While the evidence for the benefits of antihypertensive medication in the reduction of cardiovascular disease is well-established, concerns have been raised about possible unintended consequences in the use of these drugs, including increasing the risk of developing cancer. It seems unlikely that blood pressure reduction per se increases the risk of cancer. However, several hypotheses have been posited linking the pathways of specific drug classes to cancer, including the blockade of angiotensin II receptors by ARBs which could increase cell proliferation, angiogenesis and tumour progression, and the photosensitising properties of thiazide diuretics that could increase skin cancer susceptibility. Findings from the literature have been inconsistent, and evidence from existing trials and their meta-analyses have been limited as it is possible that such investigations lacked statistical power to investigate cancer incidence due to small numbers of events. In the third cycle of the BPLTTC, cancer outcomes have been requested from the collaborators, providing a large number of cancer outcomes that were not published before. In this proposed study, we plan to investigate the effect of using specific classes of blood pressure-lowering treatments on the risk of cancer.
The third cycle of the BPLTTC provides the largest individual patient-level data on blood pressure-lowering trials to date. It offers an opportunity to investigate, in more detail, the effects of pharmacologic lowering of blood pressure across a number of patient groups and a range of outcomes. Considering the differences in follow-up duration across trials and the diversity in the patient populations being studies, the approach taken for standardisation of treatment effects might be relevant particularly in understanding overall and subgroup findings. Futher, the frequency of remeasurements of blood pressure vary across trials, which raises questions around comparability of blood pressure differences across the trials. We plan to obtain precise estimation of the effect of blood pressure-lowering treatment on changes in long-term blood pressure overall and across patient subgroups, and to quantify these effects on blood pressure using different methods that include simply comparing blood pressure difference between treatment arms to methods that also account for between, and within-person variability.
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.
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.
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.
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.
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.
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.
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.
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.
With > 350,000 patients included in the collaboration, the BPLTTC is the largest single data resource of individual patient-level randomized clinical trial data.
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)
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