IS A CONTROLLED TRIAL OF LONG TERM ORAL (1)
788
the two groups as noted above for the whole series. A
difference in exclusion criteria would potentially have had a
profound effect on the relative remission rates of the two
groups.
DISCUSSION
We believe this patient series to be representative of the full
clinical spectrum of AML, and have shown that if all patients
are taken into account, the clinical course may be less
successful than previously thought. 2-4
A large number of patients (43/272) were not given
chemotherapy. In most cases, this was because the attending
physician judged the patient to be unlikely to withstand
chemotherapy. These patients are never included in
treatment series and yet a discussion of treatment results and
prognosis with new patients should include this information.
31 patients were started on chemotherapy but did not
complete a single course of treatment, usually because of
infectious complications leading to early death. Treatment
series will often exclude such patients as "inevaluable", but
they are better regarded as treatment failures.
Many treatment series report an average patient age of 45 to
50 years,’ 2-14 whereas the mean age of all AML patients and
the mean age in our series, is 60.15 Protocols may exclude
patients over 50, 60, or 70 years,12,16,17 or these patients may
not be referred to treatment centres. Patients with preceding
myelodysplastic syndromes, and patients in whom AML
develops secondary to cytotoxic chemotherapy have been
shown to respond poorly to chemotherapy for leukaemia.6
Patients with poor prognostic variables have been segregated
in separate series.7,8,18 It is likely, therefore, that these
patients’ are also generally excluded from recent
chemotherapy series. If we exclude patients aged 70 and over,
patients with preceding myelodysplastic syndromes, and
patients with previous chemotherapy, analysis shows a high
complete remission rate (85-307o) as reported in other
series.2-4
Reports of recent improvements in chemotherapy for
AML may reflect inadvertent exclusions and refinements in
leukaemia classification rather than true improvement in
treatment results.190ur new treatment regimen led to an
improvement in complete remission rate but no significant
difference in overall median survival, when all patients are
taken into account. If only the second series were subject to
the exclusions we have discussed, the apparent improvement
could have been considerable. The remission rate for all
patients in the first series (35%) might then be compared with
the remission rate for patients with various exclusions in the
second series (60 - 90%).
Results of treatment trials in AML that show an overall
improvement in results should include an analysis of patients
who are untreated or partially treated, and the proportion of
patients with adverse prognostic indicators.
This work was supported by the National Cancer Institute of Canada and
Grant CA31761-04A2 from the National Cancer Institute, USA, and the
William J. Matheson Foundation.
Correspondence should be addressed to Dr Michael A. Baker, Oncology
Clinic, Toronto General Hospital, 657 University Avenue, Toronto, Ontario
M5G 1L7, Canada.
REFERENCES
1. Bloomfield CD. Treatment of adult
Med
2.
acute
nonlymphocytic leukemia-1980
Ann Int
1980; 93: 133-34.
Rees JKH, Sandler RM, Challener J, Hayhoe FGJ. Treatment of acute myeloid
leukaemia with a triple cytotoxic regimen: DAT. Br J Cancer 1977; 36: 770-76.
Trial
Design
IS A CONTROLLED TRIAL OF LONG-TERM
ORAL ANTICOAGULANTS IN PATIENTS WITH
STROKE AND NON-RHEUMATIC ATRIAL
FIBRILLATION WORTHWHILE?
CHARLES WARLOW
PETER SANDERCOCK
RICHARD PETO
BAMFORD
JOHN
IAN STARKEY
Walton Hospital, Liverpool; Radcliffe Infirmary, Oxford; and
Northern General Hospital, Sheffield
A controlled randomised trial large enough
to assess the value of anticoagulating stroke
patients in atrial fibrillation would be difficult to conduct in
the UK and the results would be applicable to only a small
proportion of stroke patients. It would be more worthwhile to
organise a trial that also assessed the value of other treatments
that are simpler and applicable to all stroke patients. A trial
that assessed the value of aspirin and beta-blockers against
control in all stroke patients would not cost much more than
one restricted to comparing anticoagulants against control in
patients with stroke and atrial fibrillation but would provide
information of more relevance to the management of patients
with stroke in the UK.
Summary
INTRODUCTION
MANY stroke patients in atrial fibrillation (AF) are given
anticoagulants, but there is little direct evidence on whether
this is wise. It would seem that a large randomised trial of
RP, Cline MJ, for the UCLA Acute Leukemia Study Group. High remissioninduction rate in acute myeloid leukaemia Lancet 1977; i: 497-99.
4. Gale RP. Progress in acute myelogenous leukaemia. Ann Int Med 1984; 101: 702-03
5. Cassileth PA, Begg CB, Bennett JM, et al. A randomized study of the efficacy of
consolidation therapy in adult acute nonlymphocytic leukemia. Blood 1984, 63:
843-47.
6. Estey EH, Keating MJ, McCredie KB, Bodey GP, Freireich EJ. Causes of initial
remission induction failure in acute myelogenous leukemia. Blood 1982; 60: 309
7. Preisler HD, Early AP, Raza A, et al. Therapy of secondary acute nonlymphocytic
leukemia with cytarabine. N Engl J Med 1983; 308: 21.
8. Capizzi RL, Poole M, Cooper MR, et al. Treatment of poor risk acute leukemia with
sequential high dose ARA-C and asparaginase. Blood 1984; 63: 694-700.
9. Harousseau JL, Castaigne S, Milpied N, Marty M, Degos L Treatment of acute nonlymphoblastic leukaemia in elderly patients. Lancet 1984; ii: 288
10. Yates J, Wallace J, Ellison RR, Holland JF Cytosine arabinoside (NSC-63878) and
daunorubicin (NSC-83142) therapy in acute nonlymphocytic leukemia. Cancer
Chem Rep 1973; 57: 485-88.
11. Baker MA, Taub RN, Carter WH, and the Toronto Leukemia Study Group
Immunotherapy for remission maintenance in acute myeloblastic leukemia Cancer
Immunol Immunother 1982; 13: 85-88
12. Sauter C, Fopp M, Imbach P, et al Acute myelogenous leukaemia: maintenance
chemotherapy after early consolidation treatment does not prolong survival Lancet
1984; i: 379-82.
13. Buchner T, Urbanitz D, Fischer J, et al. Long-term remission in acute myelogenous
leukaemia Lancet 1984; i: 571.
14. Champlin R, Gale RP, Elashoff R, et al. Prolonged survival in acute myelogenous
leukaemia without maintenance chemotherapy. Lancet 1984, i: 894-96
15 Wintrobe MM, Lee GR, Boggs DR, et al, eds. Classification, pathogenesis and etiology
of neoplastic disease of the hematopoietic system. In Clinical hematology
Philadelphia Lea and Febiger, 1981: 1455-58.
16. Weinstein HJ, Mayer RJ, Rosenthal DS, Camitta BM, Coral FS, Nathan DG, Frei E
Treatment of acute myelogenous leukemia in children and adults N Engl J Med
1980, 303: 473-78.
17. Cassileth PA, Begg CB, Bennett JM, et al A randomized study of the efficacy of
consolidation therapy in adult acute nonlymphocytic leukemia. Blood 1984; 63:
843-47.
18. Keating MJ, McCredie KB, Benjamin RS, et al. Treatment of patients over 50 years of
age with acute myelogenous leukemia with a combination of rubidazone and
cytosine arabinoside, vincristine and prednisone (ROAP) Blood 1981, 58: 584
19. Feinstein AR, Sosin DM, Wells CK. The Will Rogers phenomenon. Stage migration
and new diagnostic techniques as a source of misleading statistics for survival in
cancer. N EnglJ Med 1985; 312: 1604-08
20 The Toronto Leukemia Study Group. Survival in acute myeloblastic leukemia is not
prolonged by remission maintenance or early reinduction chemotherapy Blood
1985; 66 (suppl): 210a.
3. Gale
789
TABLE I-POSSIBLE RANDOMISED TRIAL DESIGN TO INCLUDE ALL
STROKE PATIENTS
(AF AND
SINUS
Project (OCSP),’ in which 512 consecutive cases of first-ever
were investigated .
RHYTHM)
stroke
WHAT IS A TYPICAL STROKE PATIENT IN AF LIKE?
The sort of stroke patient in whom the question of
anticoagulation typically arises might be an elderly woman
with a mild right hemiparesis, hypertension, a left carotid
bruit, and atrial fibrillation but
BB=betablocker. AC= oral anticoagulant.
To assess various anti-haemostatic therapies: X
To assess beta-blockade: 1 versus 2.
versus
Y
versus
Z.
versus control ought to be conducted.
there
are reasons why a very different trial might be
However,
better. The alternative trial would include not just those in
AF but all stroke patients; it would be a comparison of
anticoagulants versus control versus aspirin; and finally half
of each of the three groups would be given beta-blockers, to
discover whether these agents were of any additional value
(table I). The design of this trial was based on the following
general considerations; that the type and number of stroke
patients in AF likely to enter the first type of study may be
limited; that the outcome for patients with AF is not much
different from that for those in sinus rhythm and that most
stroke patients die not of stroke but of heart disease, so
treatments that might reduce heart disease need to be studied;
that anticoagulants may reduce the incidence of heart disease
and occlusive stroke but increase the incidence of
haemorrhagic stroke; that aspirin and beta-blockers may be as
effective as anticoagulants but are easier to give and less toxic;
and finally that there are many more stroke patients in sinus
rhythm than in AF, which makes the former much easier to
study and of much greater public health importance. We
conclude by asking whether a simpler trial (paradoxically,
without the two anticoagulant subgroups) might be even
better in a country, such as Great Britain, where computer
tomography (CT) is often not readily available for the
detection of haemorrhagic stroke (in which anticoagulants are
contraindicated). The evidence reviewed derives from many
sources, including the Oxfordshire Community Stroke
anticoagulant
no evidence of rheumatic
valvular disease. The decision to anticoagulate should ideally
be based on: whether the stroke was due to cerebral infarction
or primary intracerebral haemorrhage (this requires a CT
scan of the brain); if the stroke was due to infarction whether
it was a result of hypertensive small vessel disease within the
brain, embolism from an atheromatous plaque in the internal
carotid artery, or embolism from the fibrillating left atrium;
and whether it is wise to subject an elderly hypertensive
patient to the risks and inconvenience of anticoagulation.
WHAT IS THE EFFECT OF AF ON RISK OF DEATH AND
RECURRENT STROKE IN STROKE PATIENTS?
Although AF not associated with rheumatic heart disease
(NRAF) may increase the risk of death in the first 30 days
after a stroke, it has a less marked effect on mortality
Fig 1-Probability of survival (Kaplan-Meier survival curve) among
346 patients who survived at least 30 days after a first cerebral
infarction.
Data from the Oxfordshire
Community Stroke Project.
TABLE II-RISK OF DEATH OR RECURRENT STROKE IN PATIENTS WITH STROKE AND ATRIAL FIBRILLATION
RHD = cases ofAF associated with RHD; NRHD = cases ofAF
*P
the two groups as noted above for the whole series. A
difference in exclusion criteria would potentially have had a
profound effect on the relative remission rates of the two
groups.
DISCUSSION
We believe this patient series to be representative of the full
clinical spectrum of AML, and have shown that if all patients
are taken into account, the clinical course may be less
successful than previously thought. 2-4
A large number of patients (43/272) were not given
chemotherapy. In most cases, this was because the attending
physician judged the patient to be unlikely to withstand
chemotherapy. These patients are never included in
treatment series and yet a discussion of treatment results and
prognosis with new patients should include this information.
31 patients were started on chemotherapy but did not
complete a single course of treatment, usually because of
infectious complications leading to early death. Treatment
series will often exclude such patients as "inevaluable", but
they are better regarded as treatment failures.
Many treatment series report an average patient age of 45 to
50 years,’ 2-14 whereas the mean age of all AML patients and
the mean age in our series, is 60.15 Protocols may exclude
patients over 50, 60, or 70 years,12,16,17 or these patients may
not be referred to treatment centres. Patients with preceding
myelodysplastic syndromes, and patients in whom AML
develops secondary to cytotoxic chemotherapy have been
shown to respond poorly to chemotherapy for leukaemia.6
Patients with poor prognostic variables have been segregated
in separate series.7,8,18 It is likely, therefore, that these
patients’ are also generally excluded from recent
chemotherapy series. If we exclude patients aged 70 and over,
patients with preceding myelodysplastic syndromes, and
patients with previous chemotherapy, analysis shows a high
complete remission rate (85-307o) as reported in other
series.2-4
Reports of recent improvements in chemotherapy for
AML may reflect inadvertent exclusions and refinements in
leukaemia classification rather than true improvement in
treatment results.190ur new treatment regimen led to an
improvement in complete remission rate but no significant
difference in overall median survival, when all patients are
taken into account. If only the second series were subject to
the exclusions we have discussed, the apparent improvement
could have been considerable. The remission rate for all
patients in the first series (35%) might then be compared with
the remission rate for patients with various exclusions in the
second series (60 - 90%).
Results of treatment trials in AML that show an overall
improvement in results should include an analysis of patients
who are untreated or partially treated, and the proportion of
patients with adverse prognostic indicators.
This work was supported by the National Cancer Institute of Canada and
Grant CA31761-04A2 from the National Cancer Institute, USA, and the
William J. Matheson Foundation.
Correspondence should be addressed to Dr Michael A. Baker, Oncology
Clinic, Toronto General Hospital, 657 University Avenue, Toronto, Ontario
M5G 1L7, Canada.
REFERENCES
1. Bloomfield CD. Treatment of adult
Med
2.
acute
nonlymphocytic leukemia-1980
Ann Int
1980; 93: 133-34.
Rees JKH, Sandler RM, Challener J, Hayhoe FGJ. Treatment of acute myeloid
leukaemia with a triple cytotoxic regimen: DAT. Br J Cancer 1977; 36: 770-76.
Trial
Design
IS A CONTROLLED TRIAL OF LONG-TERM
ORAL ANTICOAGULANTS IN PATIENTS WITH
STROKE AND NON-RHEUMATIC ATRIAL
FIBRILLATION WORTHWHILE?
CHARLES WARLOW
PETER SANDERCOCK
RICHARD PETO
BAMFORD
JOHN
IAN STARKEY
Walton Hospital, Liverpool; Radcliffe Infirmary, Oxford; and
Northern General Hospital, Sheffield
A controlled randomised trial large enough
to assess the value of anticoagulating stroke
patients in atrial fibrillation would be difficult to conduct in
the UK and the results would be applicable to only a small
proportion of stroke patients. It would be more worthwhile to
organise a trial that also assessed the value of other treatments
that are simpler and applicable to all stroke patients. A trial
that assessed the value of aspirin and beta-blockers against
control in all stroke patients would not cost much more than
one restricted to comparing anticoagulants against control in
patients with stroke and atrial fibrillation but would provide
information of more relevance to the management of patients
with stroke in the UK.
Summary
INTRODUCTION
MANY stroke patients in atrial fibrillation (AF) are given
anticoagulants, but there is little direct evidence on whether
this is wise. It would seem that a large randomised trial of
RP, Cline MJ, for the UCLA Acute Leukemia Study Group. High remissioninduction rate in acute myeloid leukaemia Lancet 1977; i: 497-99.
4. Gale RP. Progress in acute myelogenous leukaemia. Ann Int Med 1984; 101: 702-03
5. Cassileth PA, Begg CB, Bennett JM, et al. A randomized study of the efficacy of
consolidation therapy in adult acute nonlymphocytic leukemia. Blood 1984, 63:
843-47.
6. Estey EH, Keating MJ, McCredie KB, Bodey GP, Freireich EJ. Causes of initial
remission induction failure in acute myelogenous leukemia. Blood 1982; 60: 309
7. Preisler HD, Early AP, Raza A, et al. Therapy of secondary acute nonlymphocytic
leukemia with cytarabine. N Engl J Med 1983; 308: 21.
8. Capizzi RL, Poole M, Cooper MR, et al. Treatment of poor risk acute leukemia with
sequential high dose ARA-C and asparaginase. Blood 1984; 63: 694-700.
9. Harousseau JL, Castaigne S, Milpied N, Marty M, Degos L Treatment of acute nonlymphoblastic leukaemia in elderly patients. Lancet 1984; ii: 288
10. Yates J, Wallace J, Ellison RR, Holland JF Cytosine arabinoside (NSC-63878) and
daunorubicin (NSC-83142) therapy in acute nonlymphocytic leukemia. Cancer
Chem Rep 1973; 57: 485-88.
11. Baker MA, Taub RN, Carter WH, and the Toronto Leukemia Study Group
Immunotherapy for remission maintenance in acute myeloblastic leukemia Cancer
Immunol Immunother 1982; 13: 85-88
12. Sauter C, Fopp M, Imbach P, et al Acute myelogenous leukaemia: maintenance
chemotherapy after early consolidation treatment does not prolong survival Lancet
1984; i: 379-82.
13. Buchner T, Urbanitz D, Fischer J, et al. Long-term remission in acute myelogenous
leukaemia Lancet 1984; i: 571.
14. Champlin R, Gale RP, Elashoff R, et al. Prolonged survival in acute myelogenous
leukaemia without maintenance chemotherapy. Lancet 1984, i: 894-96
15 Wintrobe MM, Lee GR, Boggs DR, et al, eds. Classification, pathogenesis and etiology
of neoplastic disease of the hematopoietic system. In Clinical hematology
Philadelphia Lea and Febiger, 1981: 1455-58.
16. Weinstein HJ, Mayer RJ, Rosenthal DS, Camitta BM, Coral FS, Nathan DG, Frei E
Treatment of acute myelogenous leukemia in children and adults N Engl J Med
1980, 303: 473-78.
17. Cassileth PA, Begg CB, Bennett JM, et al A randomized study of the efficacy of
consolidation therapy in adult acute nonlymphocytic leukemia. Blood 1984; 63:
843-47.
18. Keating MJ, McCredie KB, Benjamin RS, et al. Treatment of patients over 50 years of
age with acute myelogenous leukemia with a combination of rubidazone and
cytosine arabinoside, vincristine and prednisone (ROAP) Blood 1981, 58: 584
19. Feinstein AR, Sosin DM, Wells CK. The Will Rogers phenomenon. Stage migration
and new diagnostic techniques as a source of misleading statistics for survival in
cancer. N EnglJ Med 1985; 312: 1604-08
20 The Toronto Leukemia Study Group. Survival in acute myeloblastic leukemia is not
prolonged by remission maintenance or early reinduction chemotherapy Blood
1985; 66 (suppl): 210a.
3. Gale
789
TABLE I-POSSIBLE RANDOMISED TRIAL DESIGN TO INCLUDE ALL
STROKE PATIENTS
(AF AND
SINUS
Project (OCSP),’ in which 512 consecutive cases of first-ever
were investigated .
RHYTHM)
stroke
WHAT IS A TYPICAL STROKE PATIENT IN AF LIKE?
The sort of stroke patient in whom the question of
anticoagulation typically arises might be an elderly woman
with a mild right hemiparesis, hypertension, a left carotid
bruit, and atrial fibrillation but
BB=betablocker. AC= oral anticoagulant.
To assess various anti-haemostatic therapies: X
To assess beta-blockade: 1 versus 2.
versus
Y
versus
Z.
versus control ought to be conducted.
there
are reasons why a very different trial might be
However,
better. The alternative trial would include not just those in
AF but all stroke patients; it would be a comparison of
anticoagulants versus control versus aspirin; and finally half
of each of the three groups would be given beta-blockers, to
discover whether these agents were of any additional value
(table I). The design of this trial was based on the following
general considerations; that the type and number of stroke
patients in AF likely to enter the first type of study may be
limited; that the outcome for patients with AF is not much
different from that for those in sinus rhythm and that most
stroke patients die not of stroke but of heart disease, so
treatments that might reduce heart disease need to be studied;
that anticoagulants may reduce the incidence of heart disease
and occlusive stroke but increase the incidence of
haemorrhagic stroke; that aspirin and beta-blockers may be as
effective as anticoagulants but are easier to give and less toxic;
and finally that there are many more stroke patients in sinus
rhythm than in AF, which makes the former much easier to
study and of much greater public health importance. We
conclude by asking whether a simpler trial (paradoxically,
without the two anticoagulant subgroups) might be even
better in a country, such as Great Britain, where computer
tomography (CT) is often not readily available for the
detection of haemorrhagic stroke (in which anticoagulants are
contraindicated). The evidence reviewed derives from many
sources, including the Oxfordshire Community Stroke
anticoagulant
no evidence of rheumatic
valvular disease. The decision to anticoagulate should ideally
be based on: whether the stroke was due to cerebral infarction
or primary intracerebral haemorrhage (this requires a CT
scan of the brain); if the stroke was due to infarction whether
it was a result of hypertensive small vessel disease within the
brain, embolism from an atheromatous plaque in the internal
carotid artery, or embolism from the fibrillating left atrium;
and whether it is wise to subject an elderly hypertensive
patient to the risks and inconvenience of anticoagulation.
WHAT IS THE EFFECT OF AF ON RISK OF DEATH AND
RECURRENT STROKE IN STROKE PATIENTS?
Although AF not associated with rheumatic heart disease
(NRAF) may increase the risk of death in the first 30 days
after a stroke, it has a less marked effect on mortality
Fig 1-Probability of survival (Kaplan-Meier survival curve) among
346 patients who survived at least 30 days after a first cerebral
infarction.
Data from the Oxfordshire
Community Stroke Project.
TABLE II-RISK OF DEATH OR RECURRENT STROKE IN PATIENTS WITH STROKE AND ATRIAL FIBRILLATION
RHD = cases ofAF associated with RHD; NRHD = cases ofAF
*P