1158
interest, since a difference was found, depending on whether women had regularly received concurrent oestrogen preparations. The relative risk overall was 0-21, but in never-users of oestrogen this was reduced to zero.
Oestrogen supplementation to control menstrual disorders and induce withdrawal bleeds in amenorrhoeic women was widespread throughout the 1960s and 1970s, especially in Thailand,l the country which contributed over 90% of DMPA users to the WHO study. Indeed, many women were given oestrogens for 7-10 days every month for this purpose. The doses were sometimes equivalent to what would be a month’s supply of the oral contraceptive pill today.2 Thus, in practice, a good proportion of the women in the WHO study were not taking DMPA but a form of combination oestrogen-progestagen treatment for some or all of their years of use of the method. In view of the difference in relative risk of endometrial cancer for users vs never-users of oestrogen, and the study team’s own comment on the similarity of the breast cancer results to those found in young oral contraceptive users, it would be interesting to know if there was also a lower risk ratio for apparent breast cancer risk among the younger women who used DMPA alone, without adjunctive oestrogen. Margaret Pyke Centre, 15 Bateman’s Buildings, Soho Square, London W1V 5TW, UK
ANNE SZAREWSKI JOHN GUILLEBAUD
patients had a cerebral infarction 28 and 46 h after starting anticoagulant therapy with acenocoumarol. Both had These
two
cardiac diseases associated with increased risk of cerebral embolism-namely, AF with mitral stenosis and AF with ischaemic heart disease and left ventricular hypokinesia. Oral anticoagulants interfere with the cyclic interconversion of vitamin K and its 2,3-epoxide, thus inhibiting vitamin-K-dependent coagulation factors II, VII, IX, and X.4,5 They also inhibit production of anticoagulant proteins C and S." Antithrombotic effects of 4-hydroxycoumarins take 3-5 days to reach a peak because of the long half-lives of factors II, IX, and X. Protein C, like factor VII, has a short half-life and the protective effects of protein C pathways may thus be lost before the coagulant pathways are sufficiently inhibited. This may lead to a paradoxic hypercoagulable state during the first 24 to 48 h of oral anticoagulant therapy.4-;; In AF and, possibly, other cardiac disorders with a risk of embolism this state might trigger intercardiac thromboembolism. No measurements of coagulation and anticoagulation proteins in our patients are available and this hypothesis is based solely on the timing of the strokes in the relation of the start of oral anticoagulant therapy. Because the need for anticoagulant therapy in patients with AF is not thought to be urgent many units start treatment with warfarin or acenocoumarol. 1-4 Our experience suggests that this approach may be risky, and it may be prudent to add heparin, discontinuing it 3-5 days later when 4-hydroxycoumarins reach their peak anticoagulant activity. Department of Neurology,
1. Anno. Injectables and implants. Popul Rep 1975 (March), series K, no 1. 2. Zanartu J, Onetto E, Medina E, Dabancens A. Mammary gland nodules in women under continuous exposure to progestagens. Contraception 1973; 7: 203-12.
Strokes soon after oral anticoagulant therapy in patients with atrial fibrillation SIR,-Controlled trials have proved that warfarin prevents stroke in patients with atrial fibrillation (AF).1-3 We describe two patients who had a stroke after the initiation of oral anticoagulant treatment with acenocoumarol (a coumarin compound similar to warfarin) for atrial fibrillation. A 71-year-old man was admitted because of dyspnoea on exertion and an irregular pulse. He had a history of tuberculosis at age 21; he had stopped smoking 6 months earlier when he had a myocardial infarction. He had AF (135/min) and an echocardiogram revealed mild mitral incompetence and hypokinesia of the left ventricle. He was given digoxin and a loading dose of 8 mg acenocoumarol. The next day he received 4 mg acenocoumarol. 28 h after anticoagulant therapy was started a right hemiplegia suddenly developed, with inability to speak and a forced deviation of head and eyes to the left. Consciousness deteriorated. His blood pressure was 130/85 mm Hg. A computed tomographic (CT) scan of the brain 4 h after the onset of the stroke was normal. Coagulation indices were not examined. Anticoagulation was discontinued. A CT scan 5 days later revealed massive nonhaemorrhagic infarction affecting the whole territory of the middle cerebral artery. The patient became more alert but remained hemiplegic and aphasic. He died 20 days after the stroke from
bronchopneumonia. A 63-year-old woman with no history of rheumatic fever or risk factors for atherosclerosis was referred with a 2-month history of episodic nocturnal dyspnoea. She had AF (100/min) and echocardiography revealed moderate mitral stenosis. She was given acenocoumarol (first day 4 mg, second day 3 mg) and digoxin. 46 h after the start of acenocoumarol (before her third dose) hemiplegia developed suddenly with hemianopia and inability to speak. She admitted 3 h after the onset of symptoms. Her blood pressure 120/80 mm Hg. The prothrombin time was 23 s (control 10-6 s) and the partial thromboplastin time was 32 s. A CT brain scan 4 h after onset was normal. Radionuclide ventriculography disclosed no abnormality. The patient was further anticoagulated with acenocoumarol. A CT 5 days later revealed a non-haemorrhagic infarction in the territory of the left middle cerebral artery. Ultrasonic duplex imaging of the carotid arteries was normal. She was was
slowly improved.
Academisch Ziekenhuis, Free University of Brussels,
JACQUES DE KEYSER
B 1090 Brussels, Belgium
LUC HERROELEN
1. Petersen
P, Godtfredsen J, Boyen G, Andersen E, Andersen B. Placebo-controlled, randomized trial of warfarin and aspirin for the prevention of thromboembolic complications in chronic atrial fibrillation: the Copenhagen AFASAK study. Lancet 1989; i. 175-79. 2. Stroke Prevention in Atrial Fibrillation Study Group Investigators. Preliminary report of the Stroke Prevention and Atrial Fibrillation Study N Engl J Med 1990, 322: 836-38. 3. The Boston Area Anticoagulation Trial in Atrial Fibrillation Investigators. The effect of low-dose warfarin on the risk of stroke in patients with non-rheumatic atrial fibrillation. N Engl J Med 1990; 323: 1505-11 4. Hirsh J. Oral anticoagulant drugs. N Engl J Med 1991; 324: 1865-75. 5. Kessler CM. Anticoagulation and thrombolytic therapy: practical considerations Chest 1989, 95 (suppl): 245S-56S. 6 Vigano S, Mannucci PM, Solinas S, Bottasso B, Mariani G. Decrease in protein C antigen and formation of an abnormal protein soon after starting anticoagulant treatment. Br J Haematol 1984; 57: 213-20.
"Further studies ...’ SIR,-Dr Ruffmann (Oct 19, p 1026) deplores those authors who conclude their papers by noting that "further studies are needed". What he does not understand is that by using this formula, at least in an epidemiological context, those authors are following one of the golden rules—ensure that every study contains just enough clues to suggest that another study should be done. The next grant application can then start with a promising statement, on the following lines: "Recent studies have suggested that there is a correlation between exposure to (anything at all) and (some non-specific and usually not very important symptoms). The work described in this application is intended to confirm this observation". For the application to be successful, the fact that the recent studies alluded to are the work of the applicant has to be heavily disguised; experienced grant-seekers usually have no difficulty with this. Your correspondent should not try to deny research-workers access to this traditional device to bolster their attempts to keep themselves and their assistants in funds. I doubt if many will take his words to heart, even though some editors may breathe a sigh of relief. The other golden rule of epidemiology, which is closely related to the first, is that researchers should stop all analysis as soon as any positive results appear. For preference results should be slightly equivocal or at least controversial, thereby providing an opportunity to apply the first rule. Department of Occupational Health, St Mary’s Hospital, London W2 1NY, UK
TONY WALDRON
interest, since a difference was found, depending on whether women had regularly received concurrent oestrogen preparations. The relative risk overall was 0-21, but in never-users of oestrogen this was reduced to zero.
Oestrogen supplementation to control menstrual disorders and induce withdrawal bleeds in amenorrhoeic women was widespread throughout the 1960s and 1970s, especially in Thailand,l the country which contributed over 90% of DMPA users to the WHO study. Indeed, many women were given oestrogens for 7-10 days every month for this purpose. The doses were sometimes equivalent to what would be a month’s supply of the oral contraceptive pill today.2 Thus, in practice, a good proportion of the women in the WHO study were not taking DMPA but a form of combination oestrogen-progestagen treatment for some or all of their years of use of the method. In view of the difference in relative risk of endometrial cancer for users vs never-users of oestrogen, and the study team’s own comment on the similarity of the breast cancer results to those found in young oral contraceptive users, it would be interesting to know if there was also a lower risk ratio for apparent breast cancer risk among the younger women who used DMPA alone, without adjunctive oestrogen. Margaret Pyke Centre, 15 Bateman’s Buildings, Soho Square, London W1V 5TW, UK
ANNE SZAREWSKI JOHN GUILLEBAUD
patients had a cerebral infarction 28 and 46 h after starting anticoagulant therapy with acenocoumarol. Both had These
two
cardiac diseases associated with increased risk of cerebral embolism-namely, AF with mitral stenosis and AF with ischaemic heart disease and left ventricular hypokinesia. Oral anticoagulants interfere with the cyclic interconversion of vitamin K and its 2,3-epoxide, thus inhibiting vitamin-K-dependent coagulation factors II, VII, IX, and X.4,5 They also inhibit production of anticoagulant proteins C and S." Antithrombotic effects of 4-hydroxycoumarins take 3-5 days to reach a peak because of the long half-lives of factors II, IX, and X. Protein C, like factor VII, has a short half-life and the protective effects of protein C pathways may thus be lost before the coagulant pathways are sufficiently inhibited. This may lead to a paradoxic hypercoagulable state during the first 24 to 48 h of oral anticoagulant therapy.4-;; In AF and, possibly, other cardiac disorders with a risk of embolism this state might trigger intercardiac thromboembolism. No measurements of coagulation and anticoagulation proteins in our patients are available and this hypothesis is based solely on the timing of the strokes in the relation of the start of oral anticoagulant therapy. Because the need for anticoagulant therapy in patients with AF is not thought to be urgent many units start treatment with warfarin or acenocoumarol. 1-4 Our experience suggests that this approach may be risky, and it may be prudent to add heparin, discontinuing it 3-5 days later when 4-hydroxycoumarins reach their peak anticoagulant activity. Department of Neurology,
1. Anno. Injectables and implants. Popul Rep 1975 (March), series K, no 1. 2. Zanartu J, Onetto E, Medina E, Dabancens A. Mammary gland nodules in women under continuous exposure to progestagens. Contraception 1973; 7: 203-12.
Strokes soon after oral anticoagulant therapy in patients with atrial fibrillation SIR,-Controlled trials have proved that warfarin prevents stroke in patients with atrial fibrillation (AF).1-3 We describe two patients who had a stroke after the initiation of oral anticoagulant treatment with acenocoumarol (a coumarin compound similar to warfarin) for atrial fibrillation. A 71-year-old man was admitted because of dyspnoea on exertion and an irregular pulse. He had a history of tuberculosis at age 21; he had stopped smoking 6 months earlier when he had a myocardial infarction. He had AF (135/min) and an echocardiogram revealed mild mitral incompetence and hypokinesia of the left ventricle. He was given digoxin and a loading dose of 8 mg acenocoumarol. The next day he received 4 mg acenocoumarol. 28 h after anticoagulant therapy was started a right hemiplegia suddenly developed, with inability to speak and a forced deviation of head and eyes to the left. Consciousness deteriorated. His blood pressure was 130/85 mm Hg. A computed tomographic (CT) scan of the brain 4 h after the onset of the stroke was normal. Coagulation indices were not examined. Anticoagulation was discontinued. A CT scan 5 days later revealed massive nonhaemorrhagic infarction affecting the whole territory of the middle cerebral artery. The patient became more alert but remained hemiplegic and aphasic. He died 20 days after the stroke from
bronchopneumonia. A 63-year-old woman with no history of rheumatic fever or risk factors for atherosclerosis was referred with a 2-month history of episodic nocturnal dyspnoea. She had AF (100/min) and echocardiography revealed moderate mitral stenosis. She was given acenocoumarol (first day 4 mg, second day 3 mg) and digoxin. 46 h after the start of acenocoumarol (before her third dose) hemiplegia developed suddenly with hemianopia and inability to speak. She admitted 3 h after the onset of symptoms. Her blood pressure 120/80 mm Hg. The prothrombin time was 23 s (control 10-6 s) and the partial thromboplastin time was 32 s. A CT brain scan 4 h after onset was normal. Radionuclide ventriculography disclosed no abnormality. The patient was further anticoagulated with acenocoumarol. A CT 5 days later revealed a non-haemorrhagic infarction in the territory of the left middle cerebral artery. Ultrasonic duplex imaging of the carotid arteries was normal. She was was
slowly improved.
Academisch Ziekenhuis, Free University of Brussels,
JACQUES DE KEYSER
B 1090 Brussels, Belgium
LUC HERROELEN
1. Petersen
P, Godtfredsen J, Boyen G, Andersen E, Andersen B. Placebo-controlled, randomized trial of warfarin and aspirin for the prevention of thromboembolic complications in chronic atrial fibrillation: the Copenhagen AFASAK study. Lancet 1989; i. 175-79. 2. Stroke Prevention in Atrial Fibrillation Study Group Investigators. Preliminary report of the Stroke Prevention and Atrial Fibrillation Study N Engl J Med 1990, 322: 836-38. 3. The Boston Area Anticoagulation Trial in Atrial Fibrillation Investigators. The effect of low-dose warfarin on the risk of stroke in patients with non-rheumatic atrial fibrillation. N Engl J Med 1990; 323: 1505-11 4. Hirsh J. Oral anticoagulant drugs. N Engl J Med 1991; 324: 1865-75. 5. Kessler CM. Anticoagulation and thrombolytic therapy: practical considerations Chest 1989, 95 (suppl): 245S-56S. 6 Vigano S, Mannucci PM, Solinas S, Bottasso B, Mariani G. Decrease in protein C antigen and formation of an abnormal protein soon after starting anticoagulant treatment. Br J Haematol 1984; 57: 213-20.
"Further studies ...’ SIR,-Dr Ruffmann (Oct 19, p 1026) deplores those authors who conclude their papers by noting that "further studies are needed". What he does not understand is that by using this formula, at least in an epidemiological context, those authors are following one of the golden rules—ensure that every study contains just enough clues to suggest that another study should be done. The next grant application can then start with a promising statement, on the following lines: "Recent studies have suggested that there is a correlation between exposure to (anything at all) and (some non-specific and usually not very important symptoms). The work described in this application is intended to confirm this observation". For the application to be successful, the fact that the recent studies alluded to are the work of the applicant has to be heavily disguised; experienced grant-seekers usually have no difficulty with this. Your correspondent should not try to deny research-workers access to this traditional device to bolster their attempts to keep themselves and their assistants in funds. I doubt if many will take his words to heart, even though some editors may breathe a sigh of relief. The other golden rule of epidemiology, which is closely related to the first, is that researchers should stop all analysis as soon as any positive results appear. For preference results should be slightly equivocal or at least controversial, thereby providing an opportunity to apply the first rule. Department of Occupational Health, St Mary’s Hospital, London W2 1NY, UK
TONY WALDRON
