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Iloprost and risk of thromboembolism
1
1CORRESPONDENCE
ACADEMICMEDICINE: NO LONGERAN INDIVIDUAL SPORT
To the Editor: The article by Sadeghi-Nejad and Marquardt [l] describes, with considerable accuracy, the current plight of academic medicine. The premise that “current medical academicians . . . although not extinct, are endangered, struggling for survival” is correct, because academic medicine is in the process of an evolutionary upheaval. Extinction is, fortunately, unlikely as long as we have medical students to be taught, but the survival of the larger multifactorial academic mission of education, research, and patient care is at stake. Academic medicine, like all institutions, must adapt to the modern environment. Individual efforts must be replaced by a team approach where teaching, research, and clinical care are recognized as a group mission. The success of the academic enterprise will depend not only on the contributions of each member to the group activities, but also on the recognition that it is unnecessary, and perhaps wasteful, to demand that each member of the group participate in all aspects of the threefold mission. Some are better at research, some at teaching, and some at patient care. Most will be active in at least two areas, a few individuals in all three. But the critical factor will be the ability of the members of the group to recognize the worth of each member’s contribution to the common goal. Deans, chairpersons, other administrators, and, not the least, promotion committees must recognize the new era. The excellent clinician and superb teacher must be given the same respect that is afforded the successful investigator. Clinical departments must develop compensation for-
666
mulas that recognize all of these factors. Academic medicine is no longer an individual sport, Rarely will a single individual play both offense and defense. The multiple activities of academic medicine require a complex team effort. Our ultimate success will rest on the performance of each individual in a defined role. If we can adapt to these new requirements, we will be able to remain productive. We have few options. If we don’t adapt, we may yet go the way of the dinosaur. JORGE ~.RIos,M.D.,F.A.c.P. GARYL.. %UON, M.D., Ph.D., F.A.C.P.
George Washington University Medical Center Washington, D.C. 1. Sadeghi-Nejad A, Marquardt MM. Academic phy sicians: today’s dinosaurs? Am J Med 1991; 90:
371-3. Submitted
May 15, 1991, and accepted
May 18,
1991
ILOPROSTAND RISK OF THROMBOEMBOLISM
To the Editor:
It was with some concern that we read the recent report by Kovacs et al [l], and we write to take issue with a number of points. The report claims that iloprost, a stable prostacyclin analogue, fails to exert an antiplatelet effect in patients with peripheral vascular disease and, indeed, produces a risk of thromboembolism. This is in contrast to much published work [2,3], so the results obtained by Kovacs et al [l] need careful evaluation. The finding of increased blood coagulability is obtained using hemostatometry. Although the authors state that this method is more physiologic than conventional measures of platelet aggregation, we do not believe this to be so. This method, which employs nonanticoagulated blood, is grossly unphysiologic. It involves
December 1991 The American Journal of Medicine
Volume 91
the passage of fresh blood over thrombogenic artificial surfaces, and in the absence of anticoagulant will result in total activation of the coagulation cascade. In such a system, even significant antiplatelet effects of the drug could be overwhelmed by the activated clotting factors. Furthermore, the hemostatic plug formed during this technique is likely to be initiated by the formation of fibrin strands secondary to this coagulation factor activation with later random trapping of red blood cells and platelets. The authors suggest that anticoagulants may affect platelet behavior; however, we believe that it is far more physiologic to study platelet behavior after anticoagulation than during total activation of coagulation. Additionally, the references for this technique are all from the authors’ own laboratory; thus it has not been validated elsewhere. Careful consideration should be given to data that are in contrast to already published work when the technique employed is not one in widespread use. The authors claim that iloprost has never been evaluated in whole blood in humans. However, we have detected a significant inhibition of whole blood platelet aggregation in humans [4]. Furthermore, they suggest that any antithrombotic effects of iloprost are only obtained at higher doses, at which side effects occur. Again, our work [4] shows a significant antiplatelet effect in both plateletrich plasma and whole blood at doses of 1 and 2 rig/kg/minute, when side effects are less troublesome. Although the authors reference the failure of iloprost to improve tissue plasminogen activator-induced coronary artery patency [5], little emphasis is given to the positive studies of iloprost in peripheral vascular disease
CORRESPONDENCE
[2,3,6,7]. With the majority of clinical studies at variance with a prothrombotic effect of iloprost, alternative reasons should be sought for the results obtained by Kovacs et al [l]. We have already expressed our reservation regarding the technique employed, but would also point out that the patient part of the study was uncontrolled. There are marked diurnal variations in both platelet function [8] and fibrinolysis [9] that could easily produce the statistically significant results seen in the ex vivo part of the study. Additionally, there are very large standard errors of the mean, we are not told if the two baseline samples taken prior to the infusion have been meaned, and using pre-values of 100% (their Figure 2) rather than real data makes it very difficult to clearly assess the work as presented. In conclusion, although there is evidence for some degree of hyperaggregability after prostacyclin infusions [lo], the 8-hour infusion time recommended by the manufacturers of iloprost has been shown, using conventional tests, to minimize this. We do not believe that this recent work shows any clear evidence for a risk of thromboembolism during or following iloprost treatment. JILL J.F.BELcH,M.B.,F.R.c.P.,M.D. C.S. LAU.M.B.. M.R.C.P. A. SANIABAbI, Bik., Ph.LI. M. McLAREN,B.s~.,P~.LI. CD. FORBES, DSC., M.D.,F.R.c.P.
The University Dundee Ninewells Hospital and ILi;~W~f Dundee, Scotland 1. Kovacs 18. Mayou SC, Kirby JD. Infusion of a stable prostacyclin analogue. iloprost. to patients with peripheral vascular disease: lack of antiplatelet effect but risk of thromboembolism. Am J Med 1991; 90: 41-6. 2.Hossman V. Auel H, Schror K. Placebo-controlled, crossover study on the action of iloprost (ZK 36 374) in advanced stages of arterial occlusive disease. In: Trubestein G. editor. Conservative therapy of arterial ocdusive disease. 1986: 186-9. 3. Fitscha P, Tiso B, Krais T. Sinzinger H. Effect of iloprost on in vivo and in vitro platelet function in patients with peripheral vascular disease (PVD). Adv
Prostaglandin Thromboxane Leukotriene Res 1987; 17: 46D-4. 4. Belch JJF, Greer I, McLaren M, eta/. The effect of intravenous i!K 36-374. a stable prostacyclin analogue. on normal volunteers. Prostaglandins 1984; 28: 67-77. 5. Top01 EJ. Ellis SG, Califf RM, et al. Combined tissue-type plasminogen activator and prostacyclin therapy for acute myocardial infusion. J Am Coll Cardiol 1989; 14: 877-M 6. Rademaker M, Thomas RH. Provost G. Beacham JA, Cooke ED, Kirby JP. Prolonged increase in digital blood flow following iloprost infusion in patients with systemic sclerosis. Postgrad Med J 1987; 63:
617-20. 7. Rademaker M, Cooke ED, Almond NE, eta/. Comparison of intravenous infusion of iloprost and oral nifedipine in treatment of Raynaud’s phenomenon in patients with systemic sclerosis: a double-blind random&d study. BMJ 1989; 298: 5614. 6. Bridges A, McLaren M. Saniabadi AR, Fisher T, Belch JJF. Circadian variation of endothelial cell function, red blood cell deformability and dehydro thromboxane Bs in healthy volunteers. Blood, Coag ulation and Fibrinolysis. In press. 9. Urano T, Sumiyoshi K, Nakamuna M, Mori T, Takada Y, Takada A. Fluctuation of TPA and PAI- antigen levels in plasma: difference in their fluctuation patterns between male and female. Thromb Res
1990; 60: 133-9.
10. Sinzinger
H. Monitoring
of effectiveness
of pros-
taglandin therapy in humans. In: Gryglewski RJ. Stock G, editors. Prostacyclin and its stable analogue iloprost. New York: Springer-Verlag, 1987:
91-5. Submitted
March 29. 1991, and accepted
May 18,
1991
The Reply: The view that the technique (hemostatometry) is unspecific for antiplatelet effect and unreproducible is without foundation. Clearly, the authors did not take the trouble to read references 8 through 10 of the article, which document the histology and the mechanism of platelet thrombus formation in response to shear and collagen. The composition of thrombi (platelet aggregate with leukocytes enmeshed) and the effect of monoclonal antibodies against platelet membrane glycoproteins and plasma von Willebrand factor, completely preventing the occurrence of any thrombotic reaction, would have discouraged the authors from contemplating some ‘fibrin strand’ being responsible for the measured reactions. They should have at least considered the ef-
fect of iloprost (Figure lD), which completely prevented both shear- and collagen-induced thrombotic reactions in a concentration that does not affect plasma coagulation. They are taking to the extreme their belief that platelet function measurement is more physiologic from anticoagulated blood than from native blood [sic]. Reproducibility of the technique is reflected in the withinsubject variability of the method with a coefficient of variation of 6% to 8%. It is claimed that our work is in conflict with established methods producing irrefutable evidence for an antiplatelet effect measured ex vivo. Apart from the authors, another cited study employing ex vivo platelet aggregometry indeed showed a decrease of maximal aggregation from a preinfusion of 58% to 50% during continuous infusion of 1 rig/kg/minute iloprost [ 11. The authors stated that the “maximum effect on platelets takes place at a dose of only 1 rig/kg/minute” [2]. The real issue is whether it is theoretically possible at all to detect an antiplatelet effect at this dose. The same authors found that the concentrations of iloprost required to inhibit platelet aggregation in whole blood in vitro (decrease in platelet number by 50%) in response to ADP, collagen, and thrombin were 175, 525, and 1,000 pg/mL, respectively [3]. These concentrations are already much higher than the steady peak blood concentration during infusion (23 pg/mL) [4]. In addition, if we consider the biologic half-life of iloprost (5 minutes) and that aggregometry starts 30 minutes after obtainment of the blood, a detectable and lasting ex vivo antiplatelet effect of 1 or even 2 mg/kg/minute iloprost infusion confuses the common
December 1991 The American Journal of Medicine
Volume 91
667
1CORRESPONDENCE
ACADEMICMEDICINE: NO LONGERAN INDIVIDUAL SPORT
To the Editor: The article by Sadeghi-Nejad and Marquardt [l] describes, with considerable accuracy, the current plight of academic medicine. The premise that “current medical academicians . . . although not extinct, are endangered, struggling for survival” is correct, because academic medicine is in the process of an evolutionary upheaval. Extinction is, fortunately, unlikely as long as we have medical students to be taught, but the survival of the larger multifactorial academic mission of education, research, and patient care is at stake. Academic medicine, like all institutions, must adapt to the modern environment. Individual efforts must be replaced by a team approach where teaching, research, and clinical care are recognized as a group mission. The success of the academic enterprise will depend not only on the contributions of each member to the group activities, but also on the recognition that it is unnecessary, and perhaps wasteful, to demand that each member of the group participate in all aspects of the threefold mission. Some are better at research, some at teaching, and some at patient care. Most will be active in at least two areas, a few individuals in all three. But the critical factor will be the ability of the members of the group to recognize the worth of each member’s contribution to the common goal. Deans, chairpersons, other administrators, and, not the least, promotion committees must recognize the new era. The excellent clinician and superb teacher must be given the same respect that is afforded the successful investigator. Clinical departments must develop compensation for-
666
mulas that recognize all of these factors. Academic medicine is no longer an individual sport, Rarely will a single individual play both offense and defense. The multiple activities of academic medicine require a complex team effort. Our ultimate success will rest on the performance of each individual in a defined role. If we can adapt to these new requirements, we will be able to remain productive. We have few options. If we don’t adapt, we may yet go the way of the dinosaur. JORGE ~.RIos,M.D.,F.A.c.P. GARYL.. %UON, M.D., Ph.D., F.A.C.P.
George Washington University Medical Center Washington, D.C. 1. Sadeghi-Nejad A, Marquardt MM. Academic phy sicians: today’s dinosaurs? Am J Med 1991; 90:
371-3. Submitted
May 15, 1991, and accepted
May 18,
1991
ILOPROSTAND RISK OF THROMBOEMBOLISM
To the Editor:
It was with some concern that we read the recent report by Kovacs et al [l], and we write to take issue with a number of points. The report claims that iloprost, a stable prostacyclin analogue, fails to exert an antiplatelet effect in patients with peripheral vascular disease and, indeed, produces a risk of thromboembolism. This is in contrast to much published work [2,3], so the results obtained by Kovacs et al [l] need careful evaluation. The finding of increased blood coagulability is obtained using hemostatometry. Although the authors state that this method is more physiologic than conventional measures of platelet aggregation, we do not believe this to be so. This method, which employs nonanticoagulated blood, is grossly unphysiologic. It involves
December 1991 The American Journal of Medicine
Volume 91
the passage of fresh blood over thrombogenic artificial surfaces, and in the absence of anticoagulant will result in total activation of the coagulation cascade. In such a system, even significant antiplatelet effects of the drug could be overwhelmed by the activated clotting factors. Furthermore, the hemostatic plug formed during this technique is likely to be initiated by the formation of fibrin strands secondary to this coagulation factor activation with later random trapping of red blood cells and platelets. The authors suggest that anticoagulants may affect platelet behavior; however, we believe that it is far more physiologic to study platelet behavior after anticoagulation than during total activation of coagulation. Additionally, the references for this technique are all from the authors’ own laboratory; thus it has not been validated elsewhere. Careful consideration should be given to data that are in contrast to already published work when the technique employed is not one in widespread use. The authors claim that iloprost has never been evaluated in whole blood in humans. However, we have detected a significant inhibition of whole blood platelet aggregation in humans [4]. Furthermore, they suggest that any antithrombotic effects of iloprost are only obtained at higher doses, at which side effects occur. Again, our work [4] shows a significant antiplatelet effect in both plateletrich plasma and whole blood at doses of 1 and 2 rig/kg/minute, when side effects are less troublesome. Although the authors reference the failure of iloprost to improve tissue plasminogen activator-induced coronary artery patency [5], little emphasis is given to the positive studies of iloprost in peripheral vascular disease
CORRESPONDENCE
[2,3,6,7]. With the majority of clinical studies at variance with a prothrombotic effect of iloprost, alternative reasons should be sought for the results obtained by Kovacs et al [l]. We have already expressed our reservation regarding the technique employed, but would also point out that the patient part of the study was uncontrolled. There are marked diurnal variations in both platelet function [8] and fibrinolysis [9] that could easily produce the statistically significant results seen in the ex vivo part of the study. Additionally, there are very large standard errors of the mean, we are not told if the two baseline samples taken prior to the infusion have been meaned, and using pre-values of 100% (their Figure 2) rather than real data makes it very difficult to clearly assess the work as presented. In conclusion, although there is evidence for some degree of hyperaggregability after prostacyclin infusions [lo], the 8-hour infusion time recommended by the manufacturers of iloprost has been shown, using conventional tests, to minimize this. We do not believe that this recent work shows any clear evidence for a risk of thromboembolism during or following iloprost treatment. JILL J.F.BELcH,M.B.,F.R.c.P.,M.D. C.S. LAU.M.B.. M.R.C.P. A. SANIABAbI, Bik., Ph.LI. M. McLAREN,B.s~.,P~.LI. CD. FORBES, DSC., M.D.,F.R.c.P.
The University Dundee Ninewells Hospital and ILi;~W~f Dundee, Scotland 1. Kovacs 18. Mayou SC, Kirby JD. Infusion of a stable prostacyclin analogue. iloprost. to patients with peripheral vascular disease: lack of antiplatelet effect but risk of thromboembolism. Am J Med 1991; 90: 41-6. 2.Hossman V. Auel H, Schror K. Placebo-controlled, crossover study on the action of iloprost (ZK 36 374) in advanced stages of arterial occlusive disease. In: Trubestein G. editor. Conservative therapy of arterial ocdusive disease. 1986: 186-9. 3. Fitscha P, Tiso B, Krais T. Sinzinger H. Effect of iloprost on in vivo and in vitro platelet function in patients with peripheral vascular disease (PVD). Adv
Prostaglandin Thromboxane Leukotriene Res 1987; 17: 46D-4. 4. Belch JJF, Greer I, McLaren M, eta/. The effect of intravenous i!K 36-374. a stable prostacyclin analogue. on normal volunteers. Prostaglandins 1984; 28: 67-77. 5. Top01 EJ. Ellis SG, Califf RM, et al. Combined tissue-type plasminogen activator and prostacyclin therapy for acute myocardial infusion. J Am Coll Cardiol 1989; 14: 877-M 6. Rademaker M, Thomas RH. Provost G. Beacham JA, Cooke ED, Kirby JP. Prolonged increase in digital blood flow following iloprost infusion in patients with systemic sclerosis. Postgrad Med J 1987; 63:
617-20. 7. Rademaker M, Cooke ED, Almond NE, eta/. Comparison of intravenous infusion of iloprost and oral nifedipine in treatment of Raynaud’s phenomenon in patients with systemic sclerosis: a double-blind random&d study. BMJ 1989; 298: 5614. 6. Bridges A, McLaren M. Saniabadi AR, Fisher T, Belch JJF. Circadian variation of endothelial cell function, red blood cell deformability and dehydro thromboxane Bs in healthy volunteers. Blood, Coag ulation and Fibrinolysis. In press. 9. Urano T, Sumiyoshi K, Nakamuna M, Mori T, Takada Y, Takada A. Fluctuation of TPA and PAI- antigen levels in plasma: difference in their fluctuation patterns between male and female. Thromb Res
1990; 60: 133-9.
10. Sinzinger
H. Monitoring
of effectiveness
of pros-
taglandin therapy in humans. In: Gryglewski RJ. Stock G, editors. Prostacyclin and its stable analogue iloprost. New York: Springer-Verlag, 1987:
91-5. Submitted
March 29. 1991, and accepted
May 18,
1991
The Reply: The view that the technique (hemostatometry) is unspecific for antiplatelet effect and unreproducible is without foundation. Clearly, the authors did not take the trouble to read references 8 through 10 of the article, which document the histology and the mechanism of platelet thrombus formation in response to shear and collagen. The composition of thrombi (platelet aggregate with leukocytes enmeshed) and the effect of monoclonal antibodies against platelet membrane glycoproteins and plasma von Willebrand factor, completely preventing the occurrence of any thrombotic reaction, would have discouraged the authors from contemplating some ‘fibrin strand’ being responsible for the measured reactions. They should have at least considered the ef-
fect of iloprost (Figure lD), which completely prevented both shear- and collagen-induced thrombotic reactions in a concentration that does not affect plasma coagulation. They are taking to the extreme their belief that platelet function measurement is more physiologic from anticoagulated blood than from native blood [sic]. Reproducibility of the technique is reflected in the withinsubject variability of the method with a coefficient of variation of 6% to 8%. It is claimed that our work is in conflict with established methods producing irrefutable evidence for an antiplatelet effect measured ex vivo. Apart from the authors, another cited study employing ex vivo platelet aggregometry indeed showed a decrease of maximal aggregation from a preinfusion of 58% to 50% during continuous infusion of 1 rig/kg/minute iloprost [ 11. The authors stated that the “maximum effect on platelets takes place at a dose of only 1 rig/kg/minute” [2]. The real issue is whether it is theoretically possible at all to detect an antiplatelet effect at this dose. The same authors found that the concentrations of iloprost required to inhibit platelet aggregation in whole blood in vitro (decrease in platelet number by 50%) in response to ADP, collagen, and thrombin were 175, 525, and 1,000 pg/mL, respectively [3]. These concentrations are already much higher than the steady peak blood concentration during infusion (23 pg/mL) [4]. In addition, if we consider the biologic half-life of iloprost (5 minutes) and that aggregometry starts 30 minutes after obtainment of the blood, a detectable and lasting ex vivo antiplatelet effect of 1 or even 2 mg/kg/minute iloprost infusion confuses the common
December 1991 The American Journal of Medicine
Volume 91
667