Early invasive therapy of non ST-elevation acute coronary syndromes — combined with upstream antiplatelet therapy: yes — but how early?

Kari Niemelä* and Saila Vikman

Division of Cardiology, Department of Internal Medicine, Tampere University Hospital, PL 2000, FI-33521, Tampere, Finland

* Correspondence to: Kari Niemelä. Tel. +358-3-2474312; fax +358-3-2474157
E-mail address: kari.niemela{at}pshp.fi

Received 19 May 2003; revised 19 May 2003; accepted 21 May 2003

See doi:10.1016/S1095-668X(03)00259-8for the article to which this editorial refers

The increasing number of patients with non ST-elevation acute coronary syndromes (ACS) is placing an enormous economic burden on health care in Western countries. Recently updated European and American guidelines have clarified the recommendations for how these patients should be treated.1,2The well-conducted FRISC II trial strongly suggested the superiority of early invasive strategy compared to a more watchful ‘wait-and-see’ conservative strategy.3These observations were further confirmed by the TACTICS–TIMI 18 trial,4where early invasive strategy with an adjunctive upstream glycoprotein (GP) 2b/3a inhibitor from 4 to 48h (median 22h) before the intervention appeared to result in a remarkably favourable outcome in patients categorized as having high risk (in real life over 50% of the ACS population) for acute cardiovascular complications. As in the FRISC II trial, the benefit was most apparent in a subset of high-risk patients characterized either by ST depression on the admission ECG or by significant troponin release, which in turn is a marker of platelet microembolization. The importance of adjunctive antithrombotic therapy, including aspirin, heparin, and low-molecule GP 2b/3a inhibitors, is thus not surprising in the treatment of ACS patients. On top of this all, the use of clopidogrel also appears to have an additive beneficial effect.

Despite all the recent progress in therapy, non ST-elevation ACS has a grave prognosis; about 10% of the patients will die within 6 months and an additional 20% will suffer either myocardial infarction, a recurrent episode, or will be revascularized after hospital discharge. In real life, there is a wide variation in the therapy provided to these patients. In some hospitals ACS patients are transferred directly from the emergency room to a catheterization laboratory, whereas in others ACS patients have to wait for the coronary angiography and subsequent revascularization, if feasible, for at least a week or more, resulting in poor cost-effectiveness of the therapy. The initially higher cost of invasive strategy appears to be balanced within one year by a reduced need either for new hospitalization or revascularization compared to conservative strategy. Most observational registries appear to suggest an underuse of invasive therapy and an optimal adjunctive antithrombotic regimen.5This apparently results in a variable outcome of the disease.

Do we really know today when and how these patients should be treated invasively? There are still many open questions. Should we wait from the onset of symptoms up to 7 days before procedure to allow stabilization of the plaque, as suggested by the FRISC II investigators? Or should we go ahead invasively within the first hours from the onset of symptoms to prevent any further microembolic complications associated with the syndrome? If so, do the patients require adjunctive antiplatelet therapy, as suggested by the TACTICS–TIMI 18 investigators? In the FRISC II trial, the beneficial long-term effect of the invasive strategy was counteracted by a greater likelihood of acute complications in the invasive arm. This has been attributed to an underuse of GP 2b/3a inhibitors (in 10% of the patients) in the study. Concerning optimal timing, the FRISC II trial does not really represent an early invasive protocol, as the patients waited for the angiography almost a week, and for appropriate revascularization some days more. In TACTICS–TIMI 18 all the patients received adjunctive upstream antiplatelet medication for an average of about one day post-randomization, and post hoc subgroup analysis suggested that an optimal time frame for invasive therapy would be from 12 to 48h.

In this issue Arnoud van't Hof et al.6present an interesting pilot study where two ‘aggressive’ invasive strategies were compared in a subset of high-risk ACS patients: immediate angiography (mean 6h) vs ‘delayed’ angiography (mean 50h) with concomitant upstream tirofiban therapy. Although no differences in major cardiovascular end points in this relatively small patient population were observed, the ‘delayed’ strategy was associated with an improved angiographic result and less initial enzyme release. In coronary artery disease any reduction in minor myocardial damage is probablyimportant, since patients are likely to be exposed to new plaque ruptures over the long term. One might argue that TIMI flow might improve merely as a function of time. However, a better outcome in terms of less sequential enzyme release speaks in favour of the delayed strategy (with adjunctive antiplatelet therapy). An important part of the design of the study was to measure sequential enzyme release over a given period of time instead of paying attention only to peak values. This in fact might provide a good model to evaluate the effect of therapy for future ACS trials, enabling smaller patient populations compared to a protocol using hard end points only. Unfortunately, the study does not give a definite answer for the optimal timing of invasive therapy, because the patients in the immediate arm did not receive a GP 2b/3a inhibitor.

Thus, what can we conclude so far? Early invasive therapy of ACS without optimal adjunctive antithrombotic treatment is not enough, but together they appear to be the best option for the high- risk patient, preferably with the GP 2b/3a inhibitor given upstream. As for timing, the ‘delayed’ strategy of van't Hof et al. is quite similar to that of the TACTICS–TIMI 18 trial, suggesting that invasive therapy within 2 days from the onset of symptoms, but not immediately, might result in an optimal outcome. Preliminary data from theISAR-COOL study,7however, seem to suggest that immediate invasive strategy combining upstream therapy with GP 2b/3a inhibitors only for about 3h before intervention results in a better outcome than waiting for the invasive procedure for nearly 4 days. More delayed early strategy, as in FRISC II, with angiography within 7 days and appropriate revascularization later, is perhaps not aggressive enough, but the reality is even worse in many hospitals.

All these trials have increased our knowledge of how high-risk ACS patients should be treated. Based on these data, invasive therapy can, and perhaps should, be provided within the first 2 days from the onset of symptoms. However, the data are still preliminary and larger trials will be needed. If early aggressive invasive strategy of non ST-elevation ACS will hold its promise in the future, which appears to be a reality for patients with ST-elevation myocardial infarction, this will have a great impact on treatment strategies. This in turn will challenge our health care systems, as they ponder how to organize and provide the best therapy also for non ST-elevation patients.

References

  1. Task Force Report. Management of acute coronary syndromes: acute coronary syndromes without persistent ST segment elevation. Eur Heart J. 2000;21:1406–1432.[Free Full Text]
  2. Braunwald E, Antman EM, Beasley JW et al. ACC/AHA Guidelines for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction: executive summary and recommendations. Circulation. 2000;102:1193–1209.[Free Full Text]
  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. Lancet. 2000;356:9–16.[CrossRef][Medline]
  4. Cannon CP, Weintraub WS, Demopolous LA et al. Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban. N Engl J Med. 2001;344:1879–1887.[Abstract/Free Full Text]
  5. Fox KAA, Goodman SG, Klein W et al. Management of acute coronary syndromes. Variations in practice and outcome. Findings from the Global Registry of Acute Coronary Events (GRACE). Eur Heart J. 2002;23:1177–1189.[Abstract/Free Full Text]
  6. van't Hof AWJ, de Vries ST, Dambrink J-HE et al. A comparison of two invasive strategies in patients with non-ST elevation acute coronary syndromes: results of the Early or Late Intervention in unStable Angina (ELISA) pilot study. 2b/3a upstream therapy and acute coronary syndromes. Eur Heart J. 2003;24:1401–1405.[Abstract/Free Full Text]
  7. Neumann FJ. ISAR-COOL. Late Breaking Clinical Trial Session. American Heart Association Meeting, Chicago, November 2002..

Related articles in EHJ:

A comparison of two invasive strategies in patients with non-ST elevation acute coronary syndromes: results of the Early or Late Intervention in unStable Angina (ELISA) pilot study: 2b/3a upstream therapy and acute coronary syndromes
Arnoud W. J. van ’t Hof, Suzanna T. de Vries, Jan-Henk E. Dambrink, Kor Miedema, Harry Suryapranata, Jan C. A. Hoorntje, A.T. Marcel Gosselink, Felix Zijlstra, and Menko-Jan de Boer
EHJ 2003 24: 1401-1405. [Abstract] [Full Text]  




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