- Email: [email protected]
Pregnancy screening for cystic fibrosis
Malignant arrhythmias: tribulations post ESVEM lately emphasised in The Lancet, the patient with ventricular tachycardia or fibrillation who is fortunate enough to survive may be difficult to manage subsequently,1.2 Frequently, a remediable cause cannot be found, so one has to assume that the risk of life-threatening recurrences persists and that long-term antiarrhythmic treatment is required. Implantable defibrillators, catheter ablation, and electrophysiological surgery are increasingly available but can be used in only a proportion of cases. Consequently, there is a continuing need for antiarrhythmic drugs. Individualised therapy, based on serial drug testing in hospital, is widely held to be better than empirical prescription. Both ambulatory monitoring and programmed ventricular stimulation can be used to guide serial drug testing, since the degree of spontaneous ventricular ectopic activity and the inducibility of ventricular tachycardia both reflect the risk of recurrent arrhythmia .3,4 Moreover, suppressibility of either of these risk markers by an antiarrhythmic agent suggests a lower As
risk of recurrence in that individual than in others. Both invasive and non-invasive methods are widely used for drug evaluation, but there is considerable debate as to which approach yields a better prediction of long-term efficacy. The results of the Electrophysiologic Study versus Electrocardiographic Monitoring (ESVEM) trial, which aimed to resolve this controversy, have now been reponed.5.6 486 patients, mainly men with underlying ischaemic heart disease and a diagnosis of sustained ventricular tachycardia rather than cardiac arrest, were randomised to one of two methods of selecting antiarrhythmic therapy. Treatment was determined by serial testing of up to six drugs, either by ambulatory monitoring with exercise testing or by programmed ventricular stimulation. The non-invasive approach predicted drug efficacy in a greater proportion of patients than did electrophysiological testing, but the risk of recurrent arrhythmia did not differ between the two groups. Patients who received sotalol were at lower risk of recurrence than those receiving other drugs. However, as pointed out in an accompanying editorial, there are several reasons to interpret these findings with caution.’ First, the criteria used to predict drug efficacy in each arm of the trial8 may have substantially affected the sensitivity and specificity of that arm. More important, the randomised participants constituted a small (23 *B,) proportion of the 2103 patients enrolled with sustained ventricular arrhythmias, and the report does not state exactly how the latter were recruited from the much larger referral population of the participating centres. One important reason for the low rate of randomisation was that all patients had to have both frequent ventricular ectopy on ambulatory monitoring and inducible ventricular tachycardia on electrophysiological testing. From this highly selective sample it would be dangerous to conclude that ambulatory monitoring alone suffices in the evaluation of to abandon drug therapy. Furthermore, electrophysiological testing altogether might lead to failure to identify those patients who can be cured by ablative techniques. The design of ESVEM precluded the inclusion of amiodarone, because of its exceptionally slow pharmacokinetic properties-it is because of these and the fear of long-term side-effects that this important drug is
generally reserved for patients in whom serial drug testing fails to predict an effective drug, or is impossible. Finallyand this has been a universal shortcoming in antiarrhythmic trials-a single efficacy evaluation at the outset may not be appropriate in a group of patients with evolving cardiac disease.
Overall, the superiority of serial drug testing
over
empirical strategies, and even the role of antiarrhythmic drugs in general for these malignant arrhythmias, remain to be established. Fortunately, implantable defibrillators are providing a growing cohort of patients in whom ethical placebo-controlled trials of drug therapy can be now conducted. Meanwhile, the prudent course is to view electrocardiography, ambulatory monitoring, exercise and electrophysiological testing as complementary rather than alternative means of evaluating antiarrhythmic therapy. Evaluation and regular review along these lines should ensure that therapeutic decision-making is guided by a full clinical characterisation of each patient. Francis
Murgatroyd
Department of Cardiological Sciences, St George’s Hospital Medical School, London, UK 1
2 3
4
5
6
7
8
Shenasa M, Borggrefe M, Haverkamp W, Hindricks G, Breithardt G. Ventricular tachycardia. Lancet 1993; 341: 1512-19. O’Nunain S, Ruskin JN. Cardiac arrest. Lancet 1993; 341: 1641-47. Swerdlow CD, Winkle RA, Mason JW. Determinants of survival in patients with ventricular tachyarrhythmias. N Engl J Med 1983; 308: 1436-42. Graboys TB, Lown B, Podrid PJ, DeSilva R. Long-term survival of patients with malignant ventricular arrhythmia treated with antiarrhythmic drugs. Am J Cardiol 1982; 50: 437-43. Mason JW, ESVEM Investigators. A comparison of electrophysiologic testing with Holter monitoring to predict antiarrhythmic-drug efficacy for ventricular arrhythmias. N Engl J Med 1993; 329: 445-51. Mason JW, ESVEM Investigators. A comparison of seven antiarrhythmic drugs in patients with ventricular tachyarrhythmias. N Engl J Med 1993; 329: 452-58. Ward DE, Camm AJ. Dangerous ventricular arrhythmias—can we predict drug efficacy? N Engl J Med 1993; 329: 498-99. ESVEM Investigators. The ESVEM trial. Electrophysiologic study versus electrocardiographic monitoring for selection of antiarrhythmic therapy of ventricular tachyarrhythmias. Circulation 1989; 79: 1354-60.
Pregnancy screening for cystic fibrosis See page 624
Several pilot studies are presently exploring approaches and attitudes to cystic fibrosis carrier detection in the general population. Results so far suggest that a written invitation generates a poor response rate of between 9 and 12%. By contrast, personal "opportunistic" contact during early pregnancy, whether mediated through the antenatal clinic or general practice, is well received, with uptake rates exceeding 80%.* Brambati and colleagues have now evaluated a new option for antenatal testing, and in this issue they report the outcome of offering AF508 screening on chorionic villi obtained from pregnancies that were being monitored primarily for chromosome abnormalities. The response among the first group of almost 800 women invited to participate seems to have been enthusiastic. Proponents of this approach may reasonably argue that, since an invasive and potentially hazardous investigation is being undertaken, it is important to obtain maximum information from the biopsy sample. Parental choice is thereby enhanced and identification of an affected (homozygous) fetus with subsequent termination of 569
pregnancy could prevent a life-time of suffering. Others, whilst respecting this view, may be concerned by the practicalities. Even in communities with a relatively high proportion of AF508 cystic fibrosis mutations, a significant proportion of affected fetuses will not be detected. Nor can the parents of a AF508 heterozygous fetus be reassured that their baby will be unaffected. The request by 2 of 12 such mothers for termination of pregnancy is worrying and emphasises the importance of skilled supportive
counselling. Pregnancy screening
for cystic fibrosis highlights many of the issues and anxieties already associated with population screening and raises several more.5 Are we justified in screening for a disease that is high on the list of candidates for gene therapy? The uneasy alliance of applied molecular biology and seemingly diminishing health care resources might well be better directed at the identification of adults who are at high risk of developing cancer or coronary artery disease. Who is giving informed consent for the fetal carrier testing that is an inevitable byproduct of pregnancy screening? How and when will the offspring be informed of their carrier status and what effects will this have? If we are not yet sure how best to offer these tests to adults, whether we should be extending them to the fetus or to the newborn infant through Guthrie testing is
questionable. This study
of Brambati et al indicates that prospective much reassurance as possible about the parents future health of their unborn child, and it is difficult to argue convincingly that this should be denied. Nevertheless, the introduction of fetal AF508 testing clearly has important logistic, counselling, financial, and ethical want as
implications. ID Young Department of Clinical Genetics, City Hospital, Nottingham, UK 1 2
Bekker H, Modell M, Denniss G, et al. Uptake of cystic fibrosis testing in primary care: supply push or demand pull? BMJ 1993; 306: 1584-86. Watson EK, Mayall E, Chapple J, et al. Screening for carriers of cystic fibrosis through the primary health care services. BMJ 1991; 303: 504-07.
3 4 5
Mennie ME, Gilfillan A, Compton M, et al. Prenatal screening for cystic fibrosis. Lancet 1992; 340: 214-16. Harris H, Scotcher D, Hartley N, et al. Cystic fibrosis carrier testing in early pregnancy by general practitioners. BMJ 1993; 306: 1580-83. Editorial. Screening for cystic fibrosis. Lancet 1992; 340: 209-10.
Losing heart? Many risk factors for coronary heart disease are well established: some are genetic, some are probably associated with intrauterine experiences, and many, such as smoking and lack of exercise, are associated with lifestyle. However, despite this wealth of knowledge, epidemiologists are still unable to explain a substantial proportion of the sociodemographic variation in ischaemic heart disease rates. Other risk factors obviously exist, and await definition. In this context, there is increasing interest in the role of mental health. Whilst several studies have shown an association between aspects of psychiatric morbidity or use
570
of psychotropic drugs and an increased risk of ischaemic heart disease, very few, and none of any substantial size, have considered the specific role of depression in the occurrence of ischaemic heart disease. Depression and ischaemic heart disease are common diagnoses, so any causal relation between them is important. Anda and his colleagues1 from the Centers for Disease Control and Prevention in Atlanta used data collected in the US National Health Examination Followup Study to examine this potential relationship. 2832 subjects aged 45-77 years without pre-existing chronic disease (including angina as defined by the Rose questionnaire) completed the general wellbeing schedule, which includes four questions that provide a validated measure of depressed affect. One of the four questions relates specifically to feelings of hopelessness ("During the last month ... have you felt so sad, discouraged, hopeless or had so many problems that you wondered if anything was worthwhile?"), and the researchers paid particular attention to the responses to this question, because of the possibility that hopelessness may be a determinant of health outcome. Subjects were followed up for a mean of 12 4 years (range 16 days to 16.4 years), during which time information on deaths was collected from the National Death Index and all hospital admissions recalled by the subjects at a follow-up interview were investigated. 11% of the cohort were classified as having depressed affect; moderate and severe feelings of hopelessness were reported by 1100 and 3%, respectively. During the followup period there were 189 ischaemic heart disease deaths and 205 people were admitted to hospital for non-fatal disease. The researchers calculated the relative risk of fatal and non-fatal disease associated with depressed affect and feeling of hopelessness after adjusting for the effect of several established risk factors (age, sex, race, education, marital status, smoking, blood cholesterol concentration, systolic blood pressure, body mass index, alcohol use, and physical activity). There was a significantly increased relative risk of both fatal and non-fatal disease associated with depression. The risk of a fatal event was increased by 50% (relative risk 1-5, 95% CI 1-0-2-3) and the risk of a non-fatal event was increased by 60% (relative risk 1-6, 9500 CI 1-1-2-4) in subjects classified as depressed. Subjects who had reported a severe feeling of hopelessness experienced a greater increase in risk: their risk of fatal ischaemic heart disease was increased by 110% by comparison with those subjects reporting little or no feeling of hopelessness (adjusted relative risk 2 1, 95 % CI 1’1-3,9). Similarly, the relative risk of non-fatal disease in those with severe hopelessness was 19 (95% CI 10-36). These new data add to a growing body of evidence on the importance of psychological ill health in the development of ischaemic heart disease. There is plenty of scope here for research into underlying mechanisms and into new
preventive strategies. Margaret Thorogood Health Promotion Sciences Unit, London School of
1
Hygiene & Tropical Medicine, UK
Anda R, Williamson D, Jones D, et al. Depressed affect, hopelessness and the risk of ischemic heart disease in a cohort of US adults. Epidemiology 1993; 4: 285-94.
risk of recurrence in that individual than in others. Both invasive and non-invasive methods are widely used for drug evaluation, but there is considerable debate as to which approach yields a better prediction of long-term efficacy. The results of the Electrophysiologic Study versus Electrocardiographic Monitoring (ESVEM) trial, which aimed to resolve this controversy, have now been reponed.5.6 486 patients, mainly men with underlying ischaemic heart disease and a diagnosis of sustained ventricular tachycardia rather than cardiac arrest, were randomised to one of two methods of selecting antiarrhythmic therapy. Treatment was determined by serial testing of up to six drugs, either by ambulatory monitoring with exercise testing or by programmed ventricular stimulation. The non-invasive approach predicted drug efficacy in a greater proportion of patients than did electrophysiological testing, but the risk of recurrent arrhythmia did not differ between the two groups. Patients who received sotalol were at lower risk of recurrence than those receiving other drugs. However, as pointed out in an accompanying editorial, there are several reasons to interpret these findings with caution.’ First, the criteria used to predict drug efficacy in each arm of the trial8 may have substantially affected the sensitivity and specificity of that arm. More important, the randomised participants constituted a small (23 *B,) proportion of the 2103 patients enrolled with sustained ventricular arrhythmias, and the report does not state exactly how the latter were recruited from the much larger referral population of the participating centres. One important reason for the low rate of randomisation was that all patients had to have both frequent ventricular ectopy on ambulatory monitoring and inducible ventricular tachycardia on electrophysiological testing. From this highly selective sample it would be dangerous to conclude that ambulatory monitoring alone suffices in the evaluation of to abandon drug therapy. Furthermore, electrophysiological testing altogether might lead to failure to identify those patients who can be cured by ablative techniques. The design of ESVEM precluded the inclusion of amiodarone, because of its exceptionally slow pharmacokinetic properties-it is because of these and the fear of long-term side-effects that this important drug is
generally reserved for patients in whom serial drug testing fails to predict an effective drug, or is impossible. Finallyand this has been a universal shortcoming in antiarrhythmic trials-a single efficacy evaluation at the outset may not be appropriate in a group of patients with evolving cardiac disease.
Overall, the superiority of serial drug testing
over
empirical strategies, and even the role of antiarrhythmic drugs in general for these malignant arrhythmias, remain to be established. Fortunately, implantable defibrillators are providing a growing cohort of patients in whom ethical placebo-controlled trials of drug therapy can be now conducted. Meanwhile, the prudent course is to view electrocardiography, ambulatory monitoring, exercise and electrophysiological testing as complementary rather than alternative means of evaluating antiarrhythmic therapy. Evaluation and regular review along these lines should ensure that therapeutic decision-making is guided by a full clinical characterisation of each patient. Francis
Murgatroyd
Department of Cardiological Sciences, St George’s Hospital Medical School, London, UK 1
2 3
4
5
6
7
8
Shenasa M, Borggrefe M, Haverkamp W, Hindricks G, Breithardt G. Ventricular tachycardia. Lancet 1993; 341: 1512-19. O’Nunain S, Ruskin JN. Cardiac arrest. Lancet 1993; 341: 1641-47. Swerdlow CD, Winkle RA, Mason JW. Determinants of survival in patients with ventricular tachyarrhythmias. N Engl J Med 1983; 308: 1436-42. Graboys TB, Lown B, Podrid PJ, DeSilva R. Long-term survival of patients with malignant ventricular arrhythmia treated with antiarrhythmic drugs. Am J Cardiol 1982; 50: 437-43. Mason JW, ESVEM Investigators. A comparison of electrophysiologic testing with Holter monitoring to predict antiarrhythmic-drug efficacy for ventricular arrhythmias. N Engl J Med 1993; 329: 445-51. Mason JW, ESVEM Investigators. A comparison of seven antiarrhythmic drugs in patients with ventricular tachyarrhythmias. N Engl J Med 1993; 329: 452-58. Ward DE, Camm AJ. Dangerous ventricular arrhythmias—can we predict drug efficacy? N Engl J Med 1993; 329: 498-99. ESVEM Investigators. The ESVEM trial. Electrophysiologic study versus electrocardiographic monitoring for selection of antiarrhythmic therapy of ventricular tachyarrhythmias. Circulation 1989; 79: 1354-60.
Pregnancy screening for cystic fibrosis See page 624
Several pilot studies are presently exploring approaches and attitudes to cystic fibrosis carrier detection in the general population. Results so far suggest that a written invitation generates a poor response rate of between 9 and 12%. By contrast, personal "opportunistic" contact during early pregnancy, whether mediated through the antenatal clinic or general practice, is well received, with uptake rates exceeding 80%.* Brambati and colleagues have now evaluated a new option for antenatal testing, and in this issue they report the outcome of offering AF508 screening on chorionic villi obtained from pregnancies that were being monitored primarily for chromosome abnormalities. The response among the first group of almost 800 women invited to participate seems to have been enthusiastic. Proponents of this approach may reasonably argue that, since an invasive and potentially hazardous investigation is being undertaken, it is important to obtain maximum information from the biopsy sample. Parental choice is thereby enhanced and identification of an affected (homozygous) fetus with subsequent termination of 569
pregnancy could prevent a life-time of suffering. Others, whilst respecting this view, may be concerned by the practicalities. Even in communities with a relatively high proportion of AF508 cystic fibrosis mutations, a significant proportion of affected fetuses will not be detected. Nor can the parents of a AF508 heterozygous fetus be reassured that their baby will be unaffected. The request by 2 of 12 such mothers for termination of pregnancy is worrying and emphasises the importance of skilled supportive
counselling. Pregnancy screening
for cystic fibrosis highlights many of the issues and anxieties already associated with population screening and raises several more.5 Are we justified in screening for a disease that is high on the list of candidates for gene therapy? The uneasy alliance of applied molecular biology and seemingly diminishing health care resources might well be better directed at the identification of adults who are at high risk of developing cancer or coronary artery disease. Who is giving informed consent for the fetal carrier testing that is an inevitable byproduct of pregnancy screening? How and when will the offspring be informed of their carrier status and what effects will this have? If we are not yet sure how best to offer these tests to adults, whether we should be extending them to the fetus or to the newborn infant through Guthrie testing is
questionable. This study
of Brambati et al indicates that prospective much reassurance as possible about the parents future health of their unborn child, and it is difficult to argue convincingly that this should be denied. Nevertheless, the introduction of fetal AF508 testing clearly has important logistic, counselling, financial, and ethical want as
implications. ID Young Department of Clinical Genetics, City Hospital, Nottingham, UK 1 2
Bekker H, Modell M, Denniss G, et al. Uptake of cystic fibrosis testing in primary care: supply push or demand pull? BMJ 1993; 306: 1584-86. Watson EK, Mayall E, Chapple J, et al. Screening for carriers of cystic fibrosis through the primary health care services. BMJ 1991; 303: 504-07.
3 4 5
Mennie ME, Gilfillan A, Compton M, et al. Prenatal screening for cystic fibrosis. Lancet 1992; 340: 214-16. Harris H, Scotcher D, Hartley N, et al. Cystic fibrosis carrier testing in early pregnancy by general practitioners. BMJ 1993; 306: 1580-83. Editorial. Screening for cystic fibrosis. Lancet 1992; 340: 209-10.
Losing heart? Many risk factors for coronary heart disease are well established: some are genetic, some are probably associated with intrauterine experiences, and many, such as smoking and lack of exercise, are associated with lifestyle. However, despite this wealth of knowledge, epidemiologists are still unable to explain a substantial proportion of the sociodemographic variation in ischaemic heart disease rates. Other risk factors obviously exist, and await definition. In this context, there is increasing interest in the role of mental health. Whilst several studies have shown an association between aspects of psychiatric morbidity or use
570
of psychotropic drugs and an increased risk of ischaemic heart disease, very few, and none of any substantial size, have considered the specific role of depression in the occurrence of ischaemic heart disease. Depression and ischaemic heart disease are common diagnoses, so any causal relation between them is important. Anda and his colleagues1 from the Centers for Disease Control and Prevention in Atlanta used data collected in the US National Health Examination Followup Study to examine this potential relationship. 2832 subjects aged 45-77 years without pre-existing chronic disease (including angina as defined by the Rose questionnaire) completed the general wellbeing schedule, which includes four questions that provide a validated measure of depressed affect. One of the four questions relates specifically to feelings of hopelessness ("During the last month ... have you felt so sad, discouraged, hopeless or had so many problems that you wondered if anything was worthwhile?"), and the researchers paid particular attention to the responses to this question, because of the possibility that hopelessness may be a determinant of health outcome. Subjects were followed up for a mean of 12 4 years (range 16 days to 16.4 years), during which time information on deaths was collected from the National Death Index and all hospital admissions recalled by the subjects at a follow-up interview were investigated. 11% of the cohort were classified as having depressed affect; moderate and severe feelings of hopelessness were reported by 1100 and 3%, respectively. During the followup period there were 189 ischaemic heart disease deaths and 205 people were admitted to hospital for non-fatal disease. The researchers calculated the relative risk of fatal and non-fatal disease associated with depressed affect and feeling of hopelessness after adjusting for the effect of several established risk factors (age, sex, race, education, marital status, smoking, blood cholesterol concentration, systolic blood pressure, body mass index, alcohol use, and physical activity). There was a significantly increased relative risk of both fatal and non-fatal disease associated with depression. The risk of a fatal event was increased by 50% (relative risk 1-5, 95% CI 1-0-2-3) and the risk of a non-fatal event was increased by 60% (relative risk 1-6, 9500 CI 1-1-2-4) in subjects classified as depressed. Subjects who had reported a severe feeling of hopelessness experienced a greater increase in risk: their risk of fatal ischaemic heart disease was increased by 110% by comparison with those subjects reporting little or no feeling of hopelessness (adjusted relative risk 2 1, 95 % CI 1’1-3,9). Similarly, the relative risk of non-fatal disease in those with severe hopelessness was 19 (95% CI 10-36). These new data add to a growing body of evidence on the importance of psychological ill health in the development of ischaemic heart disease. There is plenty of scope here for research into underlying mechanisms and into new
preventive strategies. Margaret Thorogood Health Promotion Sciences Unit, London School of
1
Hygiene & Tropical Medicine, UK
Anda R, Williamson D, Jones D, et al. Depressed affect, hopelessness and the risk of ischemic heart disease in a cohort of US adults. Epidemiology 1993; 4: 285-94.