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Circulation. 1997;95:793-795

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(Circulation. 1997;95:793-795.)
© 1997 American Heart Association, Inc.

Articles

Confusion in Reperfusion

Problems in the Clinical Development of Antithrombotic Drugs

Francesca Catella-Lawson, MD; Garret A. FitzGerald, MD

the Center for Experimental Therapeutics, University of Pennsylvania, Philadelphia.


Key Words: Editorials • thrombolysis • platelet aggregation inhibitors


*    Introduction
up arrowTop
 *Introduction
down arrowReferences
 
A paradoxical effect of the administration of thrombolytic drugs, such as recombinant tissue plasminogen activator (rTPA) and streptokinase, is marked platelet activation in vivo.1 2 Multiple experiments in animal models attest to the functional importance of this observation.3 4 However, perhaps the most convincing evidence is that the effects of aspirin, which inhibits thromboxane (Tx) A2–dependent platelet activation, and streptokinase are roughly additive in reducing 30-day mortality in patients presenting with myocardial infarction.5 The data supporting the concomitant use of heparin with therapeutic thrombolysis in this disease are somewhat less convincing.6 7 However, this may reflect such variables as the timing and route of heparin administration.8 Comparable efficacy of unfractionated and low-molecular-weight heparins has recently been established in the treatment of unstable angina.9 However, irrespective of the quality of the evidence, heparins are commonly administered to patients with myocardial infarction in combination with thrombolytic drugs and aspirin.

Given the multiple pathways by which platelets may be activated, it seems surprising that a drug such as aspirin should exhibit clinical efficacy in the prevention of thrombosis. Perhaps this reflects its role in blocking formation of TxA2, an amplification signal for other platelet agonists.10 However, the quest for a more potent but well-tolerated platelet inhibitor continues. This has proven to be no easy task, as exemplified most recently by the outcome of the CAPRIE trial of clopidogrel.11 This drug, a thienopyridine, like ticlopidine, predominantly inhibits platelet activation induced by ADP, although the precise molecular basis of action of these compounds remains to be defined.12 Ticlopidine is perhaps marginally superior to aspirin in the prevention of strokes in patients presenting with transient ischemic attacks13 but is associated with some unpleasant side effects, including profound neutropenia in up to 2% of cases.14 15 The CAPRIE study, conducted in more than 19 000 patients surviving a recent stroke or myocardial infarction or presenting with symptomatic peripheral vascular disease, has established that clopidogrel is indeed well tolerated. However, as might have been predicted by the experience with ticlopidine, the superiority of this expensive choice over aspirin was marginal (5.32% versus 5.83% in the annual risk of the primary end point; P=.043). It remains to be determined whether it will be sufficient to justify the expenditure of the hundreds of millions of dollars required to complete this trial.

The extraordinary cost of such phase III clinical trials and the potential for disappointment would seem to counsel careful consideration in these times of budgetary restraint in healthcare expenditure. It would seem prudent to advance to phase three trials only those drugs that possess properties likely to confer substantial benefit over established treatment. This is a particular challenge when the established treatment is not only effective but very cheap (aspirin is roughly $.20 per tablet) and reasonably well tolerated. Inhibitors of the platelet glycoprotein IIb/IIIa integrin have shown promise as just such a class of drugs. They inhibit the binding of fibrinogen, which stabilizes platelet aggregates after activation by any primary agonist, be it TxA2, ADP, thrombin, or collagen. Preventing this final step in platelet activation has an intuitive appeal, and the superior potency of this approach over aspirin has been adequately demonstrated in animal models of thrombosis. Furthermore, proof of the concept in patients was established with a chimeric monoclonal antibody Fab fragment inhibitor (c7E3, now known as abciximab) in patients at high risk undergoing percutaneous transluminal coronary angioplasty (PTCA) in the EPIC study.16 Addition of abciximab to conventional therapy with heparin and aspirin decreased the incidence of death, myocardial infarction, and unplanned revascularization by 35%. This benefit was still evident 30 days after the procedure. Abciximab was associated with a higher incidence of bleeding events, and two patients suffered retroperitoneal bleeds. However, the EPILOG study has subsequently shown that adjustments in concomitant anticoagulation (use of low-dose, weight-adjusted heparin) and vascular access management (early sheath removal) allow improvement of the safety profile without a concomitant reduction in relative efficacy.17 The results of the EPIC study opened the door to further development of antithrombotic drugs.18

Several features of abciximab seemed open to improvement. Its half-life was long, and the drug was relatively nonspecific with respect to integrin inhibition. It also carried the potential for antigenicity. This prompted the development of several highly specific, relatively short-lived synthetic inhibitors of platelet glycoprotein IIb/IIIa. These include integrilin, a KGD cyclic hexapeptide, and tirofiban, a nonpeptide tyrosine derivative. Despite expectations, experience with these compounds in phase three trials has been disappointing. Thus, although they appeared to reduce early ischemic events at the time of PTCA, this apparent benefit was no longer evident 30 days after the procedure, the prespecified primary end point of the studies.19 20

There has been much speculation as to why the experience with these compounds has differed from that with abciximab. In particular, attention has focused on their inability to inhibit the vitronectin receptor, an integrin en vogue in vascular biology, which is antagonized by abciximab in vitro. Suggestions have been made that differences in the end-point definitions might explain the heterogeneity among these trial results. However, the paper by Ohman et al21 in the current issue of Circulation raises a more mundane issue, the basis of dose selection before progression into phase three evaluation of such drugs.

Ohman et al pursue a worthy objective: selection of a dose of integrilin for evaluation in a phase three trial. The initial part of their study represents an open-label dose-escalation study. This seems appropriate given their desire to evaluate the effects of integrilin in the setting of concomitant administration of rTPA, aspirin, and heparin. Small numbers of patients were involved, weighted toward the integrilin group to increase the experience with the study drug. The idea was to get a crude impression of tolerance, as reflected by the incidence of bleeding, and an indication of a dose that inhibited platelet aggregation ex vivo by an arbitrary figure, a common surrogate variable with these drugs. However, Ohman et al failed to demonstrate a true dose-response relationship with respect to aggregation induced by 20 µmol/L ADP. This was unfortunate, because inhibition by a mean 80% was achieved with the therapeutically efficacious regimen of abciximab in the EPIC study, which would have served as a benchmark for platelet inhibition by integrilin in combination with heparin and rTPA. The failure to detect a dose-response relationship is dismissed by the investigators as "perhaps not the optimal way to explore the antiaggregatory effect of glycoprotein IIb/IIIa receptor blockers." Indeed. However, it is also likely to have reflected a failure to appreciate that blood was collected into a calcium chelating agent that is known to overestimate artifactually the degree of platelet inhibition by this drug in vitro.17 22 Similarly, there is no reason to believe that the aggregatory response to the thrombin receptor agonist peptide (TRAP) should "provide further insight" into the platelet effects of collagen and epinephrine, as suggested by the authors.

Irrespective of the limitations of the dose-escalation study, it did provide some limited experience of the tolerability of the drug combination, albeit two of the six groups did not receive the bolus of heparin and the heparin infusion was not begun until 60 minutes after rTPA had been initiated. Next the authors performed a randomized, double-blind evaluation of the effects of a single dose (180 µg/kg bolus followed by a 24-hour infusion of 0.75 µg·kg-1·min-1) in 48 patients, randomized 3:1 in favor of integrilin. The primary end point of this study was the restoration of TIMI grade 3 flow, a surrogate clinical end point for cardiovascular efficacy. This sequence of investigation would seem entirely logical, particularly if the dose-escalation phase had identified a rational dose on the basis of the mechanism of action of the drug. Such information was not available due to the technical limitations previously described. Along with the uncertainty of dose selection, the authors failed to power the study adequately to detect a reasonable difference in the primary end point between the treated and untreated groups. They then took a further step that unfortunately is not unusual in studies of this kind. They combined the results they had obtained at the highest dose in the open, dose-escalation study with the integrilin limb of the double-blind study. They then compared these data with placebo, performed statistical tests, and presented the results. These purported to show the superiority of the selected dose of integrilin over placebo in restoring TIMI grade 3 flow. Indeed, integrilin also seemed superior in restoring either TIMI grade 2 or 3 flow in these patients.

This approach and the derivative claim of drug efficacy are entirely misplaced. The basis of statistical inference assumes an a priori statement of the hypothesis to be tested, random allocation to the treatments compared, and blinded collection of the data and comparison of the results. Sadly, blinded grading of the TIMI stages does not substitute for the failure to include the merged patients in a randomized protocol a priori. It is difficult to know what the authors mean when they say that this strategy will provide "more stable outcome estimates." If they mean that an adequate sample size may be approached in this manner, the blinded phase should have been adequately powered to draw reasonable conclusions. For example, the HERO study, as reported at the 45th American College of Cardiology Meeting (March 24 through 27, 1996), was designed to assess the effect of hirulog versus heparin on early patency in patients receiving streptokinase. This trial enrolled 400 patients and conclusively demonstrated the superiority of hirulog in this setting. The blinded phase of the present study involved just 48 patients, and the authors conclude that the combination of integrilin with accelerated rTPA, aspirin, and heparin will enhance the speed and incidence of coronary reperfusion. In fact, analysis of the data from the randomized, blinded phase of the study, designed to address this possibility, suggests precisely the opposite conclusion (FigureDown).



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  		Figure 1. These data include only the information from the double-blind study. The placebo group received tissue plasminogen activator, aspirin, and heparin. The integrilin group also received integrilin as described in the text. Solid bars indicate TIMI grade 3; open bars, TIMI grades 2 and 3.

The performance of large-scale clinical trials demands a rigor and organizational talent of its own. However, the lessons of CAPRIE, the attempts to develop specific thrombin inhibitors,23 and the present experience with glycoprotein IIb/IIIa inhibitors suggest that dose finding and the investigation of tolerance and pharmacodynamics in phase II trials require a distinct repertoire of skills. These might be deployed usefully before costly adventures into phase three trials.


*    Footnotes
 
Reprint requests to G.A. FitzGerald, MD, Center for Experimental Therapeutics, 901 Stellar Chance Laboratories, University of Pennsylvania, 422 Curie Blvd, Philadelphia, PA 19104. E-mail garret@spirit.gcrc.upenn.edu.

The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.


*    References
up arrowTop
 up arrowIntroduction
 *References
 

  1. Fitzgerald DJ, Catella F, Roy L, FitzGerald GA. Marked platelet activation in vivo following intravenous streptokinase in acute myocardial infarction. Circulation.. 1988;77:143-150.
  2. Kerins DM, Roy L, FitzGerald GA, Fitzgerald DJ. Platelet and vascular function during coronary thrombolysis with tissue-type plasminogen activator. Circulation.. 1989;80:1718-1725.[Abstract/Free Full Text]
  3. Schumacher WA, Lee EC, Luchessi BR. Augmentation of streptokinase-induced thrombolysis by heparin and prostacyclin. J Cardiovasc Pharmacol.. 1985;7:739-746.[Medline] [Order article via Infotrieve]
  4. Fitzgerald DJ, Wright F, FitzGerald GA. Increased thromboxane biosynthesis during coronary thrombolysis: evidence that platelet activation and thromboxane A2 modulate the response to tissue-type plasminogen activator in vivo. Circ Res.. 1989;65:83-94.[Abstract/Free Full Text]
  5. ISIS-2 Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both or neither among 17187 cases of suspected acute myocardial infarction: ISIS-2. Lancet.. 1988;2:349-360.[Medline] [Order article via Infotrieve]
  6. Gruppo Italiano per lo Studio della Streptochinasi nell'infarto miocardico (GISSI). GISSI-2: a factorial randomised trial of alteplase versus streptokinase and heparin versus no heparin among 12490 patients with acute myocardial infarction. Lancet.. 1990;336:65-71.[Medline] [Order article via Infotrieve]
  7. ISIS-3 Collaborative Group. ISIS-3: a randomized comparison of streptokinase vs tissue plasminogen activator vs anistreplase and of aspirin plus heparin vs aspirin alone among 41299 cases of suspected acute myocardial infarction. Lancet.. 1992;339:753-770.[Medline] [Order article via Infotrieve]
  8. Kroon C, ten Hove WR, de Boer A, Kroon JM, van der Pol JMJ, Harthoorn-Lasthuizen EJ, Schoemaker HC, van der Meer FJM, Cohen AF. Highly variable anticoagulant response after subcutaneous administration of high-dose (12 500 IU) heparin in patients with myocardial infarction and healthy volunteers. Circulation.. 1992;86:1370-1375.[Abstract/Free Full Text]
  9. FRISC Study Group. Low-molecular-weight heparin during instability in coronary artery disease: Fragmin during instability in coronary artery disease (FRISC). Lancet.. 1996;347:561-568.[Medline] [Order article via Infotrieve]
  10. FitzGerald GA. Mechanisms of platelet activation: thromboxane A2 as an amplifying signal for other agonists. Am J Cardiol.. 1991;68:11B-15B.[Medline] [Order article via Infotrieve]
  11. CAPRIE Steering Committee. A randomised, blinded, trial of Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE). Lancet.. 1996;348:1329-1339.[Medline] [Order article via Infotrieve]
  12. Di Minno G, Cerbone AM, Mattioli PL, Turco S, Iovine C, Mancini M. Functionally thromboasthenic state in normal platelets following the administration of ticlopidine. J Clin Invest.. 1985;75:328-338.
  13. Hass WK, Easton JD, Adams HP Jr, Pryse-Phillips W, Molony BA, Anderson S, Kamm B, for the Ticlopidine Aspirin Stroke Study Group. A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients. N Engl J Med. 1989;321:501-507.[Abstract]
  14. Gent M, Blakely JA, Easton JD, Ellis DJ, Hachinski VC, Harbison JW, Panak E, Roberts RS, Sicurella J, Turpie AGG, and the CATS Group. The Canadian American Ticlopidine Study (CATS) in thromboembolic stroke. Lancet.. 1989;6:1215-1220.
  15. FitzGerald GA. Ticlopidine in unstable angina: a more expensive aspirin? Circulation.. 1990;82:296-298.[Free Full Text]
  16. The EPIC Investigators. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. N Engl J Med.. 1994;330:956-961.[Abstract/Free Full Text]
  17. Tcheng JE. Glycoprotein IIb/IIIa receptor inhibitors: putting the EPIC, IMPACT II, RESTORE and EPILOG Trials into perspective. Am J Cardiol.. 1996;78:35-40.[Medline] [Order article via Infotrieve]
  18. FitzGerald GA. Beyond aspirin: EPIC opens the door. Vessels.. 1995;1:3-8.
  19. Tcheng JE, Lincoff AM, Sigmon KN, Kitt MM, Califf RM, Topol EJ, for the IMPACT II Investigators. Platelet glycoprotein IIb/IIIa inhibition with integrelin during percutaneous coronary intervention: the IMPACT II Trial. Circulation.. 1995;92:543. Abstract.
  20. King SB, Willerson JT, Ross AM, Herrmann HC, Lipschutz KH, and the RESTORE Investigators. Time course of reduction in adverse cardiac events following angioplasty using a IIb/IIIa receptor blocker, tirofiban: the Restore Trial. Circulation.. 1995;94:1155. Abstract.
  21. Ohman EM, Kleiman NS, Gacioch G, Worley SJ, Navetta FI, Talley JD, Anderson HV, Ellis SG, Cohen MD, Spriggs D, Miller M, Kereiakes D, Yakubov S, Kitt MM, Sigmon KN, Califf RM, Krucoff MW, Topol EJ, for the IMPACT-AMI Investigators. Combined accelerated tissue-plasminogen activator and platelet glycoprotein IIb/IIIa integrin receptor blockade with integrilin in acute myocardial infarction: results of a randomized, placebo-controlled, dose-ranging trial. Circulation. 1997;95:846-854.[Abstract/Free Full Text]
  22. Resar JR, Brinker JA, Gerstenblith G, Blumenthal RS, Dudek A, Coombs VJ, Goldshmidt-Clermont P. Disparity of integrilin inhibition of platelet aggregation and GP IIb/IIIa fibrinogen binding in angioplasty patients. Circulation.. 1996;94:567. Abstract.
  23. FitzGerald GA. The human pharmacology of thrombin inhibition. Coron Artery Dis. In press.



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