- Email: [email protected]
Heparins in management of acute coronary syndromes without ST-segment elevation
COMMENTARY
Guidelines for preclinical assessment of neuroprotectants in acute ischaemic stroke models* Drug dose
Establish dose-response curves and determine likelihood of drug penetration of target tissue; include different animal species Time window Determine drug effectiveness in post-occlusion and reperfusion models Type of animal Study small and large animals for permanent and temporary occlusion with replication of findings by independent laboratories Physiological monitoring Include blood pressure, blood gases, haemoglobin, glucose, cerebral blood flow and temperature Outcomes Include at least infarct volume and functional response (acute and chronic) Target population Is extrapolation from young healthy animals to older, frail stroke patients valid? Consider influence of sex Combination therapy Consider targeting more than one ischaemic mechanism *After STAIR.3
volume in the citicoline group. This finding suggests that patients with acute ischaemic stroke and appropriate target lesions, at least as defined by the eligibility criteria for ECCO 2000, and in its MRI substudy, may be a subgroup of acute stroke patients who will respond to citicoline. Moreover, the size of the therapeutic response in this select subgroup is such that testable hypotheses about citicoline in acute ischaemic stroke may be adequately studied with as few as 50–100 patients per treatment group.9 Thus, although the GAIN International and GAIN Americas MRI substudy10 did not replicate the encouraging efficacy results from the ECCO 2000 MRI substudy, it is premature to dismiss neuroprotectants as a treatment for acute ischemic stroke. Instead, the contribution of advanced neuroimaging technology such as MRI to help select appropriate patients should be investigated, with careful attention to technologyassessment methods.11 What may the future hold for neuroprotectant therapy in acute stroke? The complexities of the ischaemic cascade offer an opportunity for multiple simultaneous inhibition therapies (eg, by inhibition of excitotoxic necrosis and ischaemic apoptosis, or by antagonism of NMDA and AMPA receptors), for therapy that restores ionic homoestasis around the neuron, for blockage of “downstream” mediators of excitotoxicity (eg, oxygen free radicals, nitric oxide synthase), for interference with the inflammatory cascade, for inhibition of pre-inflammatory cytokines, and for other integrated approaches.1,12–14. A possibly desirable combination therapy is a thrombolytic drug with a neuroprotective agent.14 A neuroprotectant could extend the period for salvage of potentially reversible ischaemic brain tissue, extend the time window for start of thrombolytic therapy, and extend the window for thrombolysis in “reperfusion” injury. Thrombolytic therapy could improve vessel patency and allow larger amounts of a neuroprotectant to reach ischaemic tissue. The agent that turns out to be effective in protecting 1926
against stroke may be as simple as the key ingredient in a cup of Irish coffee,15 but scientific advances tend to be painfully slow, and the amount of ischaemic brain tissue that can realistically be salvaged may be small.16,17 Whatever the case, assessment of efficacy of new agents requires patience. It is too early for the death knell for neuroprotectants to toll. Philip B Gorelick Center for Stroke Research, Rush Medical College, Chicago, Illinois 60612, USA 1 2
3
4 5 6
7
8 9
10
11 12
13 14 15
16
17
Lee J-M, Zipfel GJ, Choi D.The changing landscape of ischemic brain injury mechanisms. Nature 1999; 399 (suppl 24): A7–14. Ahmed S-H, Shaikh AY, Shaikh ZY, Hsu CY.What animal models have taught us about the treatment of acute stroke and brain protection. Curr Atheroscl Rep 2000; 2: 167–80. Stroke Therapy Academic Industry Roundtable (STAIR). Recommendations for standards regarding preclinical neuroprotective and restorative drug development. Stroke 1999; 30: 2752–58. Zivin JA.Thrombolytic stroke therapy. Past, present and future. Neurology 1999; 53: 14–19. Muir KW, Grosset DG. Neuroprotection for acute stroke: making clinical trials work. Stroke 1999; 30: 180–82. Duncan PW,Wallace D, Lai SM, et al.The stroke impact scale version 2.0. Evaluation of reliability, validity and sensitivity to change. Stroke 1999; 30: 2131–40. Wahlgren NG, Bornhov S, Sharma A, et al.The Clomethiazole Acute Stroke Study (CLASS): efficacy results in 545 patients classified as total anterior circulation syndrome (TACS). J Stroke Cerebrovasc Dis 1999; 8: 231–39. Kidwell CS,Villablanca JP, Saver JL. Advances in neuroimaging of acute stroke. Curr Atheroscl Rep 2000; 2: 126–35. Warach S. MRI in stroke trials. Presented at the 22nd Princeton Conference on Cerebrovascular Disease, Redwood City, CA, March 11, 2000. Warach S, Kaste M, Fisher M, on behalf of the GAIN Americas and GAIN International MRI substudy investigators, and Glaxo Wellcome Collaborative Group.The effect of GV150526 on ischemic lesion volume: the GAIN Americas and GAIN International MRI substudy. Neurology 2000; 54: A87-88 (abstr). Powers WJ.Testing a test; a report card for DWI in acute stroke. Neurology 2000; 54: 1549–51. Lyden P, Lonzo L, Nunez S. Combination chemotherapy extends the therapeutic window to 60 minutes after stroke. J Neurotrauma 1995; 12: 223–30. DeGraba TJ, Pettigrew LC.Why do neuroprotective drugs work in animals but not in humans? Neurol Clinics 2000; 19: 475–93. Lindsberg PJ, Roine RO,Tatlisumak T, Sairanen T, Kaste M.The future of stroke treatment. Neurol Clinics 2000; 19: 495–510. Grotta J, Strong R, Aronowski J.Will a glass of wine or Irish coffee lessen the severity of ischemic stroke? A lesson from rats. Ann Neurol 1999; 46: 496 (abstr). Fagan SC, Bowes MP, Berri SA, Zivin JA. Combination treatment for acute ischemic stroke: a ray of hope? J Stroke Cerebrovasc Dis 1999; 8: 359–67. Heiss W-D,Thiel A, Grond M, Graf R.Which targets are relevant for therapy of acute ischemic stroke? Stroke 1999: 30: 1486–89.
Heparins in management of acute coronary syndromes without ST-segment elevation See page 1936
The rapid transformation of fluid blood to a gel-like substance has been a subject of great interest to scholars, philosophers, and scientists since the days of Plato and Aristotle.1 However, it was not until the early 18th century that blood clotting was recognised as a teleologically vital means of stemming blood loss following vascular injury.2 Over the past several decades, many clinician-scientists and physicians have turned their attention toward preventing or attenuating pathological thrombosis, the dark side of haemostasis. This focus is especially true of acute coronary syndromes, a universally common spectrum of atherothrombotic disorders characterised by plaque disruption, platelet-dependent thrombus formation, and clot
THE LANCET • Vol 355 • June 3, 2000
For personal use only. Not to be reproduced without permission of The Lancet.
COMMENTARY
growth mediated by coagulation proteins, manifest clinically as unstable angina, myocardial infarction (MI) without STsegment elevation, and MI with ST-segment elevation or bundle- branch block. The comprehensive management of acute coronary syndromes without ST-segment elevation, which occurs in nearly 2 million individuals yearly within the USA, should include a full complement of anti-ischaemic and antithrombotic therapy. Although aspirin is of proven benefit for such patients,3 there is question about the added value of anticoagulation with heparin compounds. In today’s Lancet John Eikelboom and colleagues provide supportive evidence favouring combination therapy. A pooled analysis of clinical trials showed that risk of death or MI in aspirin-treated patients during the first week of treatment with unfractionated heparin was 7·9% compared with 10·4% in untreated or placebo-treated patients (33% reduction), and that with low-molecular-weight heparin (LMWH) was 1·6% compared with 5·2% (66% reduction). When the two types of heparin are considered together, the risk of death or MI with aspirin plus heparin in the first week was 4·5% compared with 7·4% for untreated or placebo-treated patients, thus preventing 29 events for every 1000 patients treated. Studies comparing LMWH with unfractionated heparin did not reveal a difference in efficacy (2·2% vs 2·3, respectively). However, after treatment of equal duration, LMWH was associated with a moderate reduction (OR 0·88, 95% CI 0·69–1·12, p=0·34) in the risk of death or MI compared with unfractionated heparin. How will the findings influence choice of heparin? A clinician’s decision to use a specific pharmacological agent or management strategy is typically based on its safety, efficacy, general acceptance, and future applications. This framework can be applied to LMWH in the management of thrombotic disorders. In meta-analyses of studies assessing heparins for patients with venous thromboembolism4 and acute coronary syndromes,5 and in Eikelboom and colleagues’ paper, LMWH preparations were found to be at least as safe as unfractionated heparin. Also, LMWH has been associated with similar or reduced4,5 frequency of outcomes such as death and recurrent thrombotic events during the acute phase of illness. The concept of general acceptance is complex and consists of several integrated components. Clearly, safety and efficacy, especially when found in carefully designed, randomised clinical trials, carry the most weight; however, cost, ease of administration, practicality, and recommendations offered by recognised authorities are also instrumental. Several large-scale international randomised trials done by highly respected investigative groups have shown that LMWH is, at the very least, as effective as unfractionated heparin6,7 and perhaps superior,8,9 particularly among high-risk patients (those with diabetes, troponin positivity, electrocardiographic ST shifts) with unstable angina or MI without ST-segment elevation. In each study, fixed-dose, subcutaneously administered LMWH stood up to unfractionated heparin, titrated to a target coagulation measurement. The 50% success rates for achieving a prespecified activated partial thromboplastin time (aPTT) observed in the ESSENCE9 and FRIC (Fragmin in Unstable Coronary Artery Disease) studies is in keeping with standard practice,10 and it reflects the complex pharmacokinetics of and the lack of standardised testing procedures for unfractionated heparin. Although an inadequate level of anticoagulation is of concern for most
THE LANCET • Vol 355 • June 3, 2000
clinicians, emerging data have highlighted the risk associated with high-intensity anticoagulation and the potential for “rebound”11 as well. As a result, the bioavailability and predictable response to LMWH12 are highly attractive, as are the potential cost savings resulting from a reduced need for hospital admission and revascularisation procedures.13 At present LMWH is used in the prevention and treatment of venous thromboembolism (both in hospital and at home) as well as acute coronary syndromes,14 for which initial plaque stabilisation preceding coronary angioplasty may reduce subsequent mortality and reinfarction rates,15 whereas unfractionated heparin has not been shown to stabilise plaque or influence 6 month outcome after angioplasty. Experience with outpatient anticoagulation has created great interest in the application of LMWH for “bridging therapy” to or from warfarin for patients with atrial fibrillation after mechanical heart-valve replacement, and those undergoing elective surgical procedures for whom hospital admission may otherwise not be required or can be shortened.The flexibility in terms of possibility of outpatient use afforded by subcutaneously administered LMWH has appeal for patients, clinicians, and administrators alike. Last, but certainly not least, future applications of LMWH, particularly when administered in combination with platelet-glycoprotein (GPIIb/IIIa) antagonists,16,17 creates various opportunities for use in patients with acute coronary syndromes, such as MI with ST-segment elevation or bundle-branch block. Studies in progress, such as GUSTO IV-ACS (Global Use of Strategies to Open Occluded Coronary Arteries-Acute Coronary Syndromes), ENTIRE (Enoxaparin and TNK-TPA with or without GPIIb/IIIa Inhibitor as Reperfusion Strategy in ST-elevation MI,TIMI 23), and A2Z (Aggrastat to Zocor), will help determine the full potential of LMWH used in combination with fibrinolytic therapy and percutaneous coronary interventions. Richard C Becker Cardiovascular Thrombosis Research Center, University of Massachusetts Medical School, Worcester MA 01655, USA 1
Jewett B (ed).The dialogues of Plato, 3rd ed. New York, Macmillan, 1892; 3: 339–543. 2 Petit JL. Dissertation sur la mannière d'arrester le sang dans les hémorrhagies. Mem Acad R Sci 1731; 1: 85–102. 3 Antiplatelet Trialists Collaboration. Collaborative overview of randomized trials of antiplatelet therapy-I. Prevention of death, myocardial infarction and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ 1994; 308: 81–106. 4 Gould MK, Dembitzer AD, Doyle RL, Hastie TJ, Garber AM. Lowmolecular weight heparins compared with unfractionated heparin for treatment of acute deep venous thrombosis: a meta-analysis of randomized, controlled trials. Ann Intern Med 1999; 130: 800–09. 5 Antman EM, Cohen M, Radley D, et al. Assessment of the treatment effect of enoxaparin for unstable angina/non-Q wave myocardial infarction: TIMI 11B-ESSENCE meta-analysis. Circulation 1999; 100: 1602–08. 6 Klein W, Buchwald A, Hillis SE, et alFragmin in unstable coronary artery disease study. Comparison of low-molecular-weight heparin with unfractionated heparin acutely and with placebo for 6 weeks in the management of unstable coronary artery disease. Circulation 1997; 96: 61–68. 7 FRISC Study Group. Low molecular weight heparin during instability in coronary artery disease. Lancet 1996; 347: 561–68. 8 Cohen M, Demer S, Gurfinkel EP, et al. A comparison of low-molecularweight heparin with unfractionated heparin for unstable coronary artery disease. Efficacy and safety of subcutaneous enoxaparin in non-Q wave coronary events study group. N Engl J Med 1997; 337: 447–52. 9 Antman EM, McCabe CH, Gurfinkel EP, et al. Enoxaparin prevents death and cardiac ischemic events in unstable angina/non-Q wave myocardial infarction: results of the TIMI 11B Trial. Circulation 1999; 100: 1593–601. 10 Becker RC, Ball SP, Eisenberg , et al. For the Antithrombotic Therapy
1927
For personal use only. Not to be reproduced without permission of The Lancet.
COMMENTARY
12 13
14
15
16
17
Variation in couple fecundity and time to pregnancy, an essential concept in human reproduction See page 1961
In clinical practice infertility is usually defined as a failure to become pregnant during a 12-month period of regular, unprotected intercourse. Hence fertility is assumed to be normal when a pregnancy occurs within this period. This definition has led to a dichotomous concept—of fertility or infertility—which not only ignores the essence of reproduction, but also gives rise to misinterpretations. For example, couples are inclined to think that, if a pregnancy has not occurred within a year, they are sterile and require immediate infertility treatment. In fact, reproduction is a matter of chance depending on the subtle balance between success or failure of complex, mostly poorly understood, sequential processes that may lead to a pregnancy and eventually to the birth of a healthy child. These processes include spermatogenesis and oogenesis, sexual intercourse and transport of gametes, fertilisation, migration of the embryo to the uterus and its subsequent implantation, and finally intrauterine development of the fetus. Failure can occur at any link of this delicate chain, but most commonly does so at the early stages.With regular intercourse a new chance of pregnancy arises every menstrual cycle. Demographic studies show that the distribution of monthly fertility of couples trying to conceive is heterogeneous and fits a -distribution.1,2 Each couple has a more or less constant monthly probability of conceiving, but between couples the probabilities vary widely, from 0% to an upper limit of about 60%. A monthly fertility of zero corresponds to true infertility in the sense of sterility, which occurs in 3–5% of all couples.3 With a high monthly fertility the average time to pregnancy is short, and vice versa.4 Survival analysis is the appropriate method for assessing time-to-pregnancy data. Since the more-fertile couples tend to conceive first, as time goes by progressively less-fertile couples selectively remain in the population of couples who have not achieved a pregnancy.5 Hence how long couples have been unsuccessful at conceiving is an essential estimate of the 1928
Probability of conceiving
100% 84%
80% % Pregnant
11
Consortium Investigators. A randomized, multicenter trial of weightadjusted intravenous heparin dose titration and point-of-care coagulation monitoring in hospitalized patients with active thromboembolic disease. Am Heart J 1999; 137: 59–71. Becker RC, Spencer FA, Li Y, et al.Thrombin generation after the abrupt cessation of intravenous unfractionated heparin among patients with acute coronary syndromes: Potential mechanisms for heightened prothrombotic potential. J Am Coll Cardiol 1999, 34: 1020–27. Becker RC, Fibrinolytic and antithrombotic therapy: theory, practice and management. Oxford: Oxford University Press, 2000: 119–22. O'Brien BJ,Willan A, Blackhouse G, Goeree R, Cohen M, Goodman S. Will the use of low-molecular-weight heparin (enoxaparin) in patients with acute coronary syndrome save costs in Canada? Am Heart J 2000; 139: 423–29. Ryan TJ, Antman EM, Brooks NH, et al. American College of Cardiology/American Heart Association guidelines for the management of patients with acute myocardial infarction. Circulation 1999; 100: 1016–30. FRISC II Investigators. Invasive compared with non-invasive treatment in unstable coronary artery disease: FRISC II prospective randomized multicenter trial. Lancet 1999: 354: 708–15. Li Y, Spencer FA, Ball SP, Becker RC. Inhibition of platelet-dependent prothrombinase activity and thrombin generation by GPIIb/IIIa antagonists: potential contributing mechanism of benefit in acute coronary syndromes. J Thromb Thrombolysis (in press). Cohen M,Théroux P,Weber S, et al. Combination therapy with tirofiban and enoxaparin in acute coronary syndromes. Int J Cardiology 1999; 71: 273–81.
60% 49% 40% 20%
14%
0% 0
3
6 Time (months)
9
12
Probability of conceiving for periods up to 12 months directly after stopping birth control if no pregnancy has been achieved within a year if no pregnancy has been achieved within 3 years
degree of subfertility. The figure, which is derived from data collected by Bongaarts in natural, non-contraceptionpractising populations1 and based on a sterility rate of 4%, shows that, as the duration of inability to achieve a pregnancy increases, the probability of success during the subsequent year sharply decreases. However, the data also show that, if the unproductive period is short (eg, 12 months), the probability of success is still considerable—half the couples will conceive during the following year. These reasonable pregnancy prospects illustrate that the definition of infertility as a failure to conceive within a year contains an oversimplification that may result in premature resort to assisted-reproduction techniques, with their associated risks. Time to pregnancy has also been used in reproductive epidemiology for assessing exposures related to lifestyle, environment, or occupation in case-control studies.4,6 If time to pregnancy is significantly longer in the exposed couples than in the controls, the conclusion that the exposure negatively affects fertility is justified. In several studies time to pregnancy seems to be a sensitive outcome measure for overall couple fertility. It does not enable conclusions as to which link of the reproduction chain is affected. Other disadvantages are that time to pregnancy in this type of studies is susceptible to bias and confounding, and that it evaluates only exposures in couples who sooner or later achieve a pregnancy; it cannot assess the effect on the proportion of truly infertile couples.4 Determinants of sperm quality such as sperm concentration are other measures used in reproductive epidemiology.7 Several studies have shown a secular trend of decline in these variables since the fifties.8,9 Because this finding may be a reflection of the effect of environmental pollution, it has raised serious concern.10 In a paper in today’s Lancet, Michael Joffe started with the hypothesis that a decline in male fertility, with an increase in time to pregnancy, is to be expected as a consequence of declining sperm quality. Instead, he reports a significant decrease in time to pregnancy over the past 40 years. He concludes that, if a decline in male fertility has occurred, it has been fully
THE LANCET • Vol 355 • June 3, 2000
For personal use only. Not to be reproduced without permission of The Lancet.
Guidelines for preclinical assessment of neuroprotectants in acute ischaemic stroke models* Drug dose
Establish dose-response curves and determine likelihood of drug penetration of target tissue; include different animal species Time window Determine drug effectiveness in post-occlusion and reperfusion models Type of animal Study small and large animals for permanent and temporary occlusion with replication of findings by independent laboratories Physiological monitoring Include blood pressure, blood gases, haemoglobin, glucose, cerebral blood flow and temperature Outcomes Include at least infarct volume and functional response (acute and chronic) Target population Is extrapolation from young healthy animals to older, frail stroke patients valid? Consider influence of sex Combination therapy Consider targeting more than one ischaemic mechanism *After STAIR.3
volume in the citicoline group. This finding suggests that patients with acute ischaemic stroke and appropriate target lesions, at least as defined by the eligibility criteria for ECCO 2000, and in its MRI substudy, may be a subgroup of acute stroke patients who will respond to citicoline. Moreover, the size of the therapeutic response in this select subgroup is such that testable hypotheses about citicoline in acute ischaemic stroke may be adequately studied with as few as 50–100 patients per treatment group.9 Thus, although the GAIN International and GAIN Americas MRI substudy10 did not replicate the encouraging efficacy results from the ECCO 2000 MRI substudy, it is premature to dismiss neuroprotectants as a treatment for acute ischemic stroke. Instead, the contribution of advanced neuroimaging technology such as MRI to help select appropriate patients should be investigated, with careful attention to technologyassessment methods.11 What may the future hold for neuroprotectant therapy in acute stroke? The complexities of the ischaemic cascade offer an opportunity for multiple simultaneous inhibition therapies (eg, by inhibition of excitotoxic necrosis and ischaemic apoptosis, or by antagonism of NMDA and AMPA receptors), for therapy that restores ionic homoestasis around the neuron, for blockage of “downstream” mediators of excitotoxicity (eg, oxygen free radicals, nitric oxide synthase), for interference with the inflammatory cascade, for inhibition of pre-inflammatory cytokines, and for other integrated approaches.1,12–14. A possibly desirable combination therapy is a thrombolytic drug with a neuroprotective agent.14 A neuroprotectant could extend the period for salvage of potentially reversible ischaemic brain tissue, extend the time window for start of thrombolytic therapy, and extend the window for thrombolysis in “reperfusion” injury. Thrombolytic therapy could improve vessel patency and allow larger amounts of a neuroprotectant to reach ischaemic tissue. The agent that turns out to be effective in protecting 1926
against stroke may be as simple as the key ingredient in a cup of Irish coffee,15 but scientific advances tend to be painfully slow, and the amount of ischaemic brain tissue that can realistically be salvaged may be small.16,17 Whatever the case, assessment of efficacy of new agents requires patience. It is too early for the death knell for neuroprotectants to toll. Philip B Gorelick Center for Stroke Research, Rush Medical College, Chicago, Illinois 60612, USA 1 2
3
4 5 6
7
8 9
10
11 12
13 14 15
16
17
Lee J-M, Zipfel GJ, Choi D.The changing landscape of ischemic brain injury mechanisms. Nature 1999; 399 (suppl 24): A7–14. Ahmed S-H, Shaikh AY, Shaikh ZY, Hsu CY.What animal models have taught us about the treatment of acute stroke and brain protection. Curr Atheroscl Rep 2000; 2: 167–80. Stroke Therapy Academic Industry Roundtable (STAIR). Recommendations for standards regarding preclinical neuroprotective and restorative drug development. Stroke 1999; 30: 2752–58. Zivin JA.Thrombolytic stroke therapy. Past, present and future. Neurology 1999; 53: 14–19. Muir KW, Grosset DG. Neuroprotection for acute stroke: making clinical trials work. Stroke 1999; 30: 180–82. Duncan PW,Wallace D, Lai SM, et al.The stroke impact scale version 2.0. Evaluation of reliability, validity and sensitivity to change. Stroke 1999; 30: 2131–40. Wahlgren NG, Bornhov S, Sharma A, et al.The Clomethiazole Acute Stroke Study (CLASS): efficacy results in 545 patients classified as total anterior circulation syndrome (TACS). J Stroke Cerebrovasc Dis 1999; 8: 231–39. Kidwell CS,Villablanca JP, Saver JL. Advances in neuroimaging of acute stroke. Curr Atheroscl Rep 2000; 2: 126–35. Warach S. MRI in stroke trials. Presented at the 22nd Princeton Conference on Cerebrovascular Disease, Redwood City, CA, March 11, 2000. Warach S, Kaste M, Fisher M, on behalf of the GAIN Americas and GAIN International MRI substudy investigators, and Glaxo Wellcome Collaborative Group.The effect of GV150526 on ischemic lesion volume: the GAIN Americas and GAIN International MRI substudy. Neurology 2000; 54: A87-88 (abstr). Powers WJ.Testing a test; a report card for DWI in acute stroke. Neurology 2000; 54: 1549–51. Lyden P, Lonzo L, Nunez S. Combination chemotherapy extends the therapeutic window to 60 minutes after stroke. J Neurotrauma 1995; 12: 223–30. DeGraba TJ, Pettigrew LC.Why do neuroprotective drugs work in animals but not in humans? Neurol Clinics 2000; 19: 475–93. Lindsberg PJ, Roine RO,Tatlisumak T, Sairanen T, Kaste M.The future of stroke treatment. Neurol Clinics 2000; 19: 495–510. Grotta J, Strong R, Aronowski J.Will a glass of wine or Irish coffee lessen the severity of ischemic stroke? A lesson from rats. Ann Neurol 1999; 46: 496 (abstr). Fagan SC, Bowes MP, Berri SA, Zivin JA. Combination treatment for acute ischemic stroke: a ray of hope? J Stroke Cerebrovasc Dis 1999; 8: 359–67. Heiss W-D,Thiel A, Grond M, Graf R.Which targets are relevant for therapy of acute ischemic stroke? Stroke 1999: 30: 1486–89.
Heparins in management of acute coronary syndromes without ST-segment elevation See page 1936
The rapid transformation of fluid blood to a gel-like substance has been a subject of great interest to scholars, philosophers, and scientists since the days of Plato and Aristotle.1 However, it was not until the early 18th century that blood clotting was recognised as a teleologically vital means of stemming blood loss following vascular injury.2 Over the past several decades, many clinician-scientists and physicians have turned their attention toward preventing or attenuating pathological thrombosis, the dark side of haemostasis. This focus is especially true of acute coronary syndromes, a universally common spectrum of atherothrombotic disorders characterised by plaque disruption, platelet-dependent thrombus formation, and clot
THE LANCET • Vol 355 • June 3, 2000
For personal use only. Not to be reproduced without permission of The Lancet.
COMMENTARY
growth mediated by coagulation proteins, manifest clinically as unstable angina, myocardial infarction (MI) without STsegment elevation, and MI with ST-segment elevation or bundle- branch block. The comprehensive management of acute coronary syndromes without ST-segment elevation, which occurs in nearly 2 million individuals yearly within the USA, should include a full complement of anti-ischaemic and antithrombotic therapy. Although aspirin is of proven benefit for such patients,3 there is question about the added value of anticoagulation with heparin compounds. In today’s Lancet John Eikelboom and colleagues provide supportive evidence favouring combination therapy. A pooled analysis of clinical trials showed that risk of death or MI in aspirin-treated patients during the first week of treatment with unfractionated heparin was 7·9% compared with 10·4% in untreated or placebo-treated patients (33% reduction), and that with low-molecular-weight heparin (LMWH) was 1·6% compared with 5·2% (66% reduction). When the two types of heparin are considered together, the risk of death or MI with aspirin plus heparin in the first week was 4·5% compared with 7·4% for untreated or placebo-treated patients, thus preventing 29 events for every 1000 patients treated. Studies comparing LMWH with unfractionated heparin did not reveal a difference in efficacy (2·2% vs 2·3, respectively). However, after treatment of equal duration, LMWH was associated with a moderate reduction (OR 0·88, 95% CI 0·69–1·12, p=0·34) in the risk of death or MI compared with unfractionated heparin. How will the findings influence choice of heparin? A clinician’s decision to use a specific pharmacological agent or management strategy is typically based on its safety, efficacy, general acceptance, and future applications. This framework can be applied to LMWH in the management of thrombotic disorders. In meta-analyses of studies assessing heparins for patients with venous thromboembolism4 and acute coronary syndromes,5 and in Eikelboom and colleagues’ paper, LMWH preparations were found to be at least as safe as unfractionated heparin. Also, LMWH has been associated with similar or reduced4,5 frequency of outcomes such as death and recurrent thrombotic events during the acute phase of illness. The concept of general acceptance is complex and consists of several integrated components. Clearly, safety and efficacy, especially when found in carefully designed, randomised clinical trials, carry the most weight; however, cost, ease of administration, practicality, and recommendations offered by recognised authorities are also instrumental. Several large-scale international randomised trials done by highly respected investigative groups have shown that LMWH is, at the very least, as effective as unfractionated heparin6,7 and perhaps superior,8,9 particularly among high-risk patients (those with diabetes, troponin positivity, electrocardiographic ST shifts) with unstable angina or MI without ST-segment elevation. In each study, fixed-dose, subcutaneously administered LMWH stood up to unfractionated heparin, titrated to a target coagulation measurement. The 50% success rates for achieving a prespecified activated partial thromboplastin time (aPTT) observed in the ESSENCE9 and FRIC (Fragmin in Unstable Coronary Artery Disease) studies is in keeping with standard practice,10 and it reflects the complex pharmacokinetics of and the lack of standardised testing procedures for unfractionated heparin. Although an inadequate level of anticoagulation is of concern for most
THE LANCET • Vol 355 • June 3, 2000
clinicians, emerging data have highlighted the risk associated with high-intensity anticoagulation and the potential for “rebound”11 as well. As a result, the bioavailability and predictable response to LMWH12 are highly attractive, as are the potential cost savings resulting from a reduced need for hospital admission and revascularisation procedures.13 At present LMWH is used in the prevention and treatment of venous thromboembolism (both in hospital and at home) as well as acute coronary syndromes,14 for which initial plaque stabilisation preceding coronary angioplasty may reduce subsequent mortality and reinfarction rates,15 whereas unfractionated heparin has not been shown to stabilise plaque or influence 6 month outcome after angioplasty. Experience with outpatient anticoagulation has created great interest in the application of LMWH for “bridging therapy” to or from warfarin for patients with atrial fibrillation after mechanical heart-valve replacement, and those undergoing elective surgical procedures for whom hospital admission may otherwise not be required or can be shortened.The flexibility in terms of possibility of outpatient use afforded by subcutaneously administered LMWH has appeal for patients, clinicians, and administrators alike. Last, but certainly not least, future applications of LMWH, particularly when administered in combination with platelet-glycoprotein (GPIIb/IIIa) antagonists,16,17 creates various opportunities for use in patients with acute coronary syndromes, such as MI with ST-segment elevation or bundle-branch block. Studies in progress, such as GUSTO IV-ACS (Global Use of Strategies to Open Occluded Coronary Arteries-Acute Coronary Syndromes), ENTIRE (Enoxaparin and TNK-TPA with or without GPIIb/IIIa Inhibitor as Reperfusion Strategy in ST-elevation MI,TIMI 23), and A2Z (Aggrastat to Zocor), will help determine the full potential of LMWH used in combination with fibrinolytic therapy and percutaneous coronary interventions. Richard C Becker Cardiovascular Thrombosis Research Center, University of Massachusetts Medical School, Worcester MA 01655, USA 1
Jewett B (ed).The dialogues of Plato, 3rd ed. New York, Macmillan, 1892; 3: 339–543. 2 Petit JL. Dissertation sur la mannière d'arrester le sang dans les hémorrhagies. Mem Acad R Sci 1731; 1: 85–102. 3 Antiplatelet Trialists Collaboration. Collaborative overview of randomized trials of antiplatelet therapy-I. Prevention of death, myocardial infarction and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ 1994; 308: 81–106. 4 Gould MK, Dembitzer AD, Doyle RL, Hastie TJ, Garber AM. Lowmolecular weight heparins compared with unfractionated heparin for treatment of acute deep venous thrombosis: a meta-analysis of randomized, controlled trials. Ann Intern Med 1999; 130: 800–09. 5 Antman EM, Cohen M, Radley D, et al. Assessment of the treatment effect of enoxaparin for unstable angina/non-Q wave myocardial infarction: TIMI 11B-ESSENCE meta-analysis. Circulation 1999; 100: 1602–08. 6 Klein W, Buchwald A, Hillis SE, et alFragmin in unstable coronary artery disease study. Comparison of low-molecular-weight heparin with unfractionated heparin acutely and with placebo for 6 weeks in the management of unstable coronary artery disease. Circulation 1997; 96: 61–68. 7 FRISC Study Group. Low molecular weight heparin during instability in coronary artery disease. Lancet 1996; 347: 561–68. 8 Cohen M, Demer S, Gurfinkel EP, et al. A comparison of low-molecularweight heparin with unfractionated heparin for unstable coronary artery disease. Efficacy and safety of subcutaneous enoxaparin in non-Q wave coronary events study group. N Engl J Med 1997; 337: 447–52. 9 Antman EM, McCabe CH, Gurfinkel EP, et al. Enoxaparin prevents death and cardiac ischemic events in unstable angina/non-Q wave myocardial infarction: results of the TIMI 11B Trial. Circulation 1999; 100: 1593–601. 10 Becker RC, Ball SP, Eisenberg , et al. For the Antithrombotic Therapy
1927
For personal use only. Not to be reproduced without permission of The Lancet.
COMMENTARY
12 13
14
15
16
17
Variation in couple fecundity and time to pregnancy, an essential concept in human reproduction See page 1961
In clinical practice infertility is usually defined as a failure to become pregnant during a 12-month period of regular, unprotected intercourse. Hence fertility is assumed to be normal when a pregnancy occurs within this period. This definition has led to a dichotomous concept—of fertility or infertility—which not only ignores the essence of reproduction, but also gives rise to misinterpretations. For example, couples are inclined to think that, if a pregnancy has not occurred within a year, they are sterile and require immediate infertility treatment. In fact, reproduction is a matter of chance depending on the subtle balance between success or failure of complex, mostly poorly understood, sequential processes that may lead to a pregnancy and eventually to the birth of a healthy child. These processes include spermatogenesis and oogenesis, sexual intercourse and transport of gametes, fertilisation, migration of the embryo to the uterus and its subsequent implantation, and finally intrauterine development of the fetus. Failure can occur at any link of this delicate chain, but most commonly does so at the early stages.With regular intercourse a new chance of pregnancy arises every menstrual cycle. Demographic studies show that the distribution of monthly fertility of couples trying to conceive is heterogeneous and fits a -distribution.1,2 Each couple has a more or less constant monthly probability of conceiving, but between couples the probabilities vary widely, from 0% to an upper limit of about 60%. A monthly fertility of zero corresponds to true infertility in the sense of sterility, which occurs in 3–5% of all couples.3 With a high monthly fertility the average time to pregnancy is short, and vice versa.4 Survival analysis is the appropriate method for assessing time-to-pregnancy data. Since the more-fertile couples tend to conceive first, as time goes by progressively less-fertile couples selectively remain in the population of couples who have not achieved a pregnancy.5 Hence how long couples have been unsuccessful at conceiving is an essential estimate of the 1928
Probability of conceiving
100% 84%
80% % Pregnant
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Consortium Investigators. A randomized, multicenter trial of weightadjusted intravenous heparin dose titration and point-of-care coagulation monitoring in hospitalized patients with active thromboembolic disease. Am Heart J 1999; 137: 59–71. Becker RC, Spencer FA, Li Y, et al.Thrombin generation after the abrupt cessation of intravenous unfractionated heparin among patients with acute coronary syndromes: Potential mechanisms for heightened prothrombotic potential. J Am Coll Cardiol 1999, 34: 1020–27. Becker RC, Fibrinolytic and antithrombotic therapy: theory, practice and management. Oxford: Oxford University Press, 2000: 119–22. O'Brien BJ,Willan A, Blackhouse G, Goeree R, Cohen M, Goodman S. Will the use of low-molecular-weight heparin (enoxaparin) in patients with acute coronary syndrome save costs in Canada? Am Heart J 2000; 139: 423–29. Ryan TJ, Antman EM, Brooks NH, et al. American College of Cardiology/American Heart Association guidelines for the management of patients with acute myocardial infarction. Circulation 1999; 100: 1016–30. FRISC II Investigators. Invasive compared with non-invasive treatment in unstable coronary artery disease: FRISC II prospective randomized multicenter trial. Lancet 1999: 354: 708–15. Li Y, Spencer FA, Ball SP, Becker RC. Inhibition of platelet-dependent prothrombinase activity and thrombin generation by GPIIb/IIIa antagonists: potential contributing mechanism of benefit in acute coronary syndromes. J Thromb Thrombolysis (in press). Cohen M,Théroux P,Weber S, et al. Combination therapy with tirofiban and enoxaparin in acute coronary syndromes. Int J Cardiology 1999; 71: 273–81.
60% 49% 40% 20%
14%
0% 0
3
6 Time (months)
9
12
Probability of conceiving for periods up to 12 months directly after stopping birth control if no pregnancy has been achieved within a year if no pregnancy has been achieved within 3 years
degree of subfertility. The figure, which is derived from data collected by Bongaarts in natural, non-contraceptionpractising populations1 and based on a sterility rate of 4%, shows that, as the duration of inability to achieve a pregnancy increases, the probability of success during the subsequent year sharply decreases. However, the data also show that, if the unproductive period is short (eg, 12 months), the probability of success is still considerable—half the couples will conceive during the following year. These reasonable pregnancy prospects illustrate that the definition of infertility as a failure to conceive within a year contains an oversimplification that may result in premature resort to assisted-reproduction techniques, with their associated risks. Time to pregnancy has also been used in reproductive epidemiology for assessing exposures related to lifestyle, environment, or occupation in case-control studies.4,6 If time to pregnancy is significantly longer in the exposed couples than in the controls, the conclusion that the exposure negatively affects fertility is justified. In several studies time to pregnancy seems to be a sensitive outcome measure for overall couple fertility. It does not enable conclusions as to which link of the reproduction chain is affected. Other disadvantages are that time to pregnancy in this type of studies is susceptible to bias and confounding, and that it evaluates only exposures in couples who sooner or later achieve a pregnancy; it cannot assess the effect on the proportion of truly infertile couples.4 Determinants of sperm quality such as sperm concentration are other measures used in reproductive epidemiology.7 Several studies have shown a secular trend of decline in these variables since the fifties.8,9 Because this finding may be a reflection of the effect of environmental pollution, it has raised serious concern.10 In a paper in today’s Lancet, Michael Joffe started with the hypothesis that a decline in male fertility, with an increase in time to pregnancy, is to be expected as a consequence of declining sperm quality. Instead, he reports a significant decrease in time to pregnancy over the past 40 years. He concludes that, if a decline in male fertility has occurred, it has been fully
THE LANCET • Vol 355 • June 3, 2000
For personal use only. Not to be reproduced without permission of The Lancet.