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Circulation. 1995;92:2026-2028

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(Circulation. 1995;92:2026-2028.)
© 1995 American Heart Association, Inc.

Articles

New Standard for Success of Thrombolytic Therapy

An Earnest Proposal

James S. Forrester, MD

From Cedars-Sinai Medical Center, Los Angeles, Calif.

Correspondence to James S. Forrester, MD, Division of Cardiology, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048.


Key Words: Editorials • angioplasty • myocardial infarction • peripheral vascular disease • plasminogen activators


*    Introduction
up arrowTop
 *Introduction
down arrowReferences
 
Some years ago, the late Lewis Thomas made "an earnest proposal"1 : that the world powers agree to restrain computers from launching nuclear warheads until we acquire a really complete set of information describing at least one living creature. "When this is done," he wrote, "and the information programmed into all our computers, I for one would be willing to take my chances." As the subject for this investigation, he proposes the simple protozoan, Myxotricha paradoxa, a fast-swimming inhabitant of the intestine of the Australian termite. But it turns out that the myxotricha is not as simple as it appears. Under the scrutiny of the electron microscope, its flagella, which beat in synchrony to propel it through its watery world, are perfectly spaced, fully formed spirochetes. Myxotricha's oval cytoplasmic organelles, engorged with undigested wood, are bacteria contributing enzymes to break down cellulose, and its centrioles are a third set of separate creatures. At the end of a decade of collecting information, Thomas envisions the moment when science's remarkable discoveries about myxotricha are fed into the computers. After a few seconds of whirring, there comes a neat and speedily printed message: "Request more data. How are spirochetes attached? Do not fire!"

So it seems to be with treatment of acute thrombotic occlusion of blood vessels: there is never quite enough information. In this issue of Circulation, Vanderschueren et al2 describe recanalization of thrombosed peripheral arteries with staphylokinase, called STAR, a proteolytic enzyme produced by certain strains of Staphylococcus aureus. The substance itself is hardly a new discovery; its fibrinolytic properties were clearly described a half century ago.3 Nevertheless, in several experimental animal models, STAR appears to be as potent as streptokinase for dissolution of whole blood clots and significantly more potent for lysing platelet-rich thrombi.4 Furthermore, STAR does not break down fibrinogen5 and thus does not induce a systemic lytic state. This property of STAR could prove to be a great advantage because, at least in principle, it could reduce the prevalence of both hemorrhagic complications and the paradoxical prothrombotic effect of many plasminogen activators and anticoagulants.6 7 In addition, the 83% recanalization rate reported by Vanderschueren et al is in the upper range of rates reported for conventional thrombolytic therapy of peripheral vessels (25% to 90%).8 9 10 More detailed comparison with these prior investigations of thrombolytics in peripheral vessels is not meaningful because of their lack of uniformity and the paucity of randomized trials.

The importance of the study, however, lies not in the application to thrombosed peripheral vessels but in the reduction in time to reperfusion. The mean time required for peripheral artery recanalization, 8.7 hours, compares favorably with prior clinical trials using conventional plasminogen activators: 40 hours for streptokinase, 30 hours for urokinase, and 22 and 4.7 hours with low- and high-dose recombinant tissue-type plasminogen activator (rTPA).11 This observation places the article in the middle of one of the most important therapeutic issues of our times, because it seems to confirm a previous brief report in which STAR induced recanalization of five of five thrombosed human coronary arteries within 20 minutes.12 In contrast, the average time to clot lysis is {approx}35 to 40 minutes for TPA, with an additional 20 minutes for streptokinase.13 14

The potential for significant reduction in time to clot lysis comes at a crucial moment, when two separate lines of investigation are forcing a reevaluation of thrombolytic therapy. Earlier this year, Simes et al15 reported the relation between mortality and postlysis angiographic coronary artery flow. The 30-day mortality rates for patients who had either occluded or partially occluded vessels at 90 minutes (TIMI 0 and II flow) were comparable (8.4% and 7.9%, respectively). In contrast, the mortality rate for fully restored flow (TIMI III) was less by half (4.0%). In fact, a meta-analysis of the 12 published angiographic studies, involving 3003 patients, concluded that TIMI III flow is associated with a 46% reduction in mortality rate compared with TIMI II flow and that patients with partial restoration of flow have an outcome similar to those with no flow.16 There is even suggestive evidence that partial reperfusion may be worse than no perfusion at all.15 The survival advantage of completely restored flow extends beyond acute hospitalization. In the GUSTO angiographic substudy of patients at 1-year follow-up, the mortality rate in those identified as TIMI III at 90 minutes after treatment was approximately half that of the other groups; their mortality rate after 30 days was only 1.4%.17 Furthermore, the importance of complete flow restoration extends beyond mortality: these patients also have better global myocardial function and clinical outcomes.18 19 The logical consequence of these new data, all published in the past year, is an uncommon event in biological research—a true paradigm shift. To be explicit: TIMI grade II flow after thrombolysis must now be designated as reperfusion failure rather than reperfusion success.

If complete restoration of flow is to be the new standard for success or failure of reperfusion therapy, then the second independent line of investigation becomes crucial. With the currently most widely used thrombolytic regimen, accelerated TPA plus intravenous heparin plus aspirin, the prevalence of angiographic complete restoration of flow at 90 minutes is {approx}55%.19 In sharp contrast, the prevalence of TIMI III flow after the therapeutic alternative, direct angioplasty, exceeds 90%.20 This difference seems to have immediate clinical significance. In a recently reported small-scale direct comparison of the two therapies, the rate of recurrent ischemic events during hospitalization was 26% for thrombolysis but only 10% for angioplasty.21 Given the huge differences in these percentages, it is a short step to concluding that direct angioplasty must be a superior therapy. Changing clinical practice patterns suggest that this has already occurred.15 We may further reason that these two new developments, the paradigm shift and the dramatic success of angioplasty, establish a difficult new standard for success of thrombolytic therapy: specifically, 90% prevalence of TIMI III flow at 90 minutes. This standard can be criticized as impractical, unrealistic, or unachievable, yet it does seem inevitable. Rather than criticizing the standard, however, we might more optimistically recall Lewis Thomas' words 2 decades earlier: "Request more data. Do not fire."

The information that supports the possibility of meeting this new target is admittedly very recent and somewhat sketchy. Nonetheless, there is good reason to suspect that newer thrombolytic agents, one of which is STAR, may turn out to be superior to our current version of TPA. A few months ago, the RAPID investigators reported that restoration of flow with reteplase, the nonglycosylated deletion mutant of wild-type TPA, was statistically superior to accelerated infusion of alteplase for restoration of TIMI III flow both at 90 minutes (63% versus 49%) and at 5 to 14 days.22 This difference is clinically important: ejection fraction and segmental wall motion at hospital discharge were also significantly better in the reteplase-treated cohort. At about the same time, a second trial evaluated a new modified TPA in which the epidermal growth factor domain is replaced by serine.23 Compared with native TPA, the modified TPA, delivered as a bolus, doubled the recanalization rate both at 15 minutes and at 30 minutes (62% versus 32%). From such preliminary data, we may reasonably conclude that in the near future, the time to reperfusion can be significantly reduced.

Furthermore, the addition of new antithrombins holds substantial promise for increasing the frequency of complete restoration of flow. In the past few months, Theroux et al24 reported the use of hirudin combined with streptokinase for treatment of acutely thrombosed vessels. At angiography at 90 minutes, 85% of patients exhibited complete restoration of flow. This frequency of TIMI III flow was obtained with the addition of a new antithrombin to a conventional thrombolytic. We may speculate that use of such new antithrombins in concert with new thrombolytics like STAR is likely to further increase the prevalence of complete restoration of flow.

Additional support for pharmacological thrombolysis in both peripheral and coronary arteries may come from entirely unanticipated sources. External ultrasound has a substantial accelerating effect on the rate of thrombolysis, possibly by disruption of clot structure. Peripheral arteries, which are readily accessible to external ultrasound, seem an ideal place to start. Considerable bench and laboratory data support its use. We have compared the percentage of clot lysis by drugs alone (TPA, streptokinase, or urokinase) with that by drugs plus external pulsed ultrasound on clots of various ages in vitro.25 The rate of lysis was accelerated by 25% over a 30-minute period. In canine left anterior descending coronary arteries, external ultrasound radiation reduced the time for recanalization by more than half (from 36 to 14 minutes).26 If practical methods of delivery are developed, ultrasound could contribute substantially to reduction in both the time for clot lysis and the prevalence of complete restoration of flow.

In broad perspective, therefore, we are in the midst of a paradigm shift. We must establish a new standard for the success of thrombolytic therapy. In this context, the new data about the speed and efficacy of STAR in occluded peripheral arteries, like the other studies on new thrombolytics, add an important new detail concerning the treatment of vascular thrombosis. Each of these small pieces of information—about STAR and reteplase and hirudin and ultrasound—represents what Ziman27 saw as the structural basis for the spectacular advance of Western science since the 17th century: "the soliciting of many modest contributions to the store of human knowledge, which achieves a collective power far greater than any one individual study can exert." Taken together, the impact of these new data concerning fibrinolytics, antithrombins, and adjuvant therapies is impossible to calculate. But when this is done, I for one would be willing to take my chances. An achievement of 90% prevalence of TIMI 3 flow at 90 minutes is, perhaps, within our capabilities.


*    References
up arrowTop
 up arrowIntroduction
 *References
 

  1. Thomas L. An earnest proposal. In: The Lives of a Cell: Notes of a Biology Watcher. London, UK: Penguin Books; 1978.
  2. Vanderschueren S, Stockx L, Wilms G, Lacroix H, Verhaeghe R, Vermylen J, Collen D. Thrombolytic therapy of peripheral arterial occlusion with recombinant staphylokinase. Circulation. 1995;92:2050-2057. [Abstract/Free Full Text]
  3. Lack CH. Staphylokinase: an activator of plasma protease. Nature. 1948;16:15-59.
  4. Collen D, Lijnen HR. Staphylokinase, a fibrin-specific plasminogen activator with therapeutic potential? Blood. 1994;84:680-686. [Free Full Text]
  5. Lijnen HR, Van Hoef B, De Cock F, Okada K, Ueshima S, Matsuo O, Collen D. On the mechanism of fibrin-specific plasminogen activation by staphylokinase. J Biol Chem. 1991;266:11826-11832. [Abstract/Free Full Text]
  6. Ambrose JA, Almeida OD, Sharma SK, Torre SR, Marmur JD, Israel DH, Ratner DE, Weiss MB, Hjemdahl-Monsen CE, Myler RK, Moses J, Unterecker WJ, Grunwald AM, Garrett JS, Cowley MJ, Anwar A, Sobolski J, for the TAUSA Investigators. Adjunctive thrombolytic therapy during angioplasty for ischemic rest angina: results of the TAUSA Trial. Circulation. 1994;90:69-77. [Abstract/Free Full Text]
  7. Eisenberg PR. Procoagulant effects of fibrinolytic agents. In: Sobel BE, Collen E, eds. Coronary Thrombolysis in Perspective: Principles Underlying Conjunctive and Adjunctive Therapy. Basel, Switzerland: Marcel Dekker Inc; 1993:77-99.
  8. Verstraeta M. Thrombolytic treatment of acute and chronic thromboembolic occlusion in leg arteries. In: Thrombolysis Year Book. Amsterdam, Netherlands: Elsevier; 1994.
  9. Graor RA, Risius B, Lucas FV, Young JR, Ruschhaupt WF, Beven EB, Grossbard EB. Thrombolysis with recombinant human tissue-type plasminogen activator in patients with peripheral artery and bypass graft occlusion. Circulation. 1986;74:115-120.
  10. The STILE Investigators. Results of a prospective randomized trial evaluating surgery versus thrombolysis for ischemia of the lower extremity (the STILE Trial). Ann Surg. 1994;220:251-268. [Medline] [Order article via Infotrieve]
  11. Graor RA. Fibrinolysis and fibrinolytic therapy. In: Young JR, Graor RA, Olin JW, Bartholomew JR, eds. Peripheral Vascular Diseases. St Louis, Mo: Mosby-Year Book; 1991:93-110.
  12. Schlott B, Hartmann M, Guhrs KH, Birch-Hirschfeld E, Pohl HD, Vanderschueren S, Van de Werf F, Michoel A, Coolen D, Behnke D. High yield production and purification of recombinant staphylokinase for thrombolytic therapy. Biotechnology. 1994;12:185. [Medline] [Order article via Infotrieve]
  13. The GUSTO Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med. 1993;329:673-682. [Abstract/Free Full Text]
  14. Chesebro JH, Knatterud G, Roberts R, Borer J, Cohen LS, Dalen J, Dodge HT, Francis CK, Hillis D, Ludbrook P, Markis JE, Mueller H, Passamani ER, Powers ER, Rao AK, Robertson T, Ross A, Ryan TJ, Sobel BE, Willerson J, Williams DO, Zaret BL, Braunwald E. Thrombolysis in Myocardial Infarction (TIMI) Trial, phase I: a comparison between intravenous tissue plasminogen activator and intravenous streptokinase. Circulation. 1987;76:142-154. [Abstract/Free Full Text]
  15. Simes RJ, Topol EJ, Holmes DR, White HD, Rutsch WR, Vahanian A, Simoons ML, Morris D, Betriu A, Califf RM, Ross AM, for the GUSTO-I Investigators. Link between the angiographic substudy and mortality outcomes in a large randomized trial of myocardial reperfusion: importance of early and complete infarct artery reperfusion. Circulation. 1995;91:1923-1928. [Abstract/Free Full Text]
  16. Fath-Ordoubadi F, Huehns TY, Al-Mohammad A, Beatt KJ. TIMI grade 2 flow is not equivalent to TIMI 3: implications for the use of thrombolytic therapy: a meta-analysis of the trials. J Am Coll Cardiol. 1995;25:401A. Abstract.
  17. Ross AM, Cho S, Lundergran C, Reiner J, Simoons M, Van de Werf F, Coyne K, Califf R, Topol E. The survival advantage of early grade 3 patency after thrombolysis for infarction increases over time. J Am Coll Cardiol. 1995;25:6A. Abstract.
  18. Anderson JL, Karagounis LA, Becker LC, Sorenson SG, Menlove RL. TIMI perfusion grade 3 but not grade 2 results in improved outcome after thrombolysis for myocardial infarction: ventriculographic, enzymatic, and electrocardiographic evidence from the TEAM-3 Study. Circulation. 1993;87:1829-1839. [Abstract/Free Full Text]
  19. The GUSTO Angiographic Investigators. The effects of tissue plasminogen activator, streptokinase, or both on coronary-artery patency, ventricular function and survival after acute myocardial infarction. N Engl J Med. 1993;87:1615-1622.
  20. Grines CL, Browne KF, Marco J, Rothbaum D, Stone GW, O'Keefe J, Overlie P, Donohue B, Chelliah N, Timmis GC. A comparison of immediate angioplasty with thrombolytic therapy for acute myocardial infarction. N Engl J Med. 1993;328:673-679. [Abstract/Free Full Text]
  21. Stone GW, Grines CL, Browne KF, Marco J, Rothbaum D, O'Keefe J, Hartzler GO, Overlie P, Donohue B, Chelliah N, Timmis GC, Vlietstra R, Puchrowicz-Ochocki S, O'Neill WW. Implications of recurrent ischemia after reperfusion therapy in acute myocardial infarction: a comparison of thrombolytic therapy and primary angioplasty. J Am Coll Cardiol. 1995;26:66-72. [Abstract]
  22. Smalling RW, Bode C, Kalbfleisch J, Sen S, Limbourg P, Forycki F, Habib G, Feldman R, Hohnloser S, Seals A, and the RAPID Investigators. More rapid, complete, and stable coronary thrombolysis with bolus administration of reteplase compared with alteplase infusion in acute myocardial infarction. Circulation. 1995;91:2725-2732. [Abstract/Free Full Text]
  23. Kawai C, Hosoda S, Yui Y, Kanmatsuse K, Suzuki S, Motomiya T, Yabe Y, Takatsu F, Kodama K, Minamino R, Sato H, Nobuyoshi M, Nakashima M. Randomized, double-blind multicenter trial of a novel modified t-PA, E6010 by I.V. bolus injection in treatment of acute myocardial infarction: comparison with native t-PA. J Am Coll Cardiol. 1995;25:5A. Abstract.
  24. Theroux P, Perez-Villa F, Waters D, Lesperance J, Shabani F, Bonan R. Randomized double-blind comparison of two doses of Hirulog with heparin as adjunctive therapy to streptokinase to promote early patency of the infarct-related artery in acute myocardial infarction. Circulation. 1995;91:2132-2139. [Abstract/Free Full Text]
  25. Luo H, Steffen W, Cercek B, Arunasalam S, Maurer G, Siegel R. Enhancement of thrombolysis by external ultrasound. Am Heart J. 1993;25:1564-1569.
  26. Sekiguchi H, Hamano K, Yoshizawa S, Muto M, Urushibara T, Kifune K, Kudo S, Hara M, Furuhata H, Okamura T. Thrombolysis enhanced by ultrasound on intracoronary thrombus. J Am Coll Cardiol. 1995;25:163A. Abstract.
  27. Ziman JM. Information, communication, knowledge. Nature. 1969;224:318-324.[Medline] [Order article via Infotrieve]



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