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Three Part Question

In [patients diagnosed with acute coronary syndrome] is [early invasive approach compared to conservative approach] the best treatment in terms of preventing [myocardial infarction or death]?

Clinical Scenario

You are a cardiology registrar who is seeing a 63 year old builder, admitted 5 days previously to coronary care unit with unstable angina. On admission it turned out that he has had NYHA grade II angina for 2 years now although he had never mentioned it, and he is a current smoker. He has now been stabilized on oral medical treatment and has been pain free for the last 4 days. He is keen to get home as he had never been in hospital before and has found the whole experience very traumatic. However you wonder whether an early angiography with revascularisation if appropriate would be safer for him while an inpatient, and if this strategy would increase his long term prognosis.

Search Strategy

Medline 1966-Feb 2004 using the OVID interface.
[exp Unstable Angina/ OR unstable coronary-artery disease.mp OR non-ST elevation infarction.mp OR acute coronary syndrom$.mp OR non-Q wave myocardial infarction.mp] AND [exp Myocardial Revascularisation OR Intervention.mp OR exp Coronary angiography OR exp Angioplasty OR exp Coronary Artery Bypass] AND
[exp Myocardial Infarction OR myocardial infarction.mp OR Death.mp OR exp treatment outcome] AND randomized controlled trial.pt

Search Outcome

A total of 282 papers were found of which 7 were deemed to be relevant (6-12). An additional 3 randomised trials were found but were not included due to small study size (3-5) and one large PRCT was excluded as the patients were recently post thrombolysed (1) MI and one large study was excluded as treatment arms were significantly out of date (2). The included studies are summarised below in the table.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Fox KA, et al, 2002, UK	N=1810 patients with non-ST elevation MI or unstable angina from 45 hospitals Patients were assigned to early intervention (895 pts) or conservative strategy. Both groups received Enoxaparin, aspirin, B-blocker, antianginals and GPIIb/IIIa if indicated Patients with evolving MI or candidates for acute reperfusion were ineligible	PRCT with blinded outcome measure assessment (Level 1b)	Treatment after randomisation	Early Treatment: 865pts, 311 had PCI at median 3 days, 184 had CABG at median 22 days Conservative Rx: 915pts 149 pts had PCI, 109 pts had CABG and 48%of pts had an angiogram within a year	Median follow up is currently 2 years although all patients will be followed up for 5 years, (results awaited) Well conducted study Also of interest: combined endpoint (1) maintained significance at 1 year (risk ratio 0.72 CI 0.58-0.90); 15 MIs in intervention group related to PCI or angiography. The symptoms of angina and use of anti-anginal medication significantly reduced with interventional strategy (p<0.0001)
			(1) Combined rate of death, non-fatal myocardial infarction, or refractory angina at 4 months	Intervention vs conservative treatment: 9.6% vs 14.5%, p= 0.001
			(2) Death or myocardial infarction at 12 months	7.6% vs 8.3%, p=0.58
FRISC-II invasive study, 1999, Sweden	N=2457 patients with unstable angina or non-ST elevation MI (ineligible for thrombolysis) from 58 hospitals randomised to early invasive treatment with revascularisation within 7 days or non-invasive treatment Note parallel randomisation to placebo or long term low molecular mass heparin for 3 months	PRCT with parallel groups (Level 1b)	Treatment after randomisation	Invasive group: 1222 pts, 522 had PCI (mean 4 days) and 430 pts had CABG (mean 7 days) Non-invasive: 1235 pts, 220 had PCI (mean 17 days) and 233 pts had CABG (mean 28 days)	During the first six months, minor elevations in cardiac markers following angioplasty were recorded as myocardial infarction even without any other signs or symptoms Conservative strategy used very stringent criteria for ischaemia and consequently only 10% of patients underwent cardiac catheterisation during initial hospital admission Definition of MI was different for those post PCI or CABG and those receiving conservative treatment, in terms of CK-MB levels
			Death or myocardial infarction at 6 months	Invasive vs non- invasive: 9.4% vs 12.1% p=0.03
			Myocardial infarction alone at 6 months	7.8 vs 10.1% p=0.045
			Mortality	1.9% vs 2.9% p=0.1
Wallentin L et al, 2000, Sweden	The FRISC-II invasive study (1999) patients followed for 12 months	PRCT (Level 1b)	Death	Invasive vs non- invasive: 2.2% vs 3.9% p=0.016
			Myocardial infarction	8.6% vs 11.6% p=0.015
			Composite mortality or MI	10.4% vs 14.1% p=0.005
Lagerqvist B et al, 2002 Sweden	FRISC-II invasive study (1999) patients followed up for 24 months	PRCT (Level 1b)	Reduction in mortality	Invasive vs non- invasive: 3.7% vs 5.4% p=0.038	In contrast to the two earlier reports MI's were now classified as procedural or non procedural MI's. During the first 6 months 2/3rds of MIs were procedure related, most after angioplasty
			MI	9.2% vs 12.7% p=0.005
			Composite end point of death or MI	12.1% vs 16.3% p=0.003
Cannon CP et al, 2001, North America	N=2220 patients from 18 hospitals with unstable angina or myocardial infarction without ST segment elevation randomised to early invasive or conservative approach All patients treated with aspirin, heparin or tirofiban	PRCT (Level 1b)	Treatment after randomisation	Invasive group: 1114 pts, 459 had PCI (mean 25hrs) and 220 pts had CABG (mean 89hrs) Non-invasive: 1106 pts, 561 had PCI (mean 79hrs) and 142 pts had CABG (mean 144 hrs)	Of note: patients with Troponin T levels>0.01 ng/mL had relative risk reduction of risk of primary end point of 39% with invasive strategy (p<0.001). In patients with Troponin T levels <0.001 there was no difference in both groups
			Death, non fatal MI and rehospitalisation for acute coronary syndrome at 6 months	Invasive vs non- invasive: 15.9% vs 19.4% p=0.025
			Death or non-fatal MI	7.3% vs 9.5% p<0.05
Boden WE et al, 1998, North America	N=920 patients with non-Q-wave myocardial infarction randomly assigned to invasive or conservative management Average follow up of 23 months All patients received aspirin and long acting diltiazem	PRCT (Level 1b)	Treatments after randomisation	Invasive group 462 pts, 98 had PTCA, 95 had CABG (mean 8 days) Conservative group, 458 pts, 55 PTCA, 87 CABG, (mean 25 days)	Study ran from 1993 to 1995. Stenting and gp II/IIIB inhibitors were not used Poor separation of treatments with 44% revascularisation in the invasive group and 33% revascularisation in the conservative group Many deaths in the intervention group occurred in patients before the intervention had been performed
			Death or non-fatal infarction at discharge	Invasive 36 pts vs conservative 15pts (p=0.004)
			Death or MI at one month	Invasive 48 pts vs conservative 26 pts (p=0.012)
			Death or MI at one year	Invasive 111 pts vs conservative 85 pts (p=0.05)
TIMI-IIIB trial, 1994, North America	N=1473 patients from 25 centres with unstable angina or non-q wave myocardial infarction randomly assigned to one of 4 treatments (1) TPA versus placebo as initial therapy (2) early invasive (early coronary angiography followed by revascularisation if suitable) or early conservative therapy (coronary angio if medical treatment failed)	PRCT (Level 1b)	Treatments after randomisation	Invasive group 740 pts: 278 pts (38%) PTCA 186 (25%) CABG Conservative group 733 pts: 193 pts (26%) PTCA, 173 pts (24%) CABG	Poor treatment separation with virtually the same revascularisation rates in the two groups by the end of the study Definition of MI was different for those post PCI or CABG and those receiving conservative treatment, in terms of enzyme marker levels Study precedes modern stents and adjuvant therapy
			Composite of death, myocardial infarction or unsatisfactory symptom limited ETT at 6 weeks	Invasive vs non- invasive 16.2% vs 18.1% (p=ns)

Comment(s)

The RITA-3 trial [12] showed that, among patients with unstable coronary syndromes, the combined end point of death, non-fatal myocardial infarction, or refractory angina is significantly reduced in patients assigned to early intervention. These results were significant at 4 months and 1 year. The biggest effect found was on refractory angina but there was a trend towards a significant reduction in death or MI and the 5 year results will give more conclusive evidence for this in 2006. Of note this was a very well conducted 45 centre trial with good treatment separation among groups and blinded outcome assessment The FRISC-2 invasive study reported their results at 6, 12 months and 24 months [8,9,11]. The study showed that in patients with unstable coronary artery disease, an early invasive approach lead to decreased mortality, morbidity, hospital readmissions and need for late revascularization. Maximum benefit was seen during the first six months. This study demonstrated a Number Needed to Treat (NNT) of 28 patients to prevent 1 death or MI and a NNT of 58 to prevent a death over the next 2 years. There were also significant reductions in the use of anti-anginal medication. The FRISC trial has had the methodology of their diagnosis of MI criticised by the RITA-3 investigators. The FRISC Trial required a CK-MB rise of above the local limit for non-procedure related MI but in those undergoing PCI an enzyme rise above 1.5 times the local limit was required and for patients post CABG new Q waves were the only method for diagnosis. The RITA Trial in contrast required a clinical event in addition to biochemical markers and had a uniform definition for CK rise in all patients whether post procedure or not. The TACTICS-TIMI-18 study [10] showed that in patients with unstable angina or myocardial infarction without ST elevation, an early invasive strategy is superior to a conservative strategy in reducing the incidence of major cardiac events. Maximum benefit was achieved in high risk patients with troponin T levels greater than 0.01 ng per litre. They demonstrated a Number Needed to Treat of 45 patients to prevent one death or MI in the first 6 months after early invasive treatment. The VANQUISH trial [7] had different findings to those above. They demonstrated that in patients with non-q wave infarction there was no significant difference in outcomes between invasive and conservative approach. However there were several drawbacks to this study. Firstly the study achieved poor treatment separation with 44% of patients in the invasive group receiving revascularisation and 33% receiving revascularisation in the conservative group. Secondly a significant proportion of those who died in the invasive group died prior to any intervention being performed on them. Lastly this study was in the pre-stenting and pre gpII/IIIb drug era. The TIMI-IIIB study [6] showed that in patients with unstable angina or non-q wave myocardial infarction, an invasive strategy reduced the length of hospitalisation and the use of antianginal medication, but no significant difference in mortality at six weeks was found. However this study also suffered from poor treatment separation between the groups with virtually identical revascularisation rates by the end of the study.

Clinical Bottom Line

Current trials clearly show a benefit for the early invasive approach of angiography followed by revascularisation in patients post acute coronary syndrome with a number needed to treat of around 50 to prevent a death or MI.

References

1. Fox KA, Poole-Wilson PA, Henderson RA, et al. 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 Lancet 2002;360(9335):743-51.
2. Anonymous Long-term low-molecular-mass heparin in unstable coronary-artery disease: FRISC II prospective randomised multicentre study. FRagmin and Fast Revascularisation during InStability in Coronary artery di Lancet 1999;354(9180):701-7. Erratum in: Lancet 1999;354:1478.
3. Wallentin L, Lagerqvist B, Husted S, et al. Outcome at 1 year after an invasive compared with a non-invasive strategy in unstable coronary-artery disease: the FRISC II invasive randomised trial. FRISC II Investigators. Fast Revascularisation du Lancet 2000;356(9223):9-16.
4. Lagerqvist B, Husted S, Kontny F, et al. Fast Revascularization during InStability in Coronary artery disease-II Investigators.A long-term perspective on the protective effects of an early invasive strategy in unstable coronary artery diseas J Am Coll Cardiol 2002;40(11):1902-14.
5. Cannon CP, Weintraub WS, Demopoulos LA, et al. TACTICS (Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy)--Thrombolysis in Myocardial Infarction 18 Investigators. Comparison of early invasive and N Engl J Med 2001;344(25):1879-87.
6. Boden WE, O'Rourke RA, Crawford MH. 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 N Engl J Med 1998;38(25):1785-92. Erratum in: N Engl J Med 1998;339(15):1091.
7. TIMI-IIIB trial. 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. Thrombol Circulation 1994;89(4):1545-56.
8. Spacek R, Widimsky P, Straka E. Value of first day angiography/angioplasty in evolving non-ST segment elevation myocardial infarction : an open multicentre randomized trial: The VINO study. Eur Heart J 2002;23:230-38.
9. Michalis LK, Stroumbis CS, Pappas K. Treatment of refractory unstable angina in geographically isolated areas without cardiac surgery: invasive versus conservative strategy. (TRUCS study). Eur Heart J 2000;21(23):1954-9.
10. McCullogh PA, O'Neill WW, Graham M. A prospective randomized trial of triage angiography in acute coronary syndromes ineligible for thrombolytic therapy. Results of the Medicine versus Angiography in Thrombolytic Exclusion (MATE Trial) J Am Coll Cardiol 1998;32:596-605.
11. Luchi RJ, Scott SM, Deupree RH. Comparison of medical and surgical treatment for unstable angina pectoris. Results of a Veterans Administration Cooperative Study. N Engl J Med 1987;316(16):977-84.