BPLTTC

Blood Pressure Lowering Treatment Trialists' Collaboration







Background

The Blood Pressure Lowering Treatment Trialists Collaboration (BPLTTC) was initiated in 1995 as a collaboration between the Principal Investigators of all the major ongoing clinical trials of blood pressure-lowering agents at the time. The first cycle of analyses included 15 trials and over 74,000 individuals. There 14 trials that were added in the second cycle, which included over 162,000 individual participants in total. These phases in the collaboration were successful in providing reliable evidence for the benefits of blood pressure-lowering for the prevention of major cardiovascular outcomes. In 2014, the BPLTTC was extended and new trialists were invited to join the collaboration. The third and current phase of the collaboration now includes over 350,000 individuals from 50 trials. This resource offers an unprecedented opportunity to clarify uncertainties in blood pressure lowering treatment and provide clinically relevant findings in specific patient subgroups.

GOVERNANCE

The current cycle of the BPLTTC is coordinated by The George Institute for Global Health UK at Oxford University. Its work is governed by a Steering Committee consisting of select Principal Investigators of some of the largest trials included in the BPLTTC and chaired by Kazem Rahimi, Deputy Director of The George Institute UK. The Steering Committee is responsible for general oversight of the BPLTTC and providing scientific leadership regarding all aspects of proposal development, analysis, interpretation and reporting. A wide network of collaborators contributes to all scientific activities and debates.

Funding

The BPLTTC was initially supported by grants from the pharmaceutical industry, including Astra Hassle AB, Bayer AG, Bristol-Myers Squibb Company, Glaxo Wellcome, Hoechst Marion Roussel, Knoll AG, Merck and Company, Pfizer Inc., Searle and Institut de Recherches Internationales Servier, as well as the British Heart Foundation. Since 2005, BPLTTC has not been funded by the pharmaceutical industry and has only been supported by peer reviewed sources, such as the National Health and Medical Research Council of Australia and the UK National Institute for Health Research. In October 2018, the BPLTTC was awarded over £150,000 from the British Heart Foundation to investigate the stratified efficacy and safety of pharmacological blood pressure-lowering.

Projects

Effects of blood pressure-lowering treatment on risk of cardiovascular disease in patients with chronic kidney disease

Status: Protocol development
8 May 2019

Hypertension is a major risk factor for the development and progression of chronic kidney disease (CKD), irrespective of the underlying cause. Recent aggregate-data meta-analyses have provided conflicting evidence on the effects of BP-lowering treatment in patients with CKD. Therefore, the impact of BP reduction on progression of CKD and prevention of cardiovascular events remains uncertain. Furthermore, whether reducing albuminuria could be a proxy for prevention of cardiovascular disease also remains controversial. There is also limited evidence suggesting that some drug classes may afford greater cardiovascular protection and reduction of proteinuria. This project aims to investigate the effects of BP reduction in patients with CKD overall and stratified by drug class. The interaction of treatment with albuminuria/proteinuria will also be investigated.

Effects of blood pressure-lowering treatment on renal function overall, by drug class and by baseline BP

Status: Protocol development
8 May 2019

As BP lowering reduces renal perfusion pressure, it is expected and not unusual for estimated glomerular filtration rate to decrease by 10 to 20% in patients treated for hypertension. Although this decline is usually limited to the first few weeks of treatment and stabilizes thereafter, concerns about potentially increased risk of renal impairment and eventual progression to renal failure often limit BP lowering treatment. Therefore, this project aims to investigate the effects of BP-lowering treatment on renal function overall and stratified by drug classes and baseline BP. The interaction with baseline comorbidities including chronic kidney disease, diabetes and cardiovascular disease will also be investigated and subgroup analysis performed if significant interactions are found.

Proportional effects of blood pressure-lowering treatment on serious vascular events by blood pressure level, age and disease status at baseline

Status: Protocol development
16 November 2018

The largest tabular meta-analysis of blood pressure-lowering trials has recently suggested similar proportional benefits of blood pressure-lowering at different baseline trial-level blood pressure for a range of cardiovascular outcomes, but it is unclear if the benefits are consistently observed across patient subgroups. Furthermore, tabular meta-analyses are unable stratify by baseline blood pressure at an individual level and to control for competing events. A detailed individual patient data meta-analysis will provide a more in-depth examination of blood pressure-lowering at different baseline levels, the impact on blood pressure changes, and the different proportional effects on major cardiovascular outcomes (coronary heart disease, stroke and heart failure). This approach will also help ascertain whether or not certain drug classes have particularly strong beneficial or adverse effects in specific patient subgroups.

Risk of total serious adverse events and other unintended consequences of pharmacologic lowering of blood pressure

Status: Protocol development
6 November 2018

Currently, there is limited or conflicting evidence about the effect of blood pressure-lowering on outcomes such as dementia, renal failure, cancer, falls, fractures and other serious adverse events. Some blood pressure-lowering trials have reported that more intensive blood pressure treatment is associated with a higher risk of serious adverse events compared with less intensive regimens. However, this association has not been investigated in detail across the whole spectrum of baseline blood pressures levels or in different patient subgroups. This project will classify serious adverse events across different trials and investigate the unintended consequences of blood pressure-lowering stratified by important patient characteristics.

The effect of blood pressure-lowering drugs and drug-drug interactions on the risk of new onset diabetes

Status: Protocol development
7 December 2018

Previous studies of effects of different classes of blood pressure-lowering drugs on risk of diabetes have reported contradictory findings. Some have reported that beta-blockers and thiazide diuretics increased the risk, while renin-angiotensin system inhibitors decreased the risk of diabetes. However, limited sample size of studies based on an individual trial may make their findings unreliable. In this project, we aim to provide robust evidence on the effect of blood pressure-lowering drugs overall and by drug classes on risk of incident diabetes.

Investigating the effects of blood pressure-lowering treatment on atrial fibrillation

Status: Protocol development
28 November 2018

Atrial fibrillation (AF) is the most common clinically significant cardiac arrhythmia and its incidence and prevalence are on the rise across the globe, fuelled by population ageing and other cardiometabolic risk factors. AF is associated with an increased risk of fatal and nonfatal cardiovascular events, particularly stroke. Although hypertension doubles the risk of developing AF, there is uncertainty around whether antihypertensive treatment can effectively reduce the risk of AF. This project aims to understand the effects of antihypertensive drugs on new-onset and recurrent AF. Hypertension is also very common in patients with AF. However, evidence demonstrating the impact of blood pressure-lowering treatment in patients with AF on cardiovascular events remains limited. Therefore, this project will also compare the effects of antihypertensive treatment in patients with and without AF at baseline.

Efficacy and safety of blood pressure-lowering treatment in patients with multiple comorbidities

Status: Protocol development
28 November 2018

Multimorbidity, defined as the presence of two or more diseases in the same patient, is a growing epidemic worldwide and it is also increasingly common in patients with cardiovascular disease. However, such patients have been typically excluded or underrepresented in clinical studies, and hence the balance of harms and benefits of blood pressure-lowering treatment in patients with multiple comorbidities remains poorly understood. Therefore, this project aims to investigate whether the efficacy and safety of antihypertensive treatment varies by number and ‘clusters’ of baseline comorbidities. Combining the large number of trials included in BPLTTC will allow overcoming the lack of power of individual trials to perform multiple subgroup analyses.

Effects of pharmacologic treatment to lower blood pressure on subsequent onset of fractures

Status: Protocol development
21 December 2018

Some observational analyses have suggested that initiation of blood pressure lowering therapy is associated with an increased risk of fractures. However, these analyses are susceptible to confounding (sicker elderly patients being initiated on BP lowering medication). In contrast, an analysis of HYVET indicated that BP lowering in the elderly reduced the rate of fractures. An IPD meta-analysis will investigate the long-term effect of antihypertensive therapy on falls/fractures in more detail.

More than 350,000 patients

With > 350,000 patients included in the collaboration, the BPLTTC is the largest single data resource of individual patient-level randomized clinical trial data.

Contributing Trials

AASK (African American Study of Kidney Disease and Hypertension)
ABCD (Appropriate Blood Pressure Control in Diabetes Trial) [Normotensive cohort]
ACCORD (Action to Control Cardiovascular Risk in Diabetes)
ACTIVE I (Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events)
ADVANCE (Action in Diabetes and Vascular Disease)
ALLHAT (Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attacks Trial)
ANBP (The Australian National Blood Pressure Study)
ANBP2 (Second Australian National Blood Pressure Study)
ASCOT-BPLA (Anglo-Scandinavian Cardiac Outcomes Trial - Blood Pressure Lowering Arm)
BENEDICT (Bergamo Nephrologic Diabetes Complications Trial)
CAMELOT (The Comparison of Amlodipine vs Enalapril to Limit Occurrences of Thrombosis)
CAPPP (Captopril Prevention Project)
CARDIO-SIS (CARDIOvascolari del Controllo della Pressione Arteriosa SIStolica)
CASE-J (Candesartan Antihypertensive Survival Evaluation in Japan)
COLM (Combination of OLMesartan and calcium channel blocker or diuretic)
CONVINCE (Controlled Onset Verapamil Investigation of Cardiovascular End Points)
COPE (Combination Therapy of Hypertension to Prevent Cardiovascular Events)
DIABHYCAR (Non-insulin-dependent diabetes, hypertension, microalbuminuria or proteinuria, cardiovascular events, and ramipril)
Dutch-TIA (Dutch Transient Ischemic Attack Trial)
ECOST (Efficacy of Candesartan on Outcome in Saitama Trial)
ELSA (Efficacy of Candesartan on Outcome in Saitama Trial)
EUROPA (European trial on reduction of cardiac events with perindopril in stable coronary artery)
EWPHE (European Working Party on High Blood Pressure in the Elderly)
HIJ-CREATE (Heart Institute of Japan Candesartan Randomized Trial for Evaluation in Coronary Heart Disease)
HOMED-BP (Hypertension Objective Treatment based on Measurement by Electrical Devices of Blood Pressure Study)

HOPE (Heart Outcomes Prevention Evaluation Study)
HYVET (Hypertension in the Very Elderly Trial)
IDNT (Irbesartan Diabetic Nephropathy Trial)
INSIGHT (International Nifedipine GITS Study: Intervention as a Goal for Hypertension Therapy)
INVEST (International Verapamil-Trandolapril Study)
JMIC-B (Japan Multicenter Investigation for Cardiovascular Diseases-B)
LIFE (Losartan Intervention for Endpoint Reduction in Hypertension Study)
MOSES (Morbidity and Mortality After Stroke, Eprosartan Compared With Nitrendipine for Secondary Prevention)
NICS-EH (National Intervention Cooperative Study in Elderly Hypertensives)
NORDIL (Nordic Diltiazem Study)
ONTARGET (Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial)
PART-2 (Prevention of Atherosclerosis with Ramipril Trial)
PEACE (Prevention of Events with Angiotensin Converting Enzyme Inhibition)
PREVEND-IT (Prevention of Renal and Vascular Endstage Disease)
PREVENT (Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial)
PROGRESS (Perindopril Protection Against Recurrent Stroke Study)
SHEP (Systolic Hypertension in the Elderly Program)
SPRINT (Systolic Blood Pressure Intervention Trial)
STOP Hypertension-2 (Swedish Trial in Old Patients with Hypertension-2)
Syst-Eur (Systolic Hypertension in Europe)
TRANSCEND (Telmisartan Randomised Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease)
UKPDS (UK Prospective Diabetes Study)
VALISH (Valsartan in Elderly Isolated Systolic Hypertension Study)
VALUE (Valsartan Antihypertensive Long-Term Use Evaluation)
VHAS (Verapamil in Hypertension and Atherosclerosis Study)

Steering Committee

Barry Davis

University of Texas
School of Public Health
USA

Carl J. Pepine

Department of Medicine
University of Florida
USA

John Chalmers

The George Institute for Global Health
University of New South Wales
Australia

Koon Teo

Population Health Research Institute
McMaster University
Canada

Kazem Rahimi (Chair)

The George Institute for Global Health
University of Oxford
UK

Publications

Effects of blood pressure lowering on cardiovascular events, in the context of regression to the mean: a systematic review of randomized trials

Salam A, Atkins E, Sundström J, Hirakawa Y, Ettehad D, Emdin C, Neal B, Woodward M, Chalmers J, Berge E, Yusuf S, Rahimi K, Rodgers A; Blood Pressure Lowering Treatment Trialists’ Collaboration
J Hypertens 2019, 37(1)16-23. doi: 10.1097/HJH.0000000000001994.

Blood pressure-lowering treatment strategies based on cardiovascular risk versus blood pressure: A meta-analysis of individual participant data

Blood Pressure Lowering Treatment Trialists' Collaboration., Kunal N. Karmali, Donald M. Lloyd-Jones, Joep van der Leeuw, David C. Goff Jr., Salim Yusuf, Alberto Zanchetti, Paul Glasziou, Rodney Jackson, Mark Woodward, Anthony Rodgers, Bruce C. Neal, Eivind Berge, Koon Teo
PLoS Med 2018, 15(3): e1002538. doi: 10.1371/journal.pmed.1002538

Effects of blood pressure lowering on cardiovascular risk according to baseline body-mass index: a meta-analysis of randomised trials.

Blood Pressure Lowering Treatment Trialists' Collaboration., Ying A, Arima H, Czernichow S, Woodward M, Huxley R, Turnbull F, Perkovic V, Neal B.
Lancet. 2015 Mar 7;385(9971):867-74. doi: 10.1016/S0140-6736(14)61171-5.

Blood pressure-lowering treatment based on cardiovascular risk: a meta-analysis of individual patient data.

Blood Pressure Lowering Treatment Trialists' Collaboration., Sundström J, Arima H, Woodward M, Jackson R, Karmali K, Lloyd-Jones D, Baigent C, Emberson J, Rahimi K, MacMahon S, Patel A, Perkovic V, Turnbull F, Neal B.
Lancet. 2014 Aug 16;384(9943):591-8. doi: 10.1016/S0140-6736(14)61212-5.

Authors' reply to Ladapo and Ogedegbe.

Ninomiya T, Perkovic V; Blood Pressure Lowering Treatment Trialists’ Collaboration.
BMJ. 2014 Jan 15;348:g148. doi: 10.1136/bmj.g148. No abstract available.

Blood pressure lowering and major cardiovascular events in people with and without chronic kidney disease: meta-analysis of randomised controlled trials.

Blood Pressure Lowering Treatment Trialists' Collaboration., Ninomiya T, Perkovic V, Turnbull F, Neal B, Barzi F, Cass A, Baigent C, Chalmers J, Li N, Woodward M, MacMahon S.
BMJ. 2013 Oct 3;347:f5680. doi: 10.1136/bmj.f5680. Review.

The effects of blood pressure reduction and of different blood pressure-lowering regimens on major cardiovascular events according to baseline blood pressure: meta-analysis of randomized trials.

Czernichow S, Zanchetti A, Turnbull F, Barzi F, Ninomiya T, Kengne AP, Lambers Heerspink HJ, Perkovic V, Huxley R, Arima H, Patel A, Chalmers J, Woodward M, MacMahon S, Neal B; Blood Pressure Lowering Treatment Trialists' Collaboration.
J Hypertens. 2011 Jan;29(1):4-16. doi: 10.1097/HJH.0b013e32834000be.

Do men and women respond differently to blood pressure-lowering treatment? Results of prospectively designed overviews of randomized trials.

Turnbull F, Woodward M, Neal B, Barzi F, Ninomiya T, Chalmers J, Perkovic V, Li N, MacMahon S; Blood Pressure Lowering Treatment Trialists' Collaboration.
Eur Heart J. 2008 Nov;29(21):2669-80. doi: 10.1093/eurheartj/ehn427. Epub 2008 Oct 13. Review.

Effects of different regimens to lower blood pressure on major cardiovascular events in older and younger adults: meta-analysis of randomised trials.

Blood Pressure Lowering Treatment Trialists' Collaboration., Turnbull F, Neal B, Ninomiya T, Algert C, Arima H, Barzi F, Bulpitt C, Chalmers J, Fagard R, Gleason A, Heritier S, Li N, Perkovic V, Woodward M, MacMahon S.
BMJ. 2008 May 17;336(7653):1121-3. doi: 10.1136/bmj.39548.738368.BE. Epub 2008 May 14. Review.

Blood pressure-dependent and independent effects of agents that inhibit the renin-angiotensin system.

Blood Pressure Lowering Treatment Trialists' Collaboration., Turnbull F, Neal B, Pfeffer M, Kostis J, Algert C, Woodward M, Chalmers J, Zanchetti A, MacMahon S.
J Hypertens. 2007 May;25(5):951-8. Erratum in: J Hypertens. 2007 Jul;25(7):1524.

Effects of different blood pressure-lowering regimens on major cardiovascular events in individuals with and without diabetes mellitus: results of prospectively designed overviews of randomized trials.

Turnbull F, Neal B, Algert C, Chalmers J, Chapman N, Cutler J, Woodward M, MacMahon S; Blood Pressure Lowering Treatment Trialists' Collaboration.
Arch Intern Med. 2005 Jun 27;165(12):1410-9.

Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials.

Turnbull F; Blood Pressure Lowering Treatment Trialists' Collaboration.
Lancet. 2003 Nov 8;362(9395):1527-35.