ISIS 2: STREPTOKINASE ASPIRIN AFTER MYOCARDIAL INFARCT

Mortality and Cancer data were supplied to the University of Oxford by the Office for National Statistics (ONS) and subsequently the Health and Social Care Information Centre (HSCIC) (which has since become known as NHS England) for the purpose of a research study referred to as ISIS 2: STREPTOKINASE ASPIRIN AFTER MYOCARDIAL INFARCT.

This Data Sharing Agreement permits the retention of the data provided under previous iterations of this Agreement. Further processing and analysis are not permitted under this Agreement.

The following information provides background information on the purpose of the original study:

ISIS-2 was a landmark randomised trial that recruited 17,187 acute myocardial patients from 16 countries (including 6231 patients from the UK) between March 1985 and December 1987. It demonstrated clear benefits of aspirin and streptokinase and changed clinical practice sharply. Similar treatments remain a part of routine care in acute heart attack today.

The aim of the ISIS-2 trial was to study the effect on cardiovascular outcomes and death of intravenous streptokinase and oral aspirin in patients suffering an acute myocardial infarction. Eligible patients were randomized within 24 hours of the onset of chest pain. In a hospital setting they received either IV Streptokinase or placebo, plus aspirin or placebo for a month. They were randomised in a 2 x 2 factorial design to the following arms:

• Placebo SK and placebo aspirin

• Placebo SK and active aspirin

• Active SK and active aspirin

• Active SK and placebo aspirin

Linkage to ONS/HSCIC mortality data provided follow-up for death for patients in the UK, contributing to the main pre-specified analyses of the study. The original trial results, showing benefits for both active treatments, were published in the Lancet in 1988 (see 5d iii ‘Yielded Benefits’). ISIS-2 changed clinical practice sharply: a year later a British Heart Foundation survey showed that 68% of doctors had switched to routine administration of the drugs for heart attack patients (see 5d iii ‘Yielded Benefits’). Similar treatments remain a part of routine care in acute heart attack today. Subsequent 10-year follow-up was sought to establish whether the benefits persisted, and this resulted in a further publication in the BMJ in 1998 (see 5d iii ‘Yielded Benefits’).

Trial participants had had an acute heart attack and had a median age of 60-69 at entry in 1985-87, and thus the majority of the participants now, 33 years later, are likely to be deceased.

Such a randomised trial costs tens of millions of pounds to conduct and remains a valuable resource. Although, no further analyses are currently planned, analyses in public health interest could be requested, for example as part of a meta-analysis or long-term follow-up, and the University of Oxford consider that it would be irresponsible and not in the public interest to allow this data to be destroyed or become unavailable to contribute.

While ISIS-2 was done many years ago, the findings are still relevant globally today. The finding of using drugs - such as streptokinase - to dissolve blood clots in patients who had had an acute heart attack has led on to other therapies (such as non-surgical procedures to treat blockages in coronary arteries) in high income countries. However, treatments similar to streptokinase remain by far the most commonly used emergency treatment for acute heart attack worldwide. This is typically because some lower income countries cannot facilitate provision of more complex and costly treatments, or because the time from symptom onset to hospital admission is too long for other treatments to be used. This can also be an issue in wealthier countries – including the USA – where healthcare transit times are long. The results from ISIS-2 still apply to other drugs similar to streptokinase (called fibrinolytic therapy) and there are now newer types of similar medications used to break down blood clots. ISIS-2 is one of the few trials demonstrating the benefits and the safety of treatment with streptokinase. It is also the only trial that has demonstrated the benefit of aspirin in the setting of acute heart attack. This means that it is of substantial public health significance globally to retain the ISIS-2 Legacy Database.

The Nuffield Department of Population Health (NDPH) study team need to retain identifiers for two purposes. 1. To be able to preserve the dataset that produced these important findings, and to have it available to recreate the published trial results (the identifiers date of birth, date of death, and gender are required for this) 2. To retain the option for future research using the original dataset, e.g., subgroup analysis, long-term data linkage (the identifiers name, address, GP information, and NHS number are required for data linkage). In such a situation, appropriate applications, e.g., to an ethics committee, Confidentiality Advisory Group (CAG) & NHS England, justifying the analyses would be made and approved before any new work could be done. Without retention of these identifiers, the database loses its usefulness, and there will be no possibility of doing future data linkage.

The University also require retention of data already received to maintain provenance and an audit trail for data used in publications and reports. In addition, access to the data may be required by an MHRA inspector in order to ensure compliance with UK regulations.

Discussions with Patient and Participant Involvement (PPI) groups considered aspects of NDPH using ISIS-2 data collected many years ago. The general feeling was that provided data was used in-line with the original research and that data protections were appropriate, that using the data as described (without explicit consent) was a good idea.

The data application is in accordance with UK GDPR Article 6(1)e as processing is necessary for a task carried out in the public interest.

Processing of the data is in accordance with UK GDPR Article 9(2)(j) exemption, i.e. that the processing of the data is necessary for archiving purposes in the public interest, scientific or historical research purposes.

Data received from ONS was used to ascertain main trial and long-term follow-up outcomes (see 5d iii ‘Yielded Benefits’).

The research study designs and statistical methods are described in the published papers (see 5d iii ‘Yielded Benefits’).

Additional data linkage is not being sought.

The University of Oxford is the sole Data Controller. No other organisations process these data for the purpose described in this Agreement.

No new outputs will be produced under this Data Sharing Agreement.

Publications:

• ISIS-2 (second international study of infarct survival) collaborative group. Randomised trial of intravenous streptokinase, oral aspirin, both or neither among 17 187 cases of suspected acute myocardial infarction: ISIS-2

Lancet 1988;332:349-360. https://doi.org/10.1016/S0140-6736(88)92833-4

• Collins R., Peto R., Sleight P. ISIS-2: a large randomized trial of intravenous streptokinase and oral aspirin in acute myocardial-infarction

Br Heart J 1989;61:71. https://dx.doi.org/10.1136/hrt.61.1.71

• Rory Collins, Desmond Julian. British Heart Foundation surveys (1987 & 1989) of United Kingdom treatment policies for acute myocardial infarction

Br Heart J 1991;66:250-5. https://heart.bmj.com/content/heartjnl/66/3/250.full.pdf

• Baigent C., Collins R., Appleby P., Parish S., Sleight P., Peto R. ISIS-2: 10 year survival among patients with suspected acute myocardial infarction in randomised comparison of intravenous streptokinase, oral aspirin, both, or neither. The ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. BMJ 1998; 316(7141):1337-1343. https://dx.doi.org/10.1136/bmj.316.7141.1337

This data and the research which uses it has significantly contributed to the body of evidence and knowledge available which led to changes in treatment, care and policies which are of benefit to the patient and the health care system.

Key points arising from publications listed in section 5c::

• The ISIS-2 trial results changed clinical practice by demonstrating that patients allocated streptokinase and aspirin, singly or in combination had significantly fewer deaths than those allocated neither. It also showed that the differences in vascular and in all-cause mortality produced by streptokinase and by aspirin remained highly significant after the median of 15 months of follow-up available at the time.

• The ISIS-2 trial demonstrated that there were significantly fewer reinfarctions, strokes and deaths among patients allocated the combination of streptokinase and aspirin than among those allocated neither. A median of 15 months follow-up indicated that the differences in early mortality also have a long-term effect.

• This BHF survey demonstrated that the ISIS-2 results changed clinical practice. Routine streptokinase use had grown from only 2–3% in patients with acute myocardial infarction in 1987, to 68% in 1989. During the same period, the use of aspirin had increased in even greater proportion.

• The ISIS-2 trial demonstrated that the early survival advantages produced by fibrinolytic therapy and one month of aspirin started in acute myocardial infarction seemed to be maintained for at least 10 years.

The previous iteration of this Agreement permitted the retention of data only with no further processing. There are therefore no additional yielded benefits to report.

Mortality and Cancer data were supplied to the University of Oxford by ONS and subsequently the Health and Social Care Information Centre (which has since become known as NHS Digital) for the purpose of a research study referred to as ISIS 2:STREPTOKINASE ASPIRIN AFTER MYOCARDIAL INFARCT.

This Data Sharing Agreement permits the retention of the data provided under previous iterations of this Agreement. Further processing and analysis is not permitted under this Agreement.

The following information provides background information on the purpose of the original study:

ISIS-2 was a landmark randomised trial that recruited 17,187 acute myocardial patients from 16 countries (including 6231 patients from the UK) between March 1985 and December 1987. It demonstrated clear benefits of aspirin and streptokinase and changed clinical practice sharply. Similar treatments remain a part of routine care in acute heart attack today.

The aim of the ISIS-2 trial was to study the effect on cardiovascular outcomes and death of intravenous streptokinase and oral aspirin in patients suffering an acute myocardial infarction. Eligible patients were randomized within 24 hours of the onset of chest pain. In a hospital setting they received either IV Streptokinase or placebo, plus aspirin or placebo for a month. They were randomised in a 2 x 2 factorial design to the following arms:

• Placebo SK and placebo aspirin

• Placebo SK and active aspirin

• Active SK and active aspirin

• Active SK and placebo aspirin

Linkage to ONS/HSCIC mortality data provided follow-up for death for patients in the UK, contributing to the main pre-specified analyses of the study. The original trial results, showing benefits for both active treatments, were published in the Lancet in 1988 (see 5d iii ‘Yielded Benefits’). ISIS-2 changed clinical practice sharply: a year later a British Heart Foundation survey showed that 68% of doctors had switched to routine administration of the drugs for heart attack patients (see 5d iii ‘Yielded Benefits’). Similar treatments remain a part of routine care in acute heart attack today. Subsequent 10-year follow-up was sought to establish whether the benefits persisted and this resulted in a further publication in the BMJ in 1998 (see 5d iii ‘Yielded Benefits’).

Trial participants had had an acute heart attack and had a median age of 60-69 at entry in 1985-87, and thus the majority of the participants now, 33 years later, are likely to be deceased.

Such a randomised trial costs tens of millions of pounds to conduct and remains a valuable resource. Although, no further analyses are currently planned, analyses in public health interest could be requested, for example as part of a meta-analysis or long-term follow-up, and the University of Oxford consider that it would be irresponsible and not in the public interest to allow this data to be destroyed or become unavailable to contribute.

While ISIS-2 was done many years ago, the findings are still relevant globally today. The finding of using drugs - such as streptokinase - to dissolve blood clots in patients who had had an acute heart attack has led on to other therapies (such as non-surgical procedures to treat blockages in coronary arteries) in high income countries. However, treatments similar to streptokinase remain by far the most commonly used emergency treatment for acute heart attack worldwide. This is typically because some lower income countries cannot facilitate provision of more complex and costly treatments, or because the time from symptom onset to hospital admission is too long for other treatments to be used. This can also be an issue in wealthier countries – including the USA – where healthcare transit times are long. The results from ISIS-2 still apply to other drugs similar to streptokinase (called fibrinolytic therapy) and there are now newer types of similar medications used to break down blood clots. ISIS-2 is one of the few trials demonstrating the benefits and the safety of treatment with streptokinase. It is also the only trial that has demonstrated the benefit of aspirin in the setting of acute heart attack. This means that it is of substantial public health significance globally to retain the ISIS-2 Legacy Database.

The Nuffield Department of Population Health (NDPH) study team need to retain identifiers for two purposes. 1. To be able to preserve the dataset that produced these important findings, and to have it available to recreate the published trial results (the identifiers date of birth, date of death, and gender are required for this) 2. To retain the option for future research using the original dataset, e.g. subgroup analysis, long-term data linkage (the identifiers name, address, GP information, and NHS number are required for data linkage). In such a situation, appropriate applications, e.g. to an ethics committee, Confidentiality Advisory Group (CAG) & NHS Digital, justifying the analyses would be made and approved before any new work could be done. Without retention of these identifiers, the database loses it’s usefulness, and there will be no possibility of doing future data linkage.

The University also require retention of data already received to maintain provenance and an audit trail for data used in publications and reports. In addition access to the data may be required by an MHRA inspector in order to ensure compliance with UK regulations.

Discussions with Patient and Participant Involvement (PPI) groups considered aspects of NDPH using ISIS-2 data collected many years ago. The general feeling was that provided data was used in-line with the original research and that data protections were appropriate, that using the data as described (without explicit consent) was a good idea.

The data application is in accordance with Article 6(1)e as processing is necessary for a task carried out in the public interest.

Processing of the data is in accordance with Article 9(2)(j) exemption, i.e. that the processing of the data is necessary for archiving purposes in the public interest, scientific or historical research purposes.

Data received from ONS was used to ascertain main trial and long-term follow-up outcomes (see 5d iii ‘Yielded Benefits’).

The research study designs and statistical methods are described in the published papers (see 5d iii ‘Yielded Benefits’).

Additional data linkage is not being sought.

The University of Oxford is the sole Data Controller. No other organisations process these data for the purpose described in this Agreement.

No new outputs will be produced under this Data Sharing Agreement.

Publications:

• ISIS-2 (second international study of infarct survival) collaborative group. Randomised trial of intravenous streptokinase, oral aspirin, both or neither among 17 187 cases of suspected acute myocardial infarction: ISIS-2

Lancet 1988;332:349-360. https://doi.org/10.1016/S0140-6736(88)92833-4

• Collins R., Peto R., Sleight P. ISIS-2: a large randomized trial of intravenous streptokinase and oral aspirin in acute myocardial-infarction

Br Heart J 1989;61:71. https://dx.doi.org/10.1136/hrt.61.1.71

• Rory Collins, Desmond Julian. British Heart Foundation surveys (1987 & 1989) of United Kingdom treatment policies for acute myocardial infarction

Br Heart J 1991;66:250-5. https://heart.bmj.com/content/heartjnl/66/3/250.full.pdf

• Baigent C., Collins R., Appleby P., Parish S., Sleight P., Peto R. ISIS-2: 10 year survival among patients with suspected acute myocardial infarction in randomised comparison of intravenous streptokinase, oral aspirin, both, or neither. The ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. BMJ 1998; 316(7141):1337-1343. https://dx.doi.org/10.1136/bmj.316.7141.1337

This data and the research which uses it has significantly contributed to the body of evidence and knowledge available which led to changes in treatment, care and policies which are of benefit to the patient and the health care system.

Key points arising from publications listed in section 5c::

• The ISIS-2 trial results changed clinical practice by demonstrating that patients allocated streptokinase and aspirin, singly or in combination had significantly fewer deaths than those allocated neither. It also showed that the differences in vascular and in all-cause mortality produced by streptokinase and by aspirin remained highly significant after the median of 15 months of follow-up available at the time.

• The ISIS-2 trial demonstrated that there were significantly fewer reinfarctions, strokes and deaths among patients allocated the combination of streptokinase and aspirin than among those allocated neither. A median of 15 months follow-up indicated that the differences in early mortality also have a long term effect.

• This BHF survey demonstrated that the ISIS-2 results changed clinical practice. Routine streptokinase use had grown from only 2–3% in patients with acute myocardial infarction in 1987, to 68% in 1989. During the same period, the use of aspirin had increased in even greater proportion.

• The ISIS-2 trial demonstrated that the early survival advantages produced by fibrinolytic therapy and one month of aspirin started in acute myocardial infarction seemed to be maintained for at least 10 years.

The previous iteration of this Agreement permitted the retention of data only with no further processing. There are therefore no additional yielded benefits to report.

Mortality and Cancer data were supplied to the University of Oxford by ONS and subsequently the Health and Social Care Information Centre (which has since become known as NHS Digital) for the purpose of a research study referred to as ISIS 2:STREPTOKINASE ASPIRIN AFTER MYOCARDIAL INFARCT.

This Data Sharing Agreement permits the retention of the data for an interim period but no other processing of the data is permitted.

Permission to retain the data for the interim period is a practical step to enable the study to comply with the necessary legal and ethical requirements. If, for any reason, it is not possible for the study to meet the necessary requirements, this Agreement will be terminated and destruction of the data will be required.

The following information provides background information on the purpose of the original study:

ISIS-2 was a landmark randomised trial that recruited 17,187 acute myocardial patients from 16 countries (including 6231 patients from the UK) between March 1985 and December 1987. It demonstrated clear benefits of aspirin and streptokinase and changed clinical practice sharply. Similar treatments remain a part of routine care in acute heart attack today.

The aim of the ISIS-2 trial was to study the effect on cardiovascular outcomes and death of intravenous streptokinase and oral aspirin in patients suffering an acute myocardial infarction. Eligible patients were randomized within 24 hours of the onset of chest pain. In a hospital setting they received either IV Streptokinase or placebo, plus aspirin or placebo for a month. They were randomised in a 2 x 2 factorial design to the following arms:

• Placebo SK and placebo aspirin

• Placebo SK and active aspirin

• Active SK and active aspirin

• Active SK and placebo aspirin

Linkage to ONS/HSCIC mortality data provided follow-up for death for patients in the UK, contributing to the main pre-specified analyses of the study. The original trial results, showing benefits for both active treatments, were published in the Lancet in 1988 (see 5d iii ‘Yielded Benefits’). ISIS-2 changed clinical practice sharply: a year later a British Heart Foundation survey showed that 68% of doctors had switched to routine administration of the drugs for heart attack patients (see 5d iii ‘Yielded Benefits’). Similar treatments remain a part of routine care in acute heart attack today. Subsequent 10-year follow-up was sought to establish whether the benefits persisted and this resulted in a further publication in the BMJ in 1998 (see 5d iii ‘Yielded Benefits’).

Trial participants had had an acute heart attack and had a median age of 60-69 at entry in 1985-87, and thus the majority of the participants now, 33 years later, are likely to be deceased.

Such a randomised trial costs tens of millions of pounds to conduct and remains a valuable resource. Although, no further analyses are currently planned, analyses in public health interest could be requested, for example as part of a meta-analysis or long-term follow-up, and the University of Oxford consider that it would be irresponsible and not in the public interest to allow this data to be destroyed or become unavailable to contribute. The University of Oxford would like to retain the linkage data already received until at least 2035.

The University also require retention of data already received to maintain provenance and an audit trail for data used in publications and reports. In addition access to the data may be required by an MHRA inspector in order to ensure compliance with UK regulations.

The data application is in accordance with Article 6(1)e as processing is necessary for a task carried out in the public interest.

Processing of the data is in accordance with Article 9(2)(j) exemption, i.e. that the processing of the data is necessary for archiving purposes in the public interest, scientific or historical research purposes.

Data received from ONS was used to ascertain main trial and long-term follow-up outcomes (see 5d iii ‘Yielded Benefits’).

The research study designs and statistical methods are described in the published papers (see 5d iii ‘Yielded Benefits’).

Additional data linkage is not being sought.

The University of Oxford is the sole Data Controller. No other organisations process these data for the purpose described in this Agreement.

No new outputs will be produced under this Data Sharing Agreement.

This data and the research which uses it has significantly contributed to the body of evidence and knowledge available which led to changes in treatment, care and policies which are of benefit to the patient and the health care system.

Publications:

• ISIS-2 (second international study of infarct survival) collaborative group. Randomised trial of intravenous streptokinase, oral aspirin, both or neither among 17 187 cases of suspected acute myocardial infarction: ISIS-2

Lancet 1988;332:349-360

https://doi.org/10.1016/S0140-6736(88)92833-4

Key point: The ISIS-2 trial results changed clinical practice by demonstrating that patients allocated streptokinase and aspirin, singly or in combination had significantly fewer deaths than those allocated neither. It also showed that the differences in vascular and in all-cause mortality produced by streptokinase and by aspirin remained highly significant after the median of 15 months of follow-up available at the time.

• Collins R., Peto R., Sleight P. ISIS-2: a large randomized trial of intravenous streptokinase and oral aspirin in acute myocardial-infarction

Br Heart J 1989;61:71

https://dx.doi.org/10.1136/hrt.61.1.71

Key point: The ISIS-2 trial demonstrated that there were significantly fewer reinfarctions, strokes and deaths among patients allocated the combination of streptokinase and aspirin than among those allocated neither. A median of 15 months follow-up indicated that the differences in early mortality also have a long term effect.

• Rory Collins, Desmond Julian. British Heart Foundation surveys (1987 & 1989) of United Kingdom treatment policies for acute myocardial infarction

Br Heart J 1991;66:250-5

https://heart.bmj.com/content/heartjnl/66/3/250.full.pdf

Key point: This BHF survey demonstrated that the ISIS-2 results changed clinical practice. Routine streptokinase use had grown from only 2–3% in patients with acute myocardial infarction in 1987, to 68% in 1989. During the same period, the use of aspirin had increased in even greater proportion.

• Baigent C., Collins R., Appleby P., Parish S., Sleight P., Peto R. ISIS-2: 10 year survival among patients with suspected acute myocardial infarction in randomised comparison of intravenous streptokinase, oral aspirin, both, or neither. The ISIS-2 (Second International Study of Infarct Survival) Collaborative Group.

BMJ 1998; 316(7141):1337-1343

https://dx.doi.org/10.1136/bmj.316.7141.1337

Key point: The ISIS-2 trial demonstrated that the early survival advantages produced by fibrinolytic therapy and one month of aspirin started in acute myocardial infarction seemed to be maintained for at least 10 years.

Mortality and Cancer data were supplied to the University of Oxford by ONS and subsequently the Health and Social Care Information Centre (which has since become NHS Digital) for the purpose of a research study referred to as ISIS 2:STREPTOKINASE ASPIRIN AFTER MYOCARDIAL INFARCT.

This Data Sharing Agreement permits the retention of the data for an interim period but no other processing of the data is permitted.

Permission to retain the data for the interim period is a practical step to enable the study to comply with the necessary legal and ethical requirements. If, for any reason, it is not possible for the study to meet the necessary requirements, this Agreement will be terminated and destruction of the data will be required.

The following information provides background information on the purpose of the original study:

ISIS-2 was a landmark randomised trial that recruited 17,187 acute myocardial patients from 16 countries (including 6231 patients from the UK) between March 1985 and December 1987. It demonstrated clear benefits of aspirin and streptokinase and changed clinical practice sharply. Similar treatments remain a part of routine care in acute heart attack today.

The aim of the ISIS-2 trial was to study the effect on cardiovascular outcomes and death of intravenous streptokinase and oral aspirin in patients suffering an acute myocardial infarction. Eligible patients were randomized within 24 hours of the onset of chest pain. In a hospital setting they received either IV Streptokinase or placebo, plus aspirin or placebo for a month. They were randomised in a 2 x 2 factorial design to the following arms:

• Placebo SK and placebo aspirin

• Placebo SK and active aspirin

• Active SK and active aspirin

• Active SK and placebo aspirin

Linkage to ONS/HSCIC mortality data provided follow-up for death for patients in the UK, contributing to the main pre-specified analyses of the study. The original trial results, showing benefits for both active treatments, were published in the Lancet in 1988 (see 5d iii ‘Yielded Benefits’). ISIS-2 changed clinical practice sharply: a year later a British Heart Foundation survey showed that 68% of doctors had switched to routine administration of the drugs for heart attack patients (see 5d iii ‘Yielded Benefits’). Similar treatments remain a part of routine care in acute heart attack today. Subsequent 10-year follow-up was sought to establish whether the benefits persisted and this resulted in a further publication in the BMJ in 1998 (see 5d iii ‘Yielded Benefits’).

Trial participants had had an acute heart attack and had a median age of 60-69 at entry in 1985-87, and thus the majority of the participants now, 33 years later, are likely to be deceased.

Such a randomised trial costs tens of millions of pounds to conduct and remains a valuable resource. Although, no further analyses are currently planned, analyses in public health interest could be requested, for example as part of a meta-analysis or long-term follow-up, and the University of Oxford consider that it would be irresponsible and not in the public interest to allow this data to be destroyed or become unavailable to contribute. The University of Oxford would like to retain the linkage data already received until at least 2035.

The University also require retention of data already received to maintain provenance and an audit trail for data used in publications and reports. In addition access to the data may be required by an MHRA inspector in order to ensure compliance with UK regulations.

The data application is in accordance with Article 6(1)e as processing is necessary for a task carried out in the public interest.

Processing of the data is in accordance with Article 9(2)(j) exemption, i.e. that the processing of the data is necessary for archiving purposes in the public interest, scientific or historical research purposes.

Data received from ONS was used to ascertain main trial and long-term follow-up outcomes (see 5d iii ‘Yielded Benefits’).

The research study designs and statistical methods are described in the published papers (see 5d iii ‘Yielded Benefits’).

Additional data linkage is not being sought.

The University of Oxford is the sole Data Controller. No other organisations process these data for the purpose described in this Agreement.

No new outputs will be produced under this Data Sharing Agreement.

This data and the research which uses it has significantly contributed to the body of evidence and knowledge available which led to changes in treatment, care and policies which are of benefit to the patient and the health care system.

Publications:

• ISIS-2 (second international study of infarct survival) collaborative group. Randomised trial of intravenous streptokinase, oral aspirin, both or neither among 17 187 cases of suspected acute myocardial infarction: ISIS-2

Lancet 1988;332:349-360

https://doi.org/10.1016/S0140-6736(88)92833-4

Key point: The ISIS-2 trial results changed clinical practice by demonstrating that patients allocated streptokinase and aspirin, singly or in combination had significantly fewer deaths than those allocated neither. It also showed that the differences in vascular and in all-cause mortality produced by streptokinase and by aspirin remained highly significant after the median of 15 months of follow-up available at the time.

• Collins R., Peto R., Sleight P. ISIS-2: a large randomized trial of intravenous streptokinase and oral aspirin in acute myocardial-infarction

Br Heart J 1989;61:71

https://dx.doi.org/10.1136/hrt.61.1.71

Key point: The ISIS-2 trial demonstrated that there were significantly fewer reinfarctions, strokes and deaths among patients allocated the combination of streptokinase and aspirin than among those allocated neither. A median of 15 months follow-up indicated that the differences in early mortality also have a long term effect.

• Rory Collins, Desmond Julian. British Heart Foundation surveys (1987 & 1989) of United Kingdom treatment policies for acute myocardial infarction

Br Heart J 1991;66:250-5

https://heart.bmj.com/content/heartjnl/66/3/250.full.pdf

Key point: This BHF survey demonstrated that the ISIS-2 results changed clinical practice. Routine streptokinase use had grown from only 2–3% in patients with acute myocardial infarction in 1987, to 68% in 1989. During the same period, the use of aspirin had increased in even greater proportion.

• Baigent C., Collins R., Appleby P., Parish S., Sleight P., Peto R. ISIS-2: 10 year survival among patients with suspected acute myocardial infarction in randomised comparison of intravenous streptokinase, oral aspirin, both, or neither. The ISIS-2 (Second International Study of Infarct Survival) Collaborative Group.

BMJ 1998; 316(7141):1337-1343

https://dx.doi.org/10.1136/bmj.316.7141.1337

Key point: The ISIS-2 trial demonstrated that the early survival advantages produced by fibrinolytic therapy and one month of aspirin started in acute myocardial infarction seemed to be maintained for at least 10 years.

Mortality and Cancer data were supplied to the University of Oxford by ONS and subsequently the Health and Social Care Information Centre (which has since become NHS Digital) for the purpose of a research study referred to as ISIS 2:STREPTOKINASE ASPIRIN AFTER MYOCARDIAL INFARCT.

This Data Sharing Agreement permits the retention of the data for an interim period but no other processing of the data is permitted.

Permission to retain the data for the interim period is a practical step to enable the study to comply with the necessary legal and ethical requirements. If, for any reason, it is not possible for the study to meet the necessary requirements, this Agreement will be terminated and destruction of the data will be required.

The following information provides background information on the purpose of the original study:

ISIS-2 was a landmark randomised trial that recruited 17,187 acute myocardial patients from 16 countries (including 6231 patients from the UK) between March 1985 and December 1987. It demonstrated clear benefits of aspirin and streptokinase and changed clinical practice sharply. Similar treatments remain a part of routine care in acute heart attack today.

The aim of the ISIS-2 trial was to study the effect on cardiovascular outcomes and death of intravenous streptokinase and oral aspirin in patients suffering an acute myocardial infarction. Eligible patients were randomized within 24 hours of the onset of chest pain. In a hospital setting they received either IV Streptokinase or placebo, plus aspirin or placebo for a month. They were randomised in a 2 x 2 factorial design to the following arms:

• Placebo SK and placebo aspirin

• Placebo SK and active aspirin

• Active SK and active aspirin

• Active SK and placebo aspirin

Linkage to ONS/HSCIC mortality data provided follow-up for death for patients in the UK, contributing to the main pre-specified analyses of the study. The original trial results, showing benefits for both active treatments, were published in the Lancet in 1988 (see 5d iii ‘Yielded Benefits’). ISIS-2 changed clinical practice sharply: a year later a British Heart Foundation survey showed that 68% of doctors had switched to routine administration of the drugs for heart attack patients (see 5d iii ‘Yielded Benefits’). Similar treatments remain a part of routine care in acute heart attack today. Subsequent 10-year follow-up was sought to establish whether the benefits persisted and this resulted in a further publication in the BMJ in 1998 (see 5d iii ‘Yielded Benefits’).

Trial participants had had an acute heart attack and had a median age of 60-69 at entry in 1985-87, and thus the majority of the participants now, 33 years later, are likely to be deceased.

Such a randomised trial costs tens of millions of pounds to conduct and remains a valuable resource. Although, no further analyses are currently planned, analyses in public health interest could be requested, for example as part of a meta-analysis or long-term follow-up, and the University of Oxford consider that it would be irresponsible and not in the public interest to allow this data to be destroyed or become unavailable to contribute. The University of Oxford would like to retain the linkage data already received until at least 2035.

The University also require retention of data already received to maintain provenance and an audit trail for data used in publications and reports. In addition access to the data may be required by an MHRA inspector in order to ensure compliance with UK regulations.

The data application is in accordance with Article 6(1)e as processing is necessary for a task carried out in the public interest.

Processing of the data is in accordance with Article 9(2)(j) exemption, i.e. that the processing of the data is necessary for archiving purposes in the public interest, scientific or historical research purposes.

Data received from ONS was used to ascertain main trial and long-term follow-up outcomes (see 5d iii ‘Yielded Benefits’).

The research study designs and statistical methods are described in the published papers (see 5d iii ‘Yielded Benefits’).

Additional data linkage is not being sought.

The University of Oxford is the sole Data Controller. No other organisations process these data for the purpose described in this Agreement.

No new outputs will be produced under this Data Sharing Agreement.

This data and the research which uses it has significantly contributed to the body of evidence and knowledge available which led to changes in treatment, care and policies which are of benefit to the patient and the health care system.

Publications:

• ISIS-2 (second international study of infarct survival) collaborative group. Randomised trial of intravenous streptokinase, oral aspirin, both or neither among 17 187 cases of suspected acute myocardial infarction: ISIS-2

Lancet 1988;332:349-360

https://doi.org/10.1016/S0140-6736(88)92833-4

Key point: The ISIS-2 trial results changed clinical practice by demonstrating that patients allocated streptokinase and aspirin, singly or in combination had significantly fewer deaths than those allocated neither. It also showed that the differences in vascular and in all-cause mortality produced by streptokinase and by aspirin remained highly significant after the median of 15 months of follow-up available at the time.

• Collins R., Peto R., Sleight P. ISIS-2: a large randomized trial of intravenous streptokinase and oral aspirin in acute myocardial-infarction

Br Heart J 1989;61:71

https://dx.doi.org/10.1136/hrt.61.1.71

Key point: The ISIS-2 trial demonstrated that there were significantly fewer reinfarctions, strokes and deaths among patients allocated the combination of streptokinase and aspirin than among those allocated neither. A median of 15 months follow-up indicated that the differences in early mortality also have a long term effect.

• Rory Collins, Desmond Julian. British Heart Foundation surveys (1987 & 1989) of United Kingdom treatment policies for acute myocardial infarction

Br Heart J 1991;66:250-5

https://heart.bmj.com/content/heartjnl/66/3/250.full.pdf

Key point: This BHF survey demonstrated that the ISIS-2 results changed clinical practice. Routine streptokinase use had grown from only 2–3% in patients with acute myocardial infarction in 1987, to 68% in 1989. During the same period, the use of aspirin had increased in even greater proportion.

• Baigent C., Collins R., Appleby P., Parish S., Sleight P., Peto R. ISIS-2: 10 year survival among patients with suspected acute myocardial infarction in randomised comparison of intravenous streptokinase, oral aspirin, both, or neither. The ISIS-2 (Second International Study of Infarct Survival) Collaborative Group.

BMJ 1998; 316(7141):1337-1343

https://dx.doi.org/10.1136/bmj.316.7141.1337

Key point: The ISIS-2 trial demonstrated that the early survival advantages produced by fibrinolytic therapy and one month of aspirin started in acute myocardial infarction seemed to be maintained for at least 10 years.

Mortality and Cancer data were supplied to the University of Oxford by ONS and subsequently the Health and Social Care Information Centre (which has since become NHS Digital) for the purpose of a research study referred to as ISIS 2:STREPTOKINASE ASPIRIN AFTER MYOCARDIAL INFARCT.

This Data Sharing Agreement permits the retention of the data for an interim period but no other processing of the data is permitted.

Permission to retain the data for the interim period is a practical step to enable the study to comply with the necessary legal and ethical requirements. If, for any reason, it is not possible for the study to meet the necessary requirements, this Agreement will be terminated and destruction of the data will be required.

The following information provides background information on the purpose of the original study:

ISIS-2 was a landmark randomised trial that recruited 17,187 acute myocardial patients from 16 countries (including 6231 patients from the UK) between March 1985 and December 1987. It demonstrated clear benefits of aspirin and streptokinase and changed clinical practice sharply. Similar treatments remain a part of routine care in acute heart attack today.

The aim of the ISIS-2 trial was to study the effect on cardiovascular outcomes and death of intravenous streptokinase and oral aspirin in patients suffering an acute myocardial infarction. Eligible patients were randomized within 24 hours of the onset of chest pain. In a hospital setting they received either IV Streptokinase or placebo, plus aspirin or placebo for a month. They were randomised in a 2 x 2 factorial design to the following arms:

• Placebo SK and placebo aspirin

• Placebo SK and active aspirin

• Active SK and active aspirin

• Active SK and placebo aspirin

Linkage to ONS/HSCIC mortality data provided follow-up for death for patients in the UK, contributing to the main pre-specified analyses of the study. The original trial results, showing benefits for both active treatments, were published in the Lancet in 1988 (see 5d iii ‘Yielded Benefits’). ISIS-2 changed clinical practice sharply: a year later a British Heart Foundation survey showed that 68% of doctors had switched to routine administration of the drugs for heart attack patients (see 5d iii ‘Yielded Benefits’). Similar treatments remain a part of routine care in acute heart attack today. Subsequent 10-year follow-up was sought to establish whether the benefits persisted and this resulted in a further publication in the BMJ in 1998 (see 5d iii ‘Yielded Benefits’).

Trial participants had had an acute heart attack and had a median age of 60-69 at entry in 1985-87, and thus the majority of the participants now, 33 years later, are likely to be deceased.

Such a randomised trial costs tens of millions of pounds to conduct and remains a valuable resource. Although, no further analyses are currently planned, analyses in public health interest could be requested, for example as part of a meta-analysis or long-term follow-up, and the University of Oxford consider that it would be irresponsible and not in the public interest to allow this data to be destroyed or become unavailable to contribute. The University of Oxford would like to retain the linkage data already received until at least 2035.

The University also require retention of data already received to maintain provenance and an audit trail for data used in publications and reports. In addition access to the data may be required by an MHRA inspector in order to ensure compliance with UK regulations.

The data application is in accordance with Article 6(1)e as processing is necessary for a task carried out in the public interest.

Processing of the data is in accordance with Article 9(2)(j) exemption, i.e. that the processing of the data is necessary for archiving purposes in the public interest, scientific or historical research purposes.

Data received from ONS was used to ascertain main trial and long-term follow-up outcomes (see 5d iii ‘Yielded Benefits’).

The research study designs and statistical methods are described in the published papers (see 5d iii ‘Yielded Benefits’).

Additional data linkage is not being sought.

The University of Oxford is the sole Data Controller. No other organisations process these data for the purpose described in this Agreement.

No new outputs will be produced under this Data Sharing Agreement.

This data and the research which uses it has significantly contributed to the body of evidence and knowledge available which led to changes in treatment, care and policies which are of benefit to the patient and the health care system.

Publications:

• ISIS-2 (second international study of infarct survival) collaborative group. Randomised trial of intravenous streptokinase, oral aspirin, both or neither among 17 187 cases of suspected acute myocardial infarction: ISIS-2

Lancet 1988;332:349-360

https://doi.org/10.1016/S0140-6736(88)92833-4

Key point: The ISIS-2 trial results changed clinical practice by demonstrating that patients allocated streptokinase and aspirin, singly or in combination had significantly fewer deaths than those allocated neither. It also showed that the differences in vascular and in all-cause mortality produced by streptokinase and by aspirin remained highly significant after the median of 15 months of follow-up available at the time.

• Collins R., Peto R., Sleight P. ISIS-2: a large randomized trial of intravenous streptokinase and oral aspirin in acute myocardial-infarction

Br Heart J 1989;61:71

https://dx.doi.org/10.1136/hrt.61.1.71

Key point: The ISIS-2 trial demonstrated that there were significantly fewer reinfarctions, strokes and deaths among patients allocated the combination of streptokinase and aspirin than among those allocated neither. A median of 15 months follow-up indicated that the differences in early mortality also have a long term effect.

• Rory Collins, Desmond Julian. British Heart Foundation surveys (1987 & 1989) of United Kingdom treatment policies for acute myocardial infarction

Br Heart J 1991;66:250-5

https://heart.bmj.com/content/heartjnl/66/3/250.full.pdf

Key point: This BHF survey demonstrated that the ISIS-2 results changed clinical practice. Routine streptokinase use had grown from only 2–3% in patients with acute myocardial infarction in 1987, to 68% in 1989. During the same period, the use of aspirin had increased in even greater proportion.

• Baigent C., Collins R., Appleby P., Parish S., Sleight P., Peto R. ISIS-2: 10 year survival among patients with suspected acute myocardial infarction in randomised comparison of intravenous streptokinase, oral aspirin, both, or neither. The ISIS-2 (Second International Study of Infarct Survival) Collaborative Group.

BMJ 1998; 316(7141):1337-1343

https://dx.doi.org/10.1136/bmj.316.7141.1337

Key point: The ISIS-2 trial demonstrated that the early survival advantages produced by fibrinolytic therapy and one month of aspirin started in acute myocardial infarction seemed to be maintained for at least 10 years.

Mortality data were supplied to University of Oxford by ONS and subsequently the Health and Social Care Information Centre (which has since become NHS Digital) for the purpose of a research study referred to as MR261 - ISIS 2:STREPTOKINASE ASPIRIN AFTER MYOCARDIAL INFARCT.

This Data Sharing Agreement permits the retention of the data for an interim period but no other processing of the data is permitted.

Permission to retain the data for the interim period is a practical step to enable the study to comply with the necessary legal and ethical requirements. If, for any reason, it is not possible for the study to meet the necessary requirements, this Agreement will be terminated and destruction of the data will be required.

The following information provides background information on the purpose of the original study:

Second International Study of Infarct Survival (ISIS 2).

A large, simple, randomised study of the effects of streptokinase and of aspirin on mortality after acute myocardial infarction.

The fundamental ISIS strategy is to assess reliably the balance of risks and benefits for streptokinase and aspirin treatments that, given as a preventative in the acute phase of myocardial infarction, might produce a moderate but worthwhile net reduction in vascular mortality.

Substantial numbers of lives might be saved if a moderate reduction in mortality from a common disease were produced by a treatment that could realistically be made available to a large proportion of affected patients. Reliable assessment of moderate effects can, however, often be achieved only by trials of unusual size.

The study cohort flagged by previous iteration of MRIS is ~10,000 individuals who have had a myocardial infarction in hospital, chosen by doctors to be included in this study and then consented to participate. The cohort currently stands at 3,432 individuals.

The data was requested to follow up the cohort of participants to help deduce if the benefit had been achieved from 4 different treatments post myocardial infarction.

No new outputs will be produced under this Data Sharing Agreement.

In any future application, the applicant will be required to provide details of the outputs that were produced and disseminated by the study as well as details of any future outputs planned.