Comparative effectiveness and safety of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on the risk of major cardiovascular events, cancer and renal outcomes

Date of ISAC Approval: 
Lay Summary: 
High blood pressure affects more than 1 in 4 adults in the UK, increasing the risk of premature death and illness due to its effects on several body organs, including the, heart and kidneys. Despite these risks, control of blood pressure generally remains suboptimal and individuals will require medication (antihypertensives) to lower blood pressure. Most guidelines recommend starting treatment with the antihypertensive drug, angiotensin-converting enzyme inhibitors (ACEIs), with angiotensin II receptor blockers (ARBs) considered as the alternative antihypertensive therapy if patients are not able to take ACEIs. Although these two types of antihypertensive medication are often considered equivalent by clinicians, there have been concerns regarding the safety of these medications. In comparative clinical trials, ACEIs were shown to reduce death from any cause and deaths due to heart disease whilst ARBs had no effect on reducing death. There are also reports that ACEIs may increase the risk of specific types of cancer. We will investigate the relationship between the use of ACEIs and ARBs and serious outcomes, including, heart disease, cancer, renal disease and death.
Technical Summary: 
Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) are widely used in the treatment of hypertension and heart failure, with the two medications deemed to be interchangeable when one class is not tolerated. However, debate has been raised regarding whether these drug classes are similarly effective, with indications of different adverse events associated with each class. Following a clinical trial in 2004, controversy surrounded the use of ARBs as it appeared to increase the risk of myocardial infarction among people with hypertension. Since then, numerous studies have tried to assess the safety of ACEIs relative to ARBs and have produced inconsistent results for cardiovascular risk and mortality. Similarly, there are conflicting reports from recent studies and meta-analyses on cancer risk associated with both drugs. Both agents have demonstrated renoprotective effects; however it is unclear if these agents offer similar benefits or if one agent is superior. As ARBs entered the market much later than ACEIs, patient profiles of those in ARB and ACEI trials were very different, with changes in primary and secondary prevention strategies occurring over that period. Therefore, it is of importance to establish and directly compare the safety of these drugs in contemporary, clinical practice with longer-term follow-up. Data will be obtained from CPRD GOLD and Aurum, with a common protocol applied across the databases for cohort construction and analysis. The study populations will consist of any individual initiating an ACEI or ARB between 01/01/1998-31/05/2018, with follow-up until 30/11/2018. Hazard ratios for the outcomes of interest among patients receiving ACEIs, as compared with those receiving ARBs, will be estimated from Cox regression models and the data from the separate study cohorts will be meta-analysed with the use of random-effects models. All analyses will be replicated in a cohort of people with type 2 diabetes.
Health Outcomes to be Measured: 
Outcome1 - Cardiovascular - 3-point major adverse cardiovascular events (MACE): myocardial infarction/acute coronary syndrome, stroke/transient ischaemic attack and cardiovascular death - 4-point MACE: unstable angina, myocardial infarction/acute coronary syndrome, stroke/transient ischaemic attack, and cardiovascular death - Myocardial infarction - Stroke - Heart failure and heart failure hospitalisation Outcome 2 - Cancer (site-specific) - Cancer incidence - Cancer mortality Outcome 3 - Death - Cause-specific mortality Outcome 4 - Renal - Renal disease: chronic kidney disease stage 3 and above, nephritis, nephritic syndrome, nephropathy - End stage renal disease including dialysis and renal transplantation: chronic kidney disease stage 5, renal failure, dialysis and/or renal transplantation Outcome 5 - Negative control outcomes - Fracture - Serious/major gastrointestinal (GI) bleeds

Professor Darren Ashcroft - Chief Investigator - University of Manchester
Alison Wright - Corresponding Applicant - University of Manchester
Dr Ireny Iskandar - Collaborator - University of Manchester
Martin Rutter - Collaborator - University of Manchester
Dr Matthew Carr - Collaborator - University of Manchester
Professor Naveed A. Sattar - Collaborator - University of Glasgow
Salwa Zghebi - Collaborator - University of Manchester
Professor Tjeerd van Staa - Collaborator - University of Manchester

HES Admitted;ONS;Patient IMD;Practice IMD (Standard)