- Email: [email protected]
Fatal aplastic anaemia associated with lisinopril
contribute to current detection rates and that all of it is in fact us, not just the screeners, who fear censure. We are grateful to Skegg, Soutter, and others who acknowledge that the Bristol programme is well run, though must take issue with the we suggestion that the less than fully involved Bristol are in anything gynaecologists abnormalities. with screen-detected women care to in giving difficult task managing women with Gynaecologists face a asymptomatic tissue change whose natural history is far from certain and there is little firm evidence on which to base national standards. Most worrying are the results of longterm follow up showing that some women develop clinically invasive cancer despite appropriate treatment.2 Skegg and several of your correspondants point out the difficulties in interpreting mortality trends. We agree; what worries us is that Skegg says it may be too soon for us to expect a drop in deaths, but describes as "compelling evidence" conclusions drawn from mortality changes seen soon after the start of screening, with coverage no higher than ours and with audit and quality control no more rigorous than ours. If the evidence is so clear, why is the method for successful screening still so much in question? If, as Robertson and Woodend suggest, it is so difficult to get a screening programme right, this message must be conveyed to those who are busy generating public optimism for new screening programmes. Campbell raises an important point about changes in death recording. However, dual coding in 1984 revealed a difference of 39 deaths for England and Wales and a conversion factor of 0-979. This suggests the impact in Bristol would be tiny. Koss invokes "an obvious system failure" to explain our death figures, although the mortality data from British Columbia are not as he says: incidence of cervical cancer was 28 per 100000, not mortality; death rates were declining before screening began; and by the time 80% coverage was achieved in 1972 (before which, Skegg argues, one would not see a screening effect), almost half the mortality drop had occurred. His sweeping dismissal of the Bristol screening programme which functions as part of a coordinated national programme, shows why workers are reluctant to publish negative findings. Anthony and Clarke present interesting figures for CIN III, proved by biopsy. The problem with interpreting these trends is that the sample of women who have biopsies has been changing. In Bristol the annual number of women referred to gynaecologists on the basis of a newly detected smear abnormality rose considerably. If you do more biopsies, you find more CIN. We accept McCartneys reprimand for our resigned attitude. At the root of this are the difficulties we see with interpretation of observational data, particularly when selfselected groups are being studied. Unless a more critical and open-minded approach is brought to the whole field of screening, then we worry that further attempts at evaluation will be a waste of effort. Sasieni is right about the information given to women: informed participation in a screening programme is crucial. However we do not see much advantage in adding HPV testing to augment cytology. This defines a different (but no smaller) subset of women as abnormal; there are no grounds for suspecting that this group is more likely to be helped by biopsy and treatment; the chances are that HPV-positive women would be referred as well as-not instead of-those with abnormal cytology; and the screening programme would become more cumbersome and of no more certain benefit. If death rates are falling and screening is working, why change the programme? If the falling death rates are nothing to do with screening, why add a further test? On the question of audit of invasive cancer cases, this is a
categorisation
matter for national debate. It could be valuable. But without wider recognition of the fact that some cases are inevitably undetectable by screening and some will not be helped even if found, then audit could become an industry in itself, chasing ’avoidable’ factors which may not even be relevant. Even defining what constitutes an ’adequate smear’ is proving difficult enough.
*A E Raffle, E F D Mackenzie, B Alden *Avon Health, Bristol and District Health Bristol BS2 SEE, UK
1 2
3 4
Authority, 10 Dighton Street,
Mihill C. Cancer tests "cause anxiety". The Guardian, June 9, 1995. McIndoe WA, McLean MR, Jones RW, Mullins PR. The invasive potential of carcinoma in situ of the cervix. Obstet Gynaecol 1984; 64: 451-58. Kolstad P, Klem V. Long-term follow up of 1121 cases of carcinoma in situ. Obstet Gynecol 1976; 48: 125-29. Creasman WT, Rutledge F. Carcinoma in situ of the cervix. An analysis of 861 patients. Obstet Gynecol 1972; 39: 373-80.
Fatal
aplastic anaemia associated with lisinopril SiR-Lisinopril is a once daily angiotensin-converting enzyme (ACE) inhibitor commonly used to control hypertension and cardiac failure. Recognised side-effects of treatment include dry cough, hypotension, and renal impairment.’ Decreases in haemoglobin (average 0.4 g/dL) and packed cell volume are frequently seen during lisinopril therapy2 but severe haematological side-effects are rare. We report a case of fatal aplastic anaemia with hepatic dysfunction after a short course of lisinopril. A 64-year-old woman had exercise-induced angina, triple vessel coronary artery disease, and severe aortic regurgitation controlled with atenolol, diltiazem, and nitrate patches. She underwent coronary artery bypass grafting with saphenous vein graft and aortic valve replacement with a metal prosthetic valve. Postoperatively she was started on frusemide, warfarin, and digoxin, the latter for control of postoperative atrial fibrillation. ACE inhibition with captopril was started routinely on the 2nd postoperative day; the patient was converted to lisinopril 5 mg daily, for ease of dosing, on the 5th postoperative day, and anti-anginal medication was stopped. She was discharged on the 7th postoperative day with haemoglobin (Hb) 9-3 g/dL, total white cell count (WBC) 10-5X10"/L (neutrophil 8.6X109/L), and platelet count 142X109/L. She was readmitted on the 12th postoperative day with fever and anorexia. Lisinopril, digoxin, frusemide, and warfarin were continued. On admission her Hb was 9-0 g/dL, WBC 4.58X109/L, neutrophil 3.48X109/L, and platelet count 185X109/L. Renal function was normal. On the 17th postoperative day she was noted to have oral candidosis and to be jaundiced. Liver function tests were: bilirubin 75 µmol/L (normal range 1-24), alanine aminotransferase 548 IU/L (21-72), alkaline phosphatase 262 IU/L (65-260), and albumin 24 g/L (36-50 g/L). Her Hb was 7-9 g/dL, WBC 0.35X109/L (no neutrophils seen), and platelet count 12X109/L. Bone marrow aspirate and trephine showed complete trilineage aplasia with reactive histiocytosis. Frusemide, warfarin, and lisinopril were stopped and granulocyte colony-stimulating factor (G-CSF) 30 MU daily subcutaneously was started. The patient’s general condition deteriorated with wound breakdown, recurrent bacterial and fungal infections, and gastrointestinal haemorrhage. G-CSF was discontinued after 8 days, with no signs of neutrophil recovery. The patient died 32 days after surgery and 17 days after development of neutropenia despite intensive supportive measures. Postmortem findings confirmed the presence of bone marrow aplasia with, in addition, changes 247
hepatorenal failure. Hepatitis A, B, and C serology and parvovirus IgM were negative and paired serum samples screened for a panel of viral and atypical infections showed no recent infection. Ham’s test was negative as was a full autoantibody screen. There is one reported case of lisinopril-induced aplastic anaemia occurring in a 79-year-old woman who presented with profound pancytopenia after treatment of hypertension with lisinopril. In this patient, partial recovery of all counts occurred after several weeks and 25 days of G-CSF and methylprednisolone therapy. Review of the Committee on Safety of Medicines’ data of lisinopril (March, 1995) reveals one case of fatal aplastic anaemia and 22 other cases of or multilineage suppression (personal unilineage communication). Amongst the other ACE inhibitors, captopril alone has been implicated in aplastic anaemia, usually in association with renal impairment.4 Although our patient had received several other drugs in the perioperative period we postulate that her fatal bone marrow aplasia was the result of lisinopril therapy although there was, in addition, limited exposure to captopril. of
introduction implies that subcutaneous allow patients to be managed at home. This is heparin may an extraordinary argument. Unstable angina is an emergency and all patients should be admitted to hospital at once. Informed consent was given but ethical committee approval is not mentioned. Studies that involve withholding treatments of proven efficacy should specifically state that such approval has been granted. The
Hugh
E
paper’s
Montgomery, *Michael
R Chester
Hatter Institute for Cardiovascular Research, Department of Cardiology, University College Hospital, London WC1; and *Department of Cardiological Sciences, St George’s Hospital Medical School, London SW17 ORE, UK
Cohen M, Adams P, Parry G, et al. Combination antithrombotic therapy in unstable rest angina and non-Q-wave infarction in nonprior aspirin user. Circulation 1994; 89: 81-88. The RISC Group. Risk of myocardial infarction and death during treatment with low dose aspirin and intravenous heparin in men with
1
2
unstable coronary artery disease. Lancet 1990; 336: 827-30. Theroux P, Waters D, Qui S, McCans J, deGuise P, Juneau M. Aspirin versus heparin to prevent myocardial infarction during the acute phase of unstable angina. Circulation 1993; 88: 2045-48.
3
Clinicians should be aware of this rare side-effect and should withdraw ACE inhibitor therapy in the face of falling blood counts.
Beth D
Harrison, Stuart T Laidlaw, *John T Reilly
Department of Haematology, Northern General Hospital, Sheffield S5 7AU, UK 1 2 3
4
Who needs nine ACE inhibitors? Drug Ther Bull 1995; 33: 1. Drug Evaluation Monographs. Lisinopril. Micromedex Inc, 1995; vol 83. Schratzlseer G, Lipp T, Riess G, Antoni D, Delius W. Severe pancytopenia in old age after 12 month ACE inhibitor therapy. Dtsch Med Wochenschr 1994; 119: 1029-33. Kim CR, Maley MB, Mohler ER Jr. Captopril and aplastic anemia. Ann Intern Med 1989; 111: 187.
Heparin in unstable angina SIR-Neri Serneri et al (May 13, p 1201) set out to "assess the efficacy of subcutaneous heparin" in unstable angina, having accepted that, given intravenously, heparin is "highly effective". Yet all patients were denied heparin for 2 days, and one-third of them never received it. Before randomisation all patients were said to receive "conventional treatment". We believe that this includes a combination of heparin and aspirin, which the authors recognise to be more effective than either alone.’ None were given this therapy. It also seems that some patients received nifedipine without beta-blockade. The use of an agent with an indirect chronotropic effect in the treatment of unstable angina must be questioned when alternatives (such as diltiazem) exist. The efficacy of aspirin in unstable angina has been demonstrated in previous studies,2,3 but aspirin therapy was withdrawn from two-thirds of patients in the trial. No inference can be made about the efficacy of aspirin alone, because failure to respond to therapy which included aspirin was an entry criterion. The conclusion that aspirin is ineffective in controlling ischaemia is misleading. Moreover, an important mode of action of aspirin is through the inhibition of thromboxane-mediated platelet aggregation at the site of coronary plaque rupture. A single 350 mg dose of aspirin reduces platelet aggregation for up to 10 days, and all received aspirin before randomisation. The crucial comparison, therefore, is between intravenous and subcutaneous heparin. Although this study was not sufficiently powerful to make that comparison, nearly all the measures of efficacy were better in the intravenous than in the subcutaneous group. 248
SIR-In the paper by Neri Serneri and colleagues the first and last paragraphs of the summary suggest that the objective of this study was to compare the efficacy of subcutaneous and intravenous heparin in the control of myocardial ischaemia in patients with unstable angina. Why was the study complicated by aspirin? Of the 108 patients 66 had reported angina previously and 47 had sustained a myocardial infarction. However, the paper does not indicate which patients were already taking aspirin for secondary prophylaxis before admission to this trial? Every patient in the trial was given aspirin for 2 days immediately before the 3 day trial therapy period so the statement "our results suggest that by itself aspirin could not affect myocardial ischaemia in unstable angina" is not supported by the data presented. Since all the patients were exposed to aspirin for 2 days and the aspirin group continued on the drug for 3 days, there is no control group or period with which to compare the aspirin-treated group. Was there a hypothesis to be tested by the inclusion of the aspirin arm? Reducing ischaemia is one aim of treatment in unstable angina but prevention of infarction is another. Indeed Theroux et al have demonstrated that aspirin alone can reduce the incidence of infarction in patients with unstable angina.’ A later study by the same group2 is twice misquoted by Neri Serneri et al. As that paper’s title indicates, myocardial infarction, not "control of myocardial ischaemia", was the endpoint; and there was no "rebound of clinical symptoms after heparin discontinuation" in the study cited. The frequency of main-stem stenosis was high. This might be explained by the fact that the trial was in a selected group of patients who had continued to experience angina after the 24 h run-in period. There were 46 patients with main-stem stenosis but only 28 were treated by coronary artery bypass grafting within the next month. What treatment did Neri Serneri and colleagues feel more appropriate for the other 18 patients with refractory unstable angina and main-stem stenosis? *David P Jenkins, Mark
Sumeray
Holmes Sellors Cardiothoracic Unit, Middlesex
1
2
Hospital, London W1N 8AA, UK
Theroux P, Ouimet H, McCans J, et al. Aspirin, heparin, or both to to treat acute unstable angina. N Engl J Med 1988; 319: 1105-11. Theroux P, Waters D, Qui S, McCans J, de Guise P, Juneau M. Aspirin versus heparin to prevent myocardial infarction during the acute phase of unstable angina. Circulation 1993; 88: 2045-48.
categorisation
matter for national debate. It could be valuable. But without wider recognition of the fact that some cases are inevitably undetectable by screening and some will not be helped even if found, then audit could become an industry in itself, chasing ’avoidable’ factors which may not even be relevant. Even defining what constitutes an ’adequate smear’ is proving difficult enough.
*A E Raffle, E F D Mackenzie, B Alden *Avon Health, Bristol and District Health Bristol BS2 SEE, UK
1 2
3 4
Authority, 10 Dighton Street,
Mihill C. Cancer tests "cause anxiety". The Guardian, June 9, 1995. McIndoe WA, McLean MR, Jones RW, Mullins PR. The invasive potential of carcinoma in situ of the cervix. Obstet Gynaecol 1984; 64: 451-58. Kolstad P, Klem V. Long-term follow up of 1121 cases of carcinoma in situ. Obstet Gynecol 1976; 48: 125-29. Creasman WT, Rutledge F. Carcinoma in situ of the cervix. An analysis of 861 patients. Obstet Gynecol 1972; 39: 373-80.
Fatal
aplastic anaemia associated with lisinopril SiR-Lisinopril is a once daily angiotensin-converting enzyme (ACE) inhibitor commonly used to control hypertension and cardiac failure. Recognised side-effects of treatment include dry cough, hypotension, and renal impairment.’ Decreases in haemoglobin (average 0.4 g/dL) and packed cell volume are frequently seen during lisinopril therapy2 but severe haematological side-effects are rare. We report a case of fatal aplastic anaemia with hepatic dysfunction after a short course of lisinopril. A 64-year-old woman had exercise-induced angina, triple vessel coronary artery disease, and severe aortic regurgitation controlled with atenolol, diltiazem, and nitrate patches. She underwent coronary artery bypass grafting with saphenous vein graft and aortic valve replacement with a metal prosthetic valve. Postoperatively she was started on frusemide, warfarin, and digoxin, the latter for control of postoperative atrial fibrillation. ACE inhibition with captopril was started routinely on the 2nd postoperative day; the patient was converted to lisinopril 5 mg daily, for ease of dosing, on the 5th postoperative day, and anti-anginal medication was stopped. She was discharged on the 7th postoperative day with haemoglobin (Hb) 9-3 g/dL, total white cell count (WBC) 10-5X10"/L (neutrophil 8.6X109/L), and platelet count 142X109/L. She was readmitted on the 12th postoperative day with fever and anorexia. Lisinopril, digoxin, frusemide, and warfarin were continued. On admission her Hb was 9-0 g/dL, WBC 4.58X109/L, neutrophil 3.48X109/L, and platelet count 185X109/L. Renal function was normal. On the 17th postoperative day she was noted to have oral candidosis and to be jaundiced. Liver function tests were: bilirubin 75 µmol/L (normal range 1-24), alanine aminotransferase 548 IU/L (21-72), alkaline phosphatase 262 IU/L (65-260), and albumin 24 g/L (36-50 g/L). Her Hb was 7-9 g/dL, WBC 0.35X109/L (no neutrophils seen), and platelet count 12X109/L. Bone marrow aspirate and trephine showed complete trilineage aplasia with reactive histiocytosis. Frusemide, warfarin, and lisinopril were stopped and granulocyte colony-stimulating factor (G-CSF) 30 MU daily subcutaneously was started. The patient’s general condition deteriorated with wound breakdown, recurrent bacterial and fungal infections, and gastrointestinal haemorrhage. G-CSF was discontinued after 8 days, with no signs of neutrophil recovery. The patient died 32 days after surgery and 17 days after development of neutropenia despite intensive supportive measures. Postmortem findings confirmed the presence of bone marrow aplasia with, in addition, changes 247
hepatorenal failure. Hepatitis A, B, and C serology and parvovirus IgM were negative and paired serum samples screened for a panel of viral and atypical infections showed no recent infection. Ham’s test was negative as was a full autoantibody screen. There is one reported case of lisinopril-induced aplastic anaemia occurring in a 79-year-old woman who presented with profound pancytopenia after treatment of hypertension with lisinopril. In this patient, partial recovery of all counts occurred after several weeks and 25 days of G-CSF and methylprednisolone therapy. Review of the Committee on Safety of Medicines’ data of lisinopril (March, 1995) reveals one case of fatal aplastic anaemia and 22 other cases of or multilineage suppression (personal unilineage communication). Amongst the other ACE inhibitors, captopril alone has been implicated in aplastic anaemia, usually in association with renal impairment.4 Although our patient had received several other drugs in the perioperative period we postulate that her fatal bone marrow aplasia was the result of lisinopril therapy although there was, in addition, limited exposure to captopril. of
introduction implies that subcutaneous allow patients to be managed at home. This is heparin may an extraordinary argument. Unstable angina is an emergency and all patients should be admitted to hospital at once. Informed consent was given but ethical committee approval is not mentioned. Studies that involve withholding treatments of proven efficacy should specifically state that such approval has been granted. The
Hugh
E
paper’s
Montgomery, *Michael
R Chester
Hatter Institute for Cardiovascular Research, Department of Cardiology, University College Hospital, London WC1; and *Department of Cardiological Sciences, St George’s Hospital Medical School, London SW17 ORE, UK
Cohen M, Adams P, Parry G, et al. Combination antithrombotic therapy in unstable rest angina and non-Q-wave infarction in nonprior aspirin user. Circulation 1994; 89: 81-88. The RISC Group. Risk of myocardial infarction and death during treatment with low dose aspirin and intravenous heparin in men with
1
2
unstable coronary artery disease. Lancet 1990; 336: 827-30. Theroux P, Waters D, Qui S, McCans J, deGuise P, Juneau M. Aspirin versus heparin to prevent myocardial infarction during the acute phase of unstable angina. Circulation 1993; 88: 2045-48.
3
Clinicians should be aware of this rare side-effect and should withdraw ACE inhibitor therapy in the face of falling blood counts.
Beth D
Harrison, Stuart T Laidlaw, *John T Reilly
Department of Haematology, Northern General Hospital, Sheffield S5 7AU, UK 1 2 3
4
Who needs nine ACE inhibitors? Drug Ther Bull 1995; 33: 1. Drug Evaluation Monographs. Lisinopril. Micromedex Inc, 1995; vol 83. Schratzlseer G, Lipp T, Riess G, Antoni D, Delius W. Severe pancytopenia in old age after 12 month ACE inhibitor therapy. Dtsch Med Wochenschr 1994; 119: 1029-33. Kim CR, Maley MB, Mohler ER Jr. Captopril and aplastic anemia. Ann Intern Med 1989; 111: 187.
Heparin in unstable angina SIR-Neri Serneri et al (May 13, p 1201) set out to "assess the efficacy of subcutaneous heparin" in unstable angina, having accepted that, given intravenously, heparin is "highly effective". Yet all patients were denied heparin for 2 days, and one-third of them never received it. Before randomisation all patients were said to receive "conventional treatment". We believe that this includes a combination of heparin and aspirin, which the authors recognise to be more effective than either alone.’ None were given this therapy. It also seems that some patients received nifedipine without beta-blockade. The use of an agent with an indirect chronotropic effect in the treatment of unstable angina must be questioned when alternatives (such as diltiazem) exist. The efficacy of aspirin in unstable angina has been demonstrated in previous studies,2,3 but aspirin therapy was withdrawn from two-thirds of patients in the trial. No inference can be made about the efficacy of aspirin alone, because failure to respond to therapy which included aspirin was an entry criterion. The conclusion that aspirin is ineffective in controlling ischaemia is misleading. Moreover, an important mode of action of aspirin is through the inhibition of thromboxane-mediated platelet aggregation at the site of coronary plaque rupture. A single 350 mg dose of aspirin reduces platelet aggregation for up to 10 days, and all received aspirin before randomisation. The crucial comparison, therefore, is between intravenous and subcutaneous heparin. Although this study was not sufficiently powerful to make that comparison, nearly all the measures of efficacy were better in the intravenous than in the subcutaneous group. 248
SIR-In the paper by Neri Serneri and colleagues the first and last paragraphs of the summary suggest that the objective of this study was to compare the efficacy of subcutaneous and intravenous heparin in the control of myocardial ischaemia in patients with unstable angina. Why was the study complicated by aspirin? Of the 108 patients 66 had reported angina previously and 47 had sustained a myocardial infarction. However, the paper does not indicate which patients were already taking aspirin for secondary prophylaxis before admission to this trial? Every patient in the trial was given aspirin for 2 days immediately before the 3 day trial therapy period so the statement "our results suggest that by itself aspirin could not affect myocardial ischaemia in unstable angina" is not supported by the data presented. Since all the patients were exposed to aspirin for 2 days and the aspirin group continued on the drug for 3 days, there is no control group or period with which to compare the aspirin-treated group. Was there a hypothesis to be tested by the inclusion of the aspirin arm? Reducing ischaemia is one aim of treatment in unstable angina but prevention of infarction is another. Indeed Theroux et al have demonstrated that aspirin alone can reduce the incidence of infarction in patients with unstable angina.’ A later study by the same group2 is twice misquoted by Neri Serneri et al. As that paper’s title indicates, myocardial infarction, not "control of myocardial ischaemia", was the endpoint; and there was no "rebound of clinical symptoms after heparin discontinuation" in the study cited. The frequency of main-stem stenosis was high. This might be explained by the fact that the trial was in a selected group of patients who had continued to experience angina after the 24 h run-in period. There were 46 patients with main-stem stenosis but only 28 were treated by coronary artery bypass grafting within the next month. What treatment did Neri Serneri and colleagues feel more appropriate for the other 18 patients with refractory unstable angina and main-stem stenosis? *David P Jenkins, Mark
Sumeray
Holmes Sellors Cardiothoracic Unit, Middlesex
1
2
Hospital, London W1N 8AA, UK
Theroux P, Ouimet H, McCans J, et al. Aspirin, heparin, or both to to treat acute unstable angina. N Engl J Med 1988; 319: 1105-11. Theroux P, Waters D, Qui S, McCans J, de Guise P, Juneau M. Aspirin versus heparin to prevent myocardial infarction during the acute phase of unstable angina. Circulation 1993; 88: 2045-48.