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Serial Angiography in Patients with Acute Coronary Syndromes: Effect of Antithrombotic Therapy on Angiographic Lesion Severity
ORIGINAL ARTICLE
Original Article
Serial Angiography in Patients with Acute Coronary Syndromes: Effect of Antithrombotic Therapy on Angiographic Lesion Severity Ananth M. Prasan, FRACP, PhD, Rohan Bhagwandeen, FRACP, Victor J. Solanki, FRACP, S. Benjamin Freedman, FRACP and David Brieger, FRACP, PhD ∗ Department of Cardiology, Concord Repatriation Hospital, Sydney, NSW, Australia
Background: Patients presenting with acute coronary syndromes (ACS) commonly have a responsible culprit coronary lesion. There is limited data on the natural history of this culprit lesion in the short term and whether there is a change in morphology of this lesion in the days following presentation. Furthermore, the effect of antithrombotic therapy on this process is unknown. Methods: Sixty-eight patients presenting with ACS had their diagnostic study performed at our institution and had coronary angioplasty performed a few days later at a different hospital. Culprit lesion characteristics including minimum luminal diameter (MLD) and percentage diameter stenosis were determined on each occasion. Results: Acute myocardial infarction patients (n = 14) had improved culprit lesion characteristics at angioplasty compared to baseline (diameter stenosis 78.9% versus 62.4%, p < 0.01). Similarly, patients presenting with unstable angina (UA) or non-ST elevation myocardial infarction (non-STEMI) (n = 54) had improved diameter stenosis (78.0% versus 72.7%, p < 0.001). The change in MLD was greater in MI patients than UAP/non-STEMI patients (0.6 mm versus 0.16 mm, p < 0.01). Conclusion: Treatment of ACS patients with aspirin with anticoagulant therapy followed by delayed intervention results in angiographic improvement in lesion severity which may provide a more favourable environment in which to undertake percutaneous coronary intervention. (Heart, Lung and Circulation 2006;15:378–382) © 2006 Australasian Society of Cardiac and Thoracic Surgeons and the Cardiac Society of Australia and New Zealand. Published by Elsevier Inc. All rights reserved. Keywords. Angioplasty; Acute coronary syndromes; Plaque remodelling
Introduction
S
everal recent studies have shown that patients presenting with an acute coronary syndrome (ACS) at high and intermediate risk of an adverse short term outcome benefit from a strategy that includes coronary angiography and, if appropriate, revascularisation during the hospital admission.1 In FRISC II2,3 and RITA 34 the patients randomised to an invasive strategy were treated for three to seven days with therapy including aspirin (ASA) and low molecular weight (LMW) heparin before undergoing coronary angiography and, where appropriate, revascularisation. In the TACTICS/TIMI 18 trial5 the invasive group underwent coronary angiography 4–48 hours after randomisation on background therapy that included ASA, unfractionated heparin and a glycoprotein (GP) IIb/IIIa Received 15 August 2005; received in revised form 2 August 2006; accepted 6 September 2006 ∗
Corresponding author. Tel.: +61 2 97676296; fax: +61 2 97676994. E-mail address: [email protected] (D. Brieger).
antagonist. This strategy of early (<48 hours) revascularisation was cost effective6 and has led to the view that early angiography and revascularisation is the preferred treatment strategy for patients with ACS. As only a minority of hospitals are equipped with angiographic facilities, most patients presenting with an ACS must be transferred expeditiously to be offered this management approach. Prior to TACTICS/TIMI 185 several observational studies had found a lower rate of complications in patients undergoing percutaneous intervention more than 48 hours after admission, during which time heparin and ASA were administered.7 This strategy theoretically allows time for passivation of the plaque8 and a reduction in the volume of thrombus that may allow the intervention to proceed in a safer environment. However, there are limited data objectively demonstrating that medical stabilisation with ASA and heparin or LMW heparin improves the appearance or severity of culprit unstable plaque. In this study a delay in performing coronary intervention following diagnostic angiography was used to
© 2006 Australasian Society of Cardiac and Thoracic Surgeons and the Cardiac Society of Australia and New Zealand. Published by Elsevier Inc. All rights reserved.
1443-9506/04/$30.00 doi:10.1016/j.hlc.2006.09.001
examine the natural history of culprit lesion progression in patients presenting with acute coronary syndromes.
Methods Patient Enrolment Data were collected on consecutive ACS patients undergoing coronary angiography in our institution if they demonstrated clinical and angiographic criteria for culprit lesion PCI. As this hospital did not perform coronary intervention, patients were routinely transferred to a nearby hospital for PCI after the coronary angiogram. The decision concerning the urgency of PCI was made by the referring physician and only cases in which transfer was requested on a semi-urgent basis were included in this study. Timing of transfer was therefore determined by bed availability at the receiving hospital and not influenced by the patient’s clinical characteristics. During this period, 54 patients presenting with unstable angina (UA) or non-ST elevation myocardial infarction (non-STEMI) and 14 patients presenting with ST elevation myocardial infarction (STEMI, all given thrombolytic therapy) were referred for PCI. All patients received aspirin 150 mg daily while awaiting transfer for PTCA. The use of other therapy, including antithrombotic agents was at the discretion of the responsible cardiologist. A thienopyridine (Ticlopidine 500 mg) was administered the night before the PCI procedure and no patients received GP IIb/IIIa antagonists during the study period.
Interpretation of Angiography The diagnostic and pre-PTCA guiding angiograms were recorded on Toshiba and Phillips digital systems, respectively. Caliper measurements were performed on still frames viewed on a digital video recorder (DVR Sony). Matched views showing the maximal luminal diameter reduction of the culprit lesion were used to assess severity of the stenosis. Angiograms were analysed in random order by two independent observers blinded to the patients’ clinical characteristics. Glyceryl trinitrate was not administered pre-procedure and it was assumed that reference diameter did not change between sequential angiograms performed days apart. To exclude a systematic bias, corresponding measurements were performed in six patients with stable angina who had delayed intervention. These angiograms were viewed in random order interspersed with those of the study cohort. The intra-observer variability expressed as maximal luminal stenosis was 4.6 ± 2.1% and the inter-observer variability was 3.7 ± 2.9% for 30 pairs of randomly selected angiograms indicating reliable reproducibility of the analysed data.
Statistics Data are described as mean ± standard deviation. Angiographic data were compared between groups by analysis of variance with post hoc comparison of group means when significance was indicated (SPSS 10.0 SPSS Inc., Chicago, IL).9 A p-value <0.05 was considered statistically significant.
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Table 1. Baseline Characteristics of Patients (%) Presenting with an Acute Coronary Syndrome Baseline Characteristics
All Patients
Sex Male Female
32 (59.3) 26 (40.7)
N Age (years)
68 60 ± 12
Past medical history MI CABG PTCA
18 6 6
Risk factors Hypertension Diabetes Cholesterol Family history Smoking
UAP/ Non-STEMI
34 (50.0) 11 (16.2) 44 (64.7) 22 (32.4) 17 (25.0)
54 60 ± 12
STEMI
12 (85.7) 2 (14.3) 14 59 ± 14
13 (26.5) 5 (10.2) 6 (12.2)
3 (21.4) 1 (7.4) 0 (0.0)
22 (44.9%) 9 (18.4%) 30 (61.2%) 19 (38.8%) 13 (28.5%)
8 (57.1) 1 (7.1) 9 (64.3) 2 (14.3) 3 (21.4)
Results Baseline Characteristics Clinical profiles of the 68 patients presenting with an unstable coronary syndrome are shown in Table 1. Fortyeight patients (34 males) presented with unstable angina and six patients had a non-ST elevation MI, diagnosed by a greater than two fold elevated creatine kinase. Assays of troponin T or I were not available during the period of this study. A total of 47 patients diagnosed with UAP/non-STEMI were treated with antithrombotic therapy (29 unfractionated heparin, 18 low molecular weight heparin). Patients were treated with antithrombotic therapy for 6.0 ± 2.6 days (range 2–13). Eighteen patients were receiving this treatment up to the time of PCI. The delay between performance of the baseline angiogram and PCI was 5.8 ± 3.8 days (range 2–15). Fourteen patients (12 males) presented with ST elevation MI. All were treated with aspirin and thrombolysis followed by anticoagulant therapy (12 unfractionated heparin, 2 low molecular weight heparin) for 5.4 ± 2.2 days (range 3–8). Percutaneous intervention and the second angiogram was performed at a mean of 7 ± 4.5 days (range 4–15) following diagnostic angiography. No patient died or experienced clinical (re)myocardial infarction during the period between diagnostic angiogram and PCI.
Angiographic Culprit Lesion Characteristics One patient presenting with STEMI had an occluded vessel both at diagnostic angiography and at PCI. At the time of PCI, three patients (one STEMI, two UAP) had an occluded target vessel which had been patent on the diagnostic angiogram. In all three patients vessel occlusion was clinically silent. In the remaining 64 patients with ACS, minimum lumen diameter (MLD) increased significantly (Table 2). There was a corresponding reduction in maximal coronary artery stenosis: from 78% to 72.7%, p < 0.001 in UAP/nonSTEMI patients and from 78.9% to 62.4%, p < 0.01 in
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Prasan et al. Serial angiography in ACS patients
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Table 2. Paired Data for Minimal Luminal Diameter at Angiogram and Pre-PTCA MLD Lesion/mm
UAP/Non-STEMI STEMI SAP
n
Angio
Pre-PTCA
p-Value
46 12 6
0.70 ± 0.04 0.72 ± 0.09 0.65 ± 0.14
0.86 ± 0.05 1.32 ± 0.21 0.66 ± 0.11
<0.001 <0.01 NS
STEMI patients (Fig. 1a and b). The reduction in lesion severity was significantly improved in STEMI versus UAP/non-STEMI patients (change in MLD 0.6 mm versus 0.16 mm p < 0.01, and reduction in stenosis severity 16.5% versus 5.3%, p < 0.01). In patients with stable angina, neither minimal lumen diameter (0.65 ± 0.14 mm versus 0.66 ± 0.11 mm, p NS) nor maximal coronary artery stenosis (79% versus 77.5%, p NS) changed between angiography and performance of PTCA (Fig. 1c).
Figure 1. Paired data for minimal luminal diameter from angiogram (angio 1) and pre-PTCA film (angio 2) in patients with (a) unstable angina/non-STEMI (n = 52); (b) STEMI (n = 12); and (c) SAP (n = 6) figure. Paired angiograms in which either the angiogram or pre-PTCA film showed a complete occlusion were excluded.
No influence of type of anticoagulant treatment (unfractionated heparin versus low molecular weight heparin) in UAP/non-STEMI patients on lesion characteristic was identified (change in percent stenosis 5.5 ± 2.5 versus 4.6 ± 1.8, p NS).
Discussion A number of observational studies have suggested that in patients with acute coronary syndromes use of antithrombotic and anti-ischaemic therapies for several days prior to angiography and revascularisation reduce the complications of the intervention.3 This was the strategy adopted in the FRISC II trial2,3 which was the first to report that a routine invasive strategy was superior to a conservative approach in these patients, a finding that was recently confirmed among lower risk patients in the RITA 3 trial.4 It has been postulated that an initial period of medical stabilisation passivates the ruptured plaque, allowing the PCI to proceed in a less hostile environment10 but to date there has been little angiographic evidence to support this. Furthermore, there is limited data documenting serial angiographic culprit lesion characteristics in patients presenting with acute coronary syndromes.11,12 At the time of undertaking our study, the availability of angiography without on-site angioplasty provided a unique opportunity to study angiographically the impact of a strategy of “plaque passivation” using antiplatelet and anticoagulant therapy on the severity of luminal stenosis. Whilst we believe that the reduction in lesion severity observed in the current study may equate to “plaque passivation” this remains unproven. However, our study does demonstrate the finding that plaque regression occurs in the context of delayed angioplasty and is of importance to the substantial proportion of acute coronary syndrome patients who routinely experience a delay in coronary intervention. Our results indicate that for patients treated medically for an average of 5.7 days prior to PCI, there is a significant reduction in the angiographic severity of the culprit lesion. All our patients received ASA and most either heparin or LMW heparin and the most likely mechanism for improvement of luminal diameter in these patients was partial thrombus dissolution with inhibition of continuing thrombus formation. This thrombus resolution may be a surrogate for diminishing threat of further coronary occlusion supporting a potential advantage for a period of medical stabilisation prior to proceeding to revascularisation. Consistent with the above hypothesis, we found the magnitude of improvement in minimal luminal diameter was greater for the STEMI than the UAP/nonSTEMI patients reflecting a greater resolution of thrombus burden in STEMI patients. No difference between unfractionated heparin and low molecular weight heparin therapy was seen on change in stenosis severity or lumen diameter was seen in this small study. Whilst we believe that antithrombotic therapy impacts on improvement in lesion severity it is conceivable that this could have occurred without administration of antithrombotic therapy.
TACTICS/TIMI 185 demonstrated that treatment with ASA, heparin and GP IIb/IIIa antagonist followed by early (median 22 hours after admission) coronary angiography and percutaneous revascularisation in patients with ACS is superior to an initial strategy of conservative management. Early coronary intervention was not associated with an increased risk of peri procedural myocardial infarction, attributed to the protective effect of pre-treatment with a glycoprotein IIb/IIIa antagonist. Furthermore, when facilities are available, this strategy is cost effective and has been adopted by many invasive centres within the United States. However, it is important to note that in TACTICS/TIMI 18 there were different definitions between peri procedural MI (increase in troponin or CK >3 times the upper limit of normal) and MI’s not related to coronary intervention (any elevation in marker or enzyme >upper limit of normal) which meant that patients randomised to a conservative strategy were subjected to the more stringent definition of MI. This may have amplified the perceived benefit in patients undergoing early intervention. Furthermore, in the GRACE registry,13 compared to patients presenting to hospitals without a catheterisation laboratory, patients admitted directly to an interventional centre had an increased risk of death and increased bleeding complications. This evidence supports a strategy of delayed coronary intervention which has been advocated by some authors.10 Analyses of coronary angiograms in the PRISM PLUS14 trial showed that treatment with tirofiban in addition to ASA and heparin reduced the thrombus load at the site of the culprit lesion in patients with ACS. Our study was undertaken before the widespread availability of glycoprotein IIb/IIIa inhibitors. It is thus possible that the use of glycoprotein IIb/IIIa inhibitors for our patients awaiting PCI,14,15 as advocated in current guidelines16 may have an additional favourable impact on culprit lesion characteristics. The majority of culprit lesions in this study were haemodynamically significant with a stenosis greater than 70% baseline. However, it is recognised that acute coronary syndromes can occur in the setting of mildly stenotic coronary lesions with evident supervening occlusive coronary thrombosis.17,18 In such cases antiplatelet and anticoagulant therapy would result in thrombus resolution whilst the impact on plaque regression is likely to be minimal. There have been no published studies showing that a strategy of ASA, heparin and GP IIb/IIIa antagonist followed by early coronary angiography and percutaneous revascularisation as performed in TACTIS/TIMI 185 is superior to one of medical stabilisation followed by delayed PCI five to seven days following presentation. Our data demonstrate that medical therapy and a delayed interventional approach alters lesion characteristics favourably in most patients, although three patients occluded the artery silently with no evidence of MI. As less than 20% of hospitals in developed countries have coronary interventional facilities, the majority of patients presenting with an ACS experience some delay before proceeding to an intervention. If symptoms permit, such patients may benefit as much from prolonged anticoagula-
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tion with unfractionated heparin or LMW heparin as from aggressive antiplatelet therapy and intervention within 24 hours. Furthermore, the early use of clopidogrel in addition to aspirin and heparin as indicated following the CURE study19 may further augment the improvement and reduce the likelihood of intervening events.
Conclusions Although urgent angiography and PCI can be performed safely and effectively in patients presenting with acute coronary syndromes, in many environments it is not currently feasible to proceed rapidly to coronary angiography within 24 hours of admission. Our study shows that the application of ASA and anticoagulant therapy and delayed intervention allows for an angiographic improvement in lesion severity in the majority of these patients which may provide a more favourable environment in which to proceed to PCI.
References 1. De Winter RJ, Windhausen F, Cornel JH, Dunselman PH, Janus CL, Bendermacher PE, et al. Early invasive versus selectively invasive management for acute coronary syndromes. N Engl J Med 2005;353(11):1095–104. 2. Wallentin L, Lagerqvist B, Husted S, Kontny F, Stahle E, Swahn E. Outcome at 1 year after an invasive compared with a non-invasive strategy in unstable coronary-artery disease: the FRISC II invasive randomised trial. Lancet 2000;356:9–16. 3. FRISC II Investigators. Invasive compared with noninvasive treatment in unstable coronary-artery disease: FRISC II prospective randomised multicentre study. Lancet 1999;354:708–15. 4. Fox KA, Poole-Wilson PA, Henderson RA, Clayton TC, Chamberlain DA, Shaw TR, et al. Interventional versus conservative treatment for patients with unstable angina or non-STelevation myocardial infarction: the British Heart Foundation RITA 3 randomised trial. Randomized Intervention Trial of unstable Angina. Lancet 2002;360(9335):743–51. 5. Cannon CP, Weintraub WS, Demopoulos LA, Vicari R, Frey MJ, Lakkis N, et al. Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban. Thrombolysis in Myocardial Infarction Investigators 18. N Engl J Med 2001;344:1879–87. 6. Mahoney EM, Jurkovitz CT, Chu H, Becker ER, Culler S, Kosinski AS, et al. Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis in Myocardial Infarction. Cost and cost-effectiveness of an early invasive vs conservative strategy for the treatment of unstable angina and non-STsegment elevation myocardial infarction. J Am Med Assoc 2002;288(15):1851–8. 7. OASIS Registry Investigators. Variations between countries in invasive cardiac procedures and outcomes in patients with suspected unstable angina or myocardial infarction without initial ST elevation. Lancet 1998;352:507–14. 8. Ross R. Atherosclerosis is an inflammatory disease. Am Heart J 1999;138:S419–20. 9. SPSS Version 11.5.1 SPSS Inc. Chicago, Ill; 2002. 10. Holmes Jr DR. Acute coronary syndromes: extending medical intervention for five days before proceeding to revascularization. Am J Cardiol 2000;86(12B):36M–41M.
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11. Topol EJ, Fuster V, Harrington RA, Califf RM, Kleimann NS, Kereiakes DJ, et al. Recombinant hirudin for unstable angina pectoris. A multicenter randomized angiographic trial. Circulation 1994;89(4):1557–66. 12. Early effects of tissue-type plasminogen activator added to conventional therapy on the culprit coronary lesion in patients presenting with ischemic cardiac pain at rest. Results of the Thrombolysis in Myocardial Ischemia (TIMI IIIA) Trial. Circulation 1993;87(1):38–52. 13. Van de Werf F, Gore JM, Avezum A, Gulba DC, Goodman SG, Budaj A, et al. Access to catheterization facilities in patients admitted with acute coronary syndrome: multinational registry study. Br Med J 2005;330(7489):441. 14. Zhao X-Q, Theroux P, Snapinn SM, Sax FL. Intracoronary thrombus and platelet glycoprotein IIb/IIIa receptor blockade with tirofiban in unstable angina or non Q wave myocardial infarction. Circulation 1999;100:1609–15. 15. Hamm CW, Heeschen C, Goldmann B, Vahanina A, Adgey J, Miguel CM, et al. Benefit of abciximab in patients with refractory unstable angina in relation to serum troponin T levels: C7E3 fab AntiPlatelet Therapy in Unstable Refractory Angina (CAPTURE) Study Investigators. Lancet 1997;349:1429–35.
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16. Smith Jr SC, Feldman TE, Hirshfeld Jr JW, Jacobs AK, Kern MJ, King 3rd SB, Morrison DA, O’Neil WW, Schaff HV, Whitlow PL, Williams DO, Antman EM, Adams CD, Anderson JL, Faxon DP, Fuster V, Halperin JL, Hiratzka LF, Hunt SA, Nishimura R, Ornato JP, Page RL, Riegel B. American College of Cardiology/American Heart Association Task Force on Practice Guidelines; American College of Cardiology/American Heart Association/Society for Cardiovascular Angiography and Interventions Writing Committee to Update 2001 Guidelines for Percutaneous Intervention. Circulation 2006;113(1):156–75. 17. Shah PK. Mechanism of plaque vulnerability and rupture. J Am Coll Cardiol 2003;41(4 Suppl. S):15S–22S. 18. Varnava AM, Mills PG, Davies MJ. Relationship between coronary artery remodelling and plaque vulnerability. Circulation 2002;105(8):939–43. 19. The Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. 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.
Original Article
Serial Angiography in Patients with Acute Coronary Syndromes: Effect of Antithrombotic Therapy on Angiographic Lesion Severity Ananth M. Prasan, FRACP, PhD, Rohan Bhagwandeen, FRACP, Victor J. Solanki, FRACP, S. Benjamin Freedman, FRACP and David Brieger, FRACP, PhD ∗ Department of Cardiology, Concord Repatriation Hospital, Sydney, NSW, Australia
Background: Patients presenting with acute coronary syndromes (ACS) commonly have a responsible culprit coronary lesion. There is limited data on the natural history of this culprit lesion in the short term and whether there is a change in morphology of this lesion in the days following presentation. Furthermore, the effect of antithrombotic therapy on this process is unknown. Methods: Sixty-eight patients presenting with ACS had their diagnostic study performed at our institution and had coronary angioplasty performed a few days later at a different hospital. Culprit lesion characteristics including minimum luminal diameter (MLD) and percentage diameter stenosis were determined on each occasion. Results: Acute myocardial infarction patients (n = 14) had improved culprit lesion characteristics at angioplasty compared to baseline (diameter stenosis 78.9% versus 62.4%, p < 0.01). Similarly, patients presenting with unstable angina (UA) or non-ST elevation myocardial infarction (non-STEMI) (n = 54) had improved diameter stenosis (78.0% versus 72.7%, p < 0.001). The change in MLD was greater in MI patients than UAP/non-STEMI patients (0.6 mm versus 0.16 mm, p < 0.01). Conclusion: Treatment of ACS patients with aspirin with anticoagulant therapy followed by delayed intervention results in angiographic improvement in lesion severity which may provide a more favourable environment in which to undertake percutaneous coronary intervention. (Heart, Lung and Circulation 2006;15:378–382) © 2006 Australasian Society of Cardiac and Thoracic Surgeons and the Cardiac Society of Australia and New Zealand. Published by Elsevier Inc. All rights reserved. Keywords. Angioplasty; Acute coronary syndromes; Plaque remodelling
Introduction
S
everal recent studies have shown that patients presenting with an acute coronary syndrome (ACS) at high and intermediate risk of an adverse short term outcome benefit from a strategy that includes coronary angiography and, if appropriate, revascularisation during the hospital admission.1 In FRISC II2,3 and RITA 34 the patients randomised to an invasive strategy were treated for three to seven days with therapy including aspirin (ASA) and low molecular weight (LMW) heparin before undergoing coronary angiography and, where appropriate, revascularisation. In the TACTICS/TIMI 18 trial5 the invasive group underwent coronary angiography 4–48 hours after randomisation on background therapy that included ASA, unfractionated heparin and a glycoprotein (GP) IIb/IIIa Received 15 August 2005; received in revised form 2 August 2006; accepted 6 September 2006 ∗
Corresponding author. Tel.: +61 2 97676296; fax: +61 2 97676994. E-mail address: [email protected] (D. Brieger).
antagonist. This strategy of early (<48 hours) revascularisation was cost effective6 and has led to the view that early angiography and revascularisation is the preferred treatment strategy for patients with ACS. As only a minority of hospitals are equipped with angiographic facilities, most patients presenting with an ACS must be transferred expeditiously to be offered this management approach. Prior to TACTICS/TIMI 185 several observational studies had found a lower rate of complications in patients undergoing percutaneous intervention more than 48 hours after admission, during which time heparin and ASA were administered.7 This strategy theoretically allows time for passivation of the plaque8 and a reduction in the volume of thrombus that may allow the intervention to proceed in a safer environment. However, there are limited data objectively demonstrating that medical stabilisation with ASA and heparin or LMW heparin improves the appearance or severity of culprit unstable plaque. In this study a delay in performing coronary intervention following diagnostic angiography was used to
© 2006 Australasian Society of Cardiac and Thoracic Surgeons and the Cardiac Society of Australia and New Zealand. Published by Elsevier Inc. All rights reserved.
1443-9506/04/$30.00 doi:10.1016/j.hlc.2006.09.001
examine the natural history of culprit lesion progression in patients presenting with acute coronary syndromes.
Methods Patient Enrolment Data were collected on consecutive ACS patients undergoing coronary angiography in our institution if they demonstrated clinical and angiographic criteria for culprit lesion PCI. As this hospital did not perform coronary intervention, patients were routinely transferred to a nearby hospital for PCI after the coronary angiogram. The decision concerning the urgency of PCI was made by the referring physician and only cases in which transfer was requested on a semi-urgent basis were included in this study. Timing of transfer was therefore determined by bed availability at the receiving hospital and not influenced by the patient’s clinical characteristics. During this period, 54 patients presenting with unstable angina (UA) or non-ST elevation myocardial infarction (non-STEMI) and 14 patients presenting with ST elevation myocardial infarction (STEMI, all given thrombolytic therapy) were referred for PCI. All patients received aspirin 150 mg daily while awaiting transfer for PTCA. The use of other therapy, including antithrombotic agents was at the discretion of the responsible cardiologist. A thienopyridine (Ticlopidine 500 mg) was administered the night before the PCI procedure and no patients received GP IIb/IIIa antagonists during the study period.
Interpretation of Angiography The diagnostic and pre-PTCA guiding angiograms were recorded on Toshiba and Phillips digital systems, respectively. Caliper measurements were performed on still frames viewed on a digital video recorder (DVR Sony). Matched views showing the maximal luminal diameter reduction of the culprit lesion were used to assess severity of the stenosis. Angiograms were analysed in random order by two independent observers blinded to the patients’ clinical characteristics. Glyceryl trinitrate was not administered pre-procedure and it was assumed that reference diameter did not change between sequential angiograms performed days apart. To exclude a systematic bias, corresponding measurements were performed in six patients with stable angina who had delayed intervention. These angiograms were viewed in random order interspersed with those of the study cohort. The intra-observer variability expressed as maximal luminal stenosis was 4.6 ± 2.1% and the inter-observer variability was 3.7 ± 2.9% for 30 pairs of randomly selected angiograms indicating reliable reproducibility of the analysed data.
Statistics Data are described as mean ± standard deviation. Angiographic data were compared between groups by analysis of variance with post hoc comparison of group means when significance was indicated (SPSS 10.0 SPSS Inc., Chicago, IL).9 A p-value <0.05 was considered statistically significant.
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Table 1. Baseline Characteristics of Patients (%) Presenting with an Acute Coronary Syndrome Baseline Characteristics
All Patients
Sex Male Female
32 (59.3) 26 (40.7)
N Age (years)
68 60 ± 12
Past medical history MI CABG PTCA
18 6 6
Risk factors Hypertension Diabetes Cholesterol Family history Smoking
UAP/ Non-STEMI
34 (50.0) 11 (16.2) 44 (64.7) 22 (32.4) 17 (25.0)
54 60 ± 12
STEMI
12 (85.7) 2 (14.3) 14 59 ± 14
13 (26.5) 5 (10.2) 6 (12.2)
3 (21.4) 1 (7.4) 0 (0.0)
22 (44.9%) 9 (18.4%) 30 (61.2%) 19 (38.8%) 13 (28.5%)
8 (57.1) 1 (7.1) 9 (64.3) 2 (14.3) 3 (21.4)
Results Baseline Characteristics Clinical profiles of the 68 patients presenting with an unstable coronary syndrome are shown in Table 1. Fortyeight patients (34 males) presented with unstable angina and six patients had a non-ST elevation MI, diagnosed by a greater than two fold elevated creatine kinase. Assays of troponin T or I were not available during the period of this study. A total of 47 patients diagnosed with UAP/non-STEMI were treated with antithrombotic therapy (29 unfractionated heparin, 18 low molecular weight heparin). Patients were treated with antithrombotic therapy for 6.0 ± 2.6 days (range 2–13). Eighteen patients were receiving this treatment up to the time of PCI. The delay between performance of the baseline angiogram and PCI was 5.8 ± 3.8 days (range 2–15). Fourteen patients (12 males) presented with ST elevation MI. All were treated with aspirin and thrombolysis followed by anticoagulant therapy (12 unfractionated heparin, 2 low molecular weight heparin) for 5.4 ± 2.2 days (range 3–8). Percutaneous intervention and the second angiogram was performed at a mean of 7 ± 4.5 days (range 4–15) following diagnostic angiography. No patient died or experienced clinical (re)myocardial infarction during the period between diagnostic angiogram and PCI.
Angiographic Culprit Lesion Characteristics One patient presenting with STEMI had an occluded vessel both at diagnostic angiography and at PCI. At the time of PCI, three patients (one STEMI, two UAP) had an occluded target vessel which had been patent on the diagnostic angiogram. In all three patients vessel occlusion was clinically silent. In the remaining 64 patients with ACS, minimum lumen diameter (MLD) increased significantly (Table 2). There was a corresponding reduction in maximal coronary artery stenosis: from 78% to 72.7%, p < 0.001 in UAP/nonSTEMI patients and from 78.9% to 62.4%, p < 0.01 in
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Table 2. Paired Data for Minimal Luminal Diameter at Angiogram and Pre-PTCA MLD Lesion/mm
UAP/Non-STEMI STEMI SAP
n
Angio
Pre-PTCA
p-Value
46 12 6
0.70 ± 0.04 0.72 ± 0.09 0.65 ± 0.14
0.86 ± 0.05 1.32 ± 0.21 0.66 ± 0.11
<0.001 <0.01 NS
STEMI patients (Fig. 1a and b). The reduction in lesion severity was significantly improved in STEMI versus UAP/non-STEMI patients (change in MLD 0.6 mm versus 0.16 mm p < 0.01, and reduction in stenosis severity 16.5% versus 5.3%, p < 0.01). In patients with stable angina, neither minimal lumen diameter (0.65 ± 0.14 mm versus 0.66 ± 0.11 mm, p NS) nor maximal coronary artery stenosis (79% versus 77.5%, p NS) changed between angiography and performance of PTCA (Fig. 1c).
Figure 1. Paired data for minimal luminal diameter from angiogram (angio 1) and pre-PTCA film (angio 2) in patients with (a) unstable angina/non-STEMI (n = 52); (b) STEMI (n = 12); and (c) SAP (n = 6) figure. Paired angiograms in which either the angiogram or pre-PTCA film showed a complete occlusion were excluded.
No influence of type of anticoagulant treatment (unfractionated heparin versus low molecular weight heparin) in UAP/non-STEMI patients on lesion characteristic was identified (change in percent stenosis 5.5 ± 2.5 versus 4.6 ± 1.8, p NS).
Discussion A number of observational studies have suggested that in patients with acute coronary syndromes use of antithrombotic and anti-ischaemic therapies for several days prior to angiography and revascularisation reduce the complications of the intervention.3 This was the strategy adopted in the FRISC II trial2,3 which was the first to report that a routine invasive strategy was superior to a conservative approach in these patients, a finding that was recently confirmed among lower risk patients in the RITA 3 trial.4 It has been postulated that an initial period of medical stabilisation passivates the ruptured plaque, allowing the PCI to proceed in a less hostile environment10 but to date there has been little angiographic evidence to support this. Furthermore, there is limited data documenting serial angiographic culprit lesion characteristics in patients presenting with acute coronary syndromes.11,12 At the time of undertaking our study, the availability of angiography without on-site angioplasty provided a unique opportunity to study angiographically the impact of a strategy of “plaque passivation” using antiplatelet and anticoagulant therapy on the severity of luminal stenosis. Whilst we believe that the reduction in lesion severity observed in the current study may equate to “plaque passivation” this remains unproven. However, our study does demonstrate the finding that plaque regression occurs in the context of delayed angioplasty and is of importance to the substantial proportion of acute coronary syndrome patients who routinely experience a delay in coronary intervention. Our results indicate that for patients treated medically for an average of 5.7 days prior to PCI, there is a significant reduction in the angiographic severity of the culprit lesion. All our patients received ASA and most either heparin or LMW heparin and the most likely mechanism for improvement of luminal diameter in these patients was partial thrombus dissolution with inhibition of continuing thrombus formation. This thrombus resolution may be a surrogate for diminishing threat of further coronary occlusion supporting a potential advantage for a period of medical stabilisation prior to proceeding to revascularisation. Consistent with the above hypothesis, we found the magnitude of improvement in minimal luminal diameter was greater for the STEMI than the UAP/nonSTEMI patients reflecting a greater resolution of thrombus burden in STEMI patients. No difference between unfractionated heparin and low molecular weight heparin therapy was seen on change in stenosis severity or lumen diameter was seen in this small study. Whilst we believe that antithrombotic therapy impacts on improvement in lesion severity it is conceivable that this could have occurred without administration of antithrombotic therapy.
TACTICS/TIMI 185 demonstrated that treatment with ASA, heparin and GP IIb/IIIa antagonist followed by early (median 22 hours after admission) coronary angiography and percutaneous revascularisation in patients with ACS is superior to an initial strategy of conservative management. Early coronary intervention was not associated with an increased risk of peri procedural myocardial infarction, attributed to the protective effect of pre-treatment with a glycoprotein IIb/IIIa antagonist. Furthermore, when facilities are available, this strategy is cost effective and has been adopted by many invasive centres within the United States. However, it is important to note that in TACTICS/TIMI 18 there were different definitions between peri procedural MI (increase in troponin or CK >3 times the upper limit of normal) and MI’s not related to coronary intervention (any elevation in marker or enzyme >upper limit of normal) which meant that patients randomised to a conservative strategy were subjected to the more stringent definition of MI. This may have amplified the perceived benefit in patients undergoing early intervention. Furthermore, in the GRACE registry,13 compared to patients presenting to hospitals without a catheterisation laboratory, patients admitted directly to an interventional centre had an increased risk of death and increased bleeding complications. This evidence supports a strategy of delayed coronary intervention which has been advocated by some authors.10 Analyses of coronary angiograms in the PRISM PLUS14 trial showed that treatment with tirofiban in addition to ASA and heparin reduced the thrombus load at the site of the culprit lesion in patients with ACS. Our study was undertaken before the widespread availability of glycoprotein IIb/IIIa inhibitors. It is thus possible that the use of glycoprotein IIb/IIIa inhibitors for our patients awaiting PCI,14,15 as advocated in current guidelines16 may have an additional favourable impact on culprit lesion characteristics. The majority of culprit lesions in this study were haemodynamically significant with a stenosis greater than 70% baseline. However, it is recognised that acute coronary syndromes can occur in the setting of mildly stenotic coronary lesions with evident supervening occlusive coronary thrombosis.17,18 In such cases antiplatelet and anticoagulant therapy would result in thrombus resolution whilst the impact on plaque regression is likely to be minimal. There have been no published studies showing that a strategy of ASA, heparin and GP IIb/IIIa antagonist followed by early coronary angiography and percutaneous revascularisation as performed in TACTIS/TIMI 185 is superior to one of medical stabilisation followed by delayed PCI five to seven days following presentation. Our data demonstrate that medical therapy and a delayed interventional approach alters lesion characteristics favourably in most patients, although three patients occluded the artery silently with no evidence of MI. As less than 20% of hospitals in developed countries have coronary interventional facilities, the majority of patients presenting with an ACS experience some delay before proceeding to an intervention. If symptoms permit, such patients may benefit as much from prolonged anticoagula-
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tion with unfractionated heparin or LMW heparin as from aggressive antiplatelet therapy and intervention within 24 hours. Furthermore, the early use of clopidogrel in addition to aspirin and heparin as indicated following the CURE study19 may further augment the improvement and reduce the likelihood of intervening events.
Conclusions Although urgent angiography and PCI can be performed safely and effectively in patients presenting with acute coronary syndromes, in many environments it is not currently feasible to proceed rapidly to coronary angiography within 24 hours of admission. Our study shows that the application of ASA and anticoagulant therapy and delayed intervention allows for an angiographic improvement in lesion severity in the majority of these patients which may provide a more favourable environment in which to proceed to PCI.
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