international
study of current practice patterns. Eur Heart J Acute Cardiovasc Care 2015.
pii: 2048872614565912. [Epub ahead of print].
7. Puymirat E, Battler A, Birkhead H, Bueno H, Clemmensen P, Cottin Y, Fox KAA,
Gorenek B, Hamm C, Huber K, Lettino M, Lindahl B, Mu¨ller C, Parkhomenko A,
Price S, Quinn T, Schiele F, Simoons M, Tatu-Chitoiu G, Tubaro M, Vrints C,
Zahger D, Zeymer U, Danchin N, on behalf of the EHS 2009 snapshot participants.
Euro Heart Survey 2009 Snapshot: regional variations in presentation and management
of patients with AMI in 47 countries. Eur Heart J Acute Cardiovasc Care 2013;2:359–370.
8. Heras M, Bueno H, Bardajı´ A, Ferna´ndez-Ortiz A, Martı´ H, Marrugat J, on behalf of the
DESCARTES investigators. Magnitude and consequences of undertreatment in highrisk patients with non-ST-segment elevation acute coronary syndromes. Insights
from the DESCARTES Registry. Heart 2006;92:1571 – 1576.
9. Yan AT, Yan RT, Tan M, Fung A, Cohen EA, Fitchett DH, Langer A, Goodman SG;
Canadian Acute Coronary Syndromes 1 and 2 Registry Investigators. Management
patterns in relation to risk stratification among patients with non-ST elevation
acute coronary syndromes. Arch Intern Med 2007;167:1009 –1016.
10. Fox KA, Anderson FA Jr, Dabbous OH, Steg PG, Lo´pez-Sendo´n J, Van de Werf F,
Budaj A, Gurfinkel EP, Goodman SG, Brieger D; GRACE investigators. Intervention
in acute coronary syndromes: do patients undergo intervention on the basis of their
risk characteristics? The Global Registry of Acute Coronary Events (GRACE). Heart
2007;93:177 –182.
11. Ferreira-Gonza´lez I, Permanyer-Miralda G, Heras M, Cun˜at J, Civeira E, Aro´s F,
Rodrı´guez JJ, Sa´nchez PL, Marsal JR, Ribera A, Marrugat J, Bueno H; MASCARA
study group. Patterns of use and effectiveness of early invasive strategy in
non-ST-segment elevation acute coronary syndromes. Am Heart J 2008;156:
946 –953.
12. Yan AT, Yan RT, Huynh T, Casanova A, Raimondo FE, Fitchett DH, Langer A,
Goodman SG; Canadian Acute Coronary Syndrome Registry 2 Investigators. Understanding physicians’ risk stratification of acute coronary syndromes: insights from the
Canadian ACS 2 Registry. Arch Intern Med 2009;169:372 – 378.
13. Van de Werf F, Gore JM, Avezum A, Gulba DC, Goodman SG, Budaj A, Brieger D,
White K, Fox KA, Eagle KA, Kennelly BM; GRACE Investigators. Access to catheterisation facilities in patients admitted with acute coronary syndrome: multinational
registry study. BMJ 2005;330:441.
14. Fox KA, Clayton TC, Damman P, Pocock SJ, de Winter RJ, Tijssen JG, Lagerqvist B,
Wallentin L; FIR Collaboration. Long-term outcome of a routine versus selective invasive strategy in patients with non-ST-segment elevation acute coronary syndrome
a meta-analysis of individual patient data. J Am Coll Cardiol 2010;55:2435 –2445.
15. Pocock S, Bueno H, Licour M, Medina J, Zhang L, Annemans L, Danchin N, Huo Y, Van
de Werf F. Predictors of one-year mortality at hospital discharge after acute coronary syndromes: A new risk score from the EPICOR (long-tErm follow uP of antithrombotic management patterns In acute CORonary syndrome patients) study. Eur
Heart J Acute Cardiovasc Care 2014. pii: 2048872614554198. [Epub ahead of print].
181
16. Roe MT, White JA, Kaul P, Tricoci P, Lokhnygina Y, Miller CD, van’t Hof AW,
Montalescot G, James SK, Saucedo J, Ohman EM, Pollack CV Jr, Hochman JS,
Armstrong PW, Giugliano RP, Harrington RA, Van de Werf F, Califf RM,
Newby LK. Regional patterns of use of a medical management strategy for patients
with non-ST-segment elevation acute coronary syndromes: insights from the EARLY
ACS Trial. Circ Cardiovasc Qual Outcomes 2012;5:205 – 213.
17. Sinnaeve PR, Zeymer U, Bueno H, Danchin N, Medina J, Sa´nchez-Covisa J, Licour M,
Annemans L, Jukema JW, Pocock S, Storey RF, Van de Werf F. Contemporary interhospital transfer patterns for the management of acute coronary syndrome patients:
Findings from the EPICOR study. Eur Heart J Acute Cardiovasc Care. 2014; [Epub ahead
of print].
18. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK. Effects of clopidogrel
in addition to aspirin in patients with acute coronary syndromes without ST-segment
elevation. N Engl J Med 2001;345:494 –502.
19. James SK, Roe MT, Cannon CP, Cornel JH, Horrow J, Husted S, Katus H, Morais J,
Steg PG, Storey RF, Stevens S, Wallentin L, Harrington RA; PLATO Study Group.
Ticagrelor versus clopidogrel in patients with acute coronary syndromes intended
for non-invasive management: substudy from prospective randomised PLATelet
inhibition and patient Outcomes (PLATO) trial. BMJ 2011;342:d3527.
20. Lindholm D, Varenhorst C, Cannon CP, Harrington RA, Himmelmann A, Maya J,
Husted S, Steg PG, Cornel JH, Storey RF, Stevens SR, Wallentin L, James SK.
Ticagrelor vs. clopidogrel in patients with non-ST-elevation acute coronary
syndrome with or without revascularization: results from the PLATO trial. Eur
Heart J 2014;35:2083 –2093.
21. Roe MT, Armstrong PW, Fox KA, White HD, Prabhakaran D, Goodman SG,
Cornel JH, Bhatt DL, Clemmensen P, Martinez F, Ardissino D, Nicolau JC,
Boden WE, Gurbel PA, Ruzyllo W, Dalby AJ, McGuire DK, Leiva-Pons JL,
Parkhomenko A, Gottlieb S, Topacio GO, Hamm C, Pavlides G, Goudev AR,
Oto A, Tseng CD, Merkely B, Gasparovic V, Corbalan R, Cinteza˘ M,
McLendon RC, Winters KJ, Brown EB, Lokhnygina Y, Aylward PE, Huber K,
Hochman JS, Ohman EM; TRILOGY ACS Investigators. Prasugrel versus clopidogrel
for acute coronary syndromes without revascularization. N Engl J Med 2012;367:
1297 –1309.
22. Wiviott SD, White HD, Ohman EM, Fox KA, Armstrong PW, Prabhakaran D,
Hafley G, Lokhnygina Y, Boden WE, Hamm C, Clemmensen P, Nicolau JC,
Menozzi A, Ruzyllo W, Widimsky P, Oto A, Leiva-Pons J, Pavlides G, Winters KJ,
Roe MT, Bhatt DL. Prasugrel versus clopidogrel for patients with unstable angina
or non-ST-segment elevation myocardial infarction with or without angiography:
a secondary, prespecified analysis of the TRILOGY ACS trial. Lancet 2013;382:
605 –613.
23. Sa´nchez E, Vida´n MT, Serra JA, Ferna´ndez-Avile´s F, Bueno H. Prevalence of geriatric
syndromes and impact on clinical and functional outcomes in older patients with
acute cardiac diseases. Heart 2011;97:1602 –1606.
24. Sanchis J, Bonanad C, Ruiz V, Ferna´ndez J, Garcı´a-Blas S, Mainar L, Ventura S,
Rodrı´guez-Borja E, Chorro FJ, Hermenegildo C, Bertomeu-Gonza´lez V, Nu´n˜ez E,
Nu´n˜ez J. Frailty and other geriatric conditions for risk stratification of older patients
with acute coronary sı´ndrome. Am Heart J 2014;168:784 – 791.
25. Savonitto S, Morici N, De Servi S. Update: acute coronary syndromes (VI): treatment
of acute coronary syndromes in the elderly and in patients with comorbidities. Rev
Esp Cardiol (Engl Ed) 2014;67:564 –573.
26. Lindman BR, Alexander KP, O’Gara PT, Afilalo J. Futility, benefit, and transcatheter
aortic valve replacement. JACC Cardiovasc Interv 2014;7:707 –716.
27. Savonitto S, Cavallini C, Petronio AS, Murena E, Antonicelli R, Sacco A, Steffenino G,
Bonechi F, Mossuti E, Manari A, Tolaro S, Toso A, Daniotti A, Piscione F, Morici N,
Cesana BM, Jori MC, De Servi S; Italian Elderly ACS Trial Investigators. Early aggressive versus initially conservative treatment in elderly patients with non-ST-segment
elevation acute coronary syndrome: a randomized controlled trial. JACC Cardiovasc
Interv 2012;5:906 –916.