ASCEND: A Study of Cardiovascular Events iN Diabetes

• ClinicalTrials.gov Identifier: NCT00135226
• Recruitment Status: Active, not recruiting
• First Posted: August 25, 2005
• Results First Posted: April 26, 2019
• Last Update Posted: December 1, 2022
• Sponsor: University of Oxford
• Collaborators: British Heart Foundation; Bayer; Medical Research Council; Solvay Pharmaceuticals; Abbott; Mylan
• Information provided by (Responsible Party): University of Oxford

Study Description

Brief Summary:

The purpose of this study is to determine whether 100mg daily aspirin versus placebo and/or supplementation with 1 gram daily omega-3 fatty acids or placebo prevents "serious vascular events" (i.e. non-fatal heart attack, non-fatal stroke or transient ischaemic attack, or death from vascular causes) in patients with diabetes who are not known to have occlusive arterial disease and to assess the effects on serious bleeding or other adverse events.

Condition or disease	Intervention/treatment	Phase
Diabetes Mellitus	Drug: Aspirin; Drug: Omega-3 Ethyl Esters; Drug: Placebo Aspirin; Drug: Placebo Omega-3 Ethyl Esters	Phase 4

Detailed Description:

The role of antiplatelet therapy (chiefly aspirin) for the secondary prevention of heart attacks and strokes is firmly established for many high-risk people with diagnosed arterial disease, and the proportional reductions in these cardiovascular events appear to be about one quarter, whether or not such patients have diabetes. But, most younger and middle-aged people with diabetes do not have manifest arterial disease - although they are still at significant cardiovascular risk - and yet few trials have tested aspirin in such individuals. As a result, there is substantial uncertainty about the role of aspirin for the prevention of heart attacks and strokes among apparently healthy people with diabetes, and only a small minority receives it.

There is consistent evidence from observational studies of lower rates of cardiovascular disease (particularly cardiac and sudden death) in people with higher intakes, or higher blood levels, of fish oils (omega-3 fatty acids). Trials in people who have survived a heart attack have shown modest, but potentially worthwhile, reductions in coronary events.

If ASCEND can reliably demonstrate that aspirin and/or fish oils safely reduce the risk of cardiovascular events and deaths in people with diabetes who do not have pre-existing arterial disease, then this would be relevant to some tens of millions of people world-wide (who are currently not receiving such therapy) and might save tens of thousands of lives each year.

The initial results (published 2018) showed that aspirin prevented serious vascular events in patients with diabetes who did not already have cardiovascular disease, but it caused almost as many major bleeds and there was no effect on cancers. There was no significant difference in the risk of serious vascular events between those who were assigned to receive n-3 fatty acid supplementation and those who were assigned to receive placebo.

ASCEND will be conducting long-term follow-up for 20-years beyond the scheduled treatment period (which ended in 2017). We will collect relevant data from UK central health registries. This will be used to assess whether the balance of benefits versus hazards of aspirin observed within the main trial, relating to major vascular events such as heart attack or stroke, continue long-term or whether additional benefits emerge during longer-term follow-up.

In addition ASCEND will use this long-term post-trial follow-up to investigate further whether low-dose aspirin might protect against cancer. The main cancer analyses is planned to take place ~5-years after the end of the treatment period.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 15480 participants
• Allocation: Randomized
• Intervention Model: Factorial Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: A Study of Cardiovascular Events iN Diabetes - A Randomized 2x2 Factorial Study of Aspirin Versus Placebo, and of Omega-3 Fatty Acid Supplementation Versus Placebo, for Primary Prevention of Cardiovascular Events in People With Diabetes
• Study Start Date: March 2005
• Actual Primary Completion Date: March 12, 2018
• Estimated Study Completion Date: July 31, 2037

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Aspirin + Omega-3 Ethyl Esters; Participants receive 100mg of aspirin once daily and 1g of omega-3 ethyl esters once daily.	Drug: Aspirin; Drug: Omega-3 Ethyl Esters; Other Names: n-3 fatty acid; Omacor
Active Comparator: Aspirin + Placebo Omega-3 Ethyl Esters; Participants receive 100mg of aspirin once daily and placebo omega-3 ethyl esters once daily.	Drug: Aspirin; Drug: Placebo Omega-3 Ethyl Esters
Active Comparator: Placebo Aspirin + Omega-3 Ethyl Esters; Participants receive placebo aspirin once daily and 1g of omega-3 ethyl esters once daily.	Drug: Omega-3 Ethyl Esters; Other Names: n-3 fatty acid; Omacor; Drug: Placebo Aspirin
Active Comparator: Placebo Aspirin + Placebo Omega-3 Ethyl Esters; Participants receive placebo aspirin once daily and placebo omega-3 ethyl esters once daily.	Drug: Placebo Aspirin; Drug: Placebo Omega-3 Ethyl Esters

Outcome Measures

Primary Outcome Measures :

1. Number of Participants With First Occurrence of Any Serious Vascular Event (SVE) [ Time Frame: Randomized treatment phase during a mean of 7.4 years ]

   The primary efficacy assessments involve intention-to-treat comparisons among all randomized participants of allocation to aspirin versus placebo and, separately, of omega-3 fatty acids versus placebo on the first occurrence of any "Serious Vascular Event" (SVE), defined as:

   • non-fatal myocardial infarction; or
   • non-fatal stroke (excluding confirmed intracranial hemorrhage) or TIA; or
   • vascular death excluding confirmed intracranial hemorrhage (defined as International Classification of Diseases 10th revision [ICD-10] I00-52 or I63-99, i.e. excluding subarachnoid hemorrhage [I60], intracerebral hemorrhage [I61], and other non-traumatic intracranial hemorrhage [I62]).
2. Number of Participants With First Occurrence of Any Major Bleed (Aspirin Comparison Only) [ Time Frame: Randomized treatment phase during a mean of 7.4 years ]

   The primary safety assessments involve intention-to-treat comparisons among all randomized patients of allocation to aspirin versus placebo on the first occurrence of "any major bleed", defined as:

   • any confirmed intracranial hemorrhage (including intracerebral, subarachnoid, subdural or any other intracranial hemorrhage); or
   • sight-threatening eye bleeding; or
   • any other serious bleeding episode.

Secondary Outcome Measures :

1. Number of Participants With Combined End-point of Serious Vascular Events (SVEs) or Revascularizations [ Time Frame: Randomized treatment phase during a mean of 7.4 years ]
   Secondary efficacy assessments involve intention-to-treat comparisons among all randomized participants of allocation to aspirin versus placebo and, separately, of omega-3 versus placebo on the first occurrence of the expanded vascular endpoint of "SVE or revascularization" (including coronary and non-coronary revascularizations).
2. Number of Participants With Any Incident Gastrointestinal (GI) Tract Cancer (Aspirin Comparison Only) [ Time Frame: Randomized treatment phase during a mean of 7.4 years ]

   Secondary efficacy assessments of aspirin involve intention-to-treat comparisons during the scheduled treatment period among all randomized participants on the first occurrence of:

   Any incident gastrointestinal (GI) tract cancer (i.e. any GI cancer excluding pancreas and hepatobiliary), overall and after exclusion of the first three years of follow-up.

Other Outcome Measures:

1. Number of Participants With Fatal Event: All-cause Mortality [ Time Frame: Randomized treatment phase during a mean of 7.4 years ]
   'All-cause mortality' includes all recorded deaths.
2. Number of Participants With Fatal Event: Coronary [ Time Frame: Randomized treatment phase during a mean of 7.4 years ]
   Fatal 'Coronary' events include deaths from: Acute MI and other CHD (unspecified Acute ischaemic heart disease; Atherosclerotic heart disease; Ischaemic cardiomyopathy; unspecified Chronic ischaemic heart disease).
3. Number of Participants With Fatal Event: All Stroke [ Time Frame: Randomized treatment phase during a mean of 7.4 years ]
   Fatal 'All stroke' events include deaths from: Haemorrhagic stroke (Intracerebral haemorrhage; Subarachnoid haemorrhage); Non-haemorrhagic stroke (Cerebral infarction; Stroke not specified as haemorrhage or infarction).
4. Number of Participants With Fatal Event: Other Vascular [ Time Frame: Randomized treatment phase during a mean of 7.4 years ]
   Fatal 'Other vascular' events include deaths from: Heart failure (excluding ischaemic cardiomyopathy); Other vascular death (excluding stroke; and Cardiac death (excluding CHD).
5. Number of Participants With Fatal Event: Cancer [ Time Frame: Randomized treatment phase during a mean of 7.4 years ]
   Fatal 'Cancer' events include any death attributed to cancer.
6. Number of Participants With Fatal Event: Respiratory [ Time Frame: Randomized treatment phase during a mean of 7.4 years ]
   Fatal 'Respiratory' events include any death attributed to respiratory causes.
7. Number of Participants With Fatal Event: Other Medical [ Time Frame: Randomized treatment phase during a mean of 7.4 years ]
   Fatal 'Other medical' events include deaths from: Non-vascular medical causes (excluding cancer and respiratory, including Fatal GI bleed or perforation); and deaths from Renal disease and Diabetes.
8. Number of Participants With Fatal Event: External Cause [ Time Frame: Randomized treatment phase during a mean of 7.4 years ]
   Fatal 'External cause' events include deaths from: Injury; Fracture; Self harm; and Medical and surgical complications
9. Number of Participants With Fatal Event: Unknown Cause [ Time Frame: Randomized treatment phase during a mean of 7.4 years ]
   Any death for which the cause is not known.
10. Number of Participants With Event: Any Cancer [ Time Frame: Randomized treatment phase during a mean of 7.4 years ]

    Incidence of fatal or non-fatal cancers. Any cancer excludes non-fatal non-melanoma skin cancer and non-fatal recurrence of a cancer that had occurred before randomization.

    A single participant may have had multiple cancers.

11. Number of Participants With Event: Other Gastrointestinal Cancer (Aspirin Comparison Only) [ Time Frame: Randomized treatment phase during a mean of 7.4 years ]
    Includes fatal and non-fatal cancers. Excludes cancers reported in the gastrointestinal tract category (see secondary outcome measure #4), and includes hepatobiliary and pancreatic cancers.
12. Number of Participants With Event: Respiratory Cancer [ Time Frame: Randomized treatment phase during a mean of 7.4 years ]
    Includes fatal and non-fatal cancers. Includes lung and larynx cancer.
13. Number of Participants With Event: Genitourinary Cancer [ Time Frame: Randomized treatment phase during a mean of 7.4 years ]
    Includes fatal and non-fatal renal, bladder, prostate, gynaecological and other GU cancers
14. Number of Participants With Event: Hematological Cancer [ Time Frame: Randomized treatment phase during a mean of 7.4 years ]
    Includes fatal and non-fatal cancers. Includes leukaemia and lymphoma.
15. Number of Participants With Event: Breast Cancer [ Time Frame: Randomized treatment phase during a mean of 7.4 years ]
    Includes fatal and non-fatal cancers.
16. Number of Participants With Event: Melanoma [ Time Frame: Randomized treatment phase during a mean of 7.4 years ]
    Includes fatal and non-fatal melanomas.
17. Number of Participants With Event: Other Cancer [ Time Frame: Randomized treatment phase during a mean of 7.4 years ]
    Includes fatal and non-fatal cancers not included elsewhere (where the type of cancer is known).
18. Number of Participants With Event: Unspecified Cancer [ Time Frame: Randomized treatment phase during a mean of 7.4 years ]
    Includes fatal and non-fatal cancers of unknown type.
19. Number of Participants With Event: Atrial Fibrillation (Omega-3 Comparison Only) [ Time Frame: Randomized treatment phase during a mean of 7.4 years ]
    Includes fatal and non-fatal events.
20. Number of Participants With Event: Other Arrhythmia (Omega-3 Comparison Only) [ Time Frame: Randomized treatment phase during a mean of 7.4 years ]
    Includes fatal and non-fatal events, excludes atrial fibrillation.

Eligibility Criteria

• Ages Eligible for Study: 40 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Males or females with type 1 or type 2 diabetes mellitus.
• Aged ≥ 40 years.
• No previous history of vascular disease.
• No clear contra-indication to aspirin.
• No other predominant life-threatening medical problem.

Exclusion Criteria:

• Definite history of myocardial infarction, stroke or arterial revascularisation procedure.
• Currently prescribed aspirin, warfarin or any other blood thinning medication.

Contacts and Locations

Locations

United Kingdom

Clinical Trial Service Unit, NDPH, University of Oxford

Oxford, United Kingdom, OX3 7LF

Sponsors and Collaborators

University of Oxford

British Heart Foundation

Bayer

Medical Research Council

Solvay Pharmaceuticals

Abbott

Mylan

Investigators

• Principal Investigator: Jane M Armitage, BSc, MBBS, MRCP, FFPH; Clinical Trial Service Unit, NDPH, University of Oxford

  Study Documents (Full-Text)

Documents provided by University of Oxford:

Study Protocol and Informed Consent Form  [PDF] May 6, 2021

Statistical Analysis Plan  [PDF] July 23, 2018

More Information

Additional Information:

The study website for information about ASCEND: A Study of Cardiovascular Events iN Diabetes 

Publications of Results:

Parish S, Mafham M, Offer A, Barton J, Wallendszus K, Stevens W, Buck G, Haynes R, Collins R, Bowman L, Armitage J. Effects of aspirin on dementia and cognitive function in diabetic patients: the ASCEND trial. Eur Heart J. 2022 Jun 1;43(21):2010-2019. doi: 10.1093/eurheartj/ehac179.

Parish S, Mafham M, Offer A, Barton J, Wallendszus K, Stevens W, Buck G, Haynes R, Collins R, Bowman L, Armitage J; ASCEND Study Collaborative Group. Effects of Omega-3 Fatty Acid Supplements on Arrhythmias. Circulation. 2020 Jan 28;141(4):331-333. doi: 10.1161/CIRCULATIONAHA.119.044165. Epub 2020 Jan 27. No abstract available.

ASCEND Study Collaborative Group; Bowman L, Mafham M, Wallendszus K, Stevens W, Buck G, Barton J, Murphy K, Aung T, Haynes R, Cox J, Murawska A, Young A, Lay M, Chen F, Sammons E, Waters E, Adler A, Bodansky J, Farmer A, McPherson R, Neil A, Simpson D, Peto R, Baigent C, Collins R, Parish S, Armitage J. Effects of Aspirin for Primary Prevention in Persons with Diabetes Mellitus. N Engl J Med. 2018 Oct 18;379(16):1529-1539. doi: 10.1056/NEJMoa1804988. Epub 2018 Aug 26.

ASCEND Study Collaborative Group; Bowman L, Mafham M, Wallendszus K, Stevens W, Buck G, Barton J, Murphy K, Aung T, Haynes R, Cox J, Murawska A, Young A, Lay M, Chen F, Sammons E, Waters E, Adler A, Bodansky J, Farmer A, McPherson R, Neil A, Simpson D, Peto R, Baigent C, Collins R, Parish S, Armitage J. Effects of n-3 Fatty Acid Supplements in Diabetes Mellitus. N Engl J Med. 2018 Oct 18;379(16):1540-1550. doi: 10.1056/NEJMoa1804989. Epub 2018 Aug 26.

Other Publications:

Bowman L, Mafham M, Stevens W, Haynes R, Aung T, Chen F, Buck G, Collins R, Armitage J; ASCEND Study Collaborative Group. ASCEND: A Study of Cardiovascular Events iN Diabetes: Characteristics of a randomized trial of aspirin and of omega-3 fatty acid supplementation in 15,480 people with diabetes. Am Heart J. 2018 Apr;198:135-144. doi: 10.1016/j.ahj.2017.12.006. Epub 2017 Dec 24.

• Responsible Party: University of Oxford
• ClinicalTrials.gov Identifier: NCT00135226
• Other Study ID Numbers: CTSUASCEND1; 60635500 ( Registry Identifier: ISRCTN )
• First Posted: August 25, 2005
• Results First Posted: April 26, 2019
• Last Update Posted: December 1, 2022
• Last Verified: November 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Proposals for substudies must be approved by the Steering Committee. Procedures for accessing the data for this study are available on: https://www.ndph.ox.ac.uk/about/data-access-policy.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP)
• Access Criteria: See URL
• URL: https://www.ndph.ox.ac.uk/about/data-access-policy

Keywords provided by University of Oxford:

Diabetes Mellitus; Cardiovascular Disease; Aspirin; Omega-3 fatty acids; Primary prevention; Randomized Controlled Trial; Type 1 Diabetes Mellitus; Type 2 Diabetes Mellitus; n-3 fatty acid

Additional relevant MeSH terms:

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Aspirin; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Molecular Mechanisms of Pharmacological Action; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Enzyme Inhibitors; Antipyretics