Hypertension is becoming more prevalent in women particularly in older age, with evidence that indicates more women die from cardiovascular disease than men in these age group. Some studies suggested noticeable differences in the patterns and trends of, and the impact of some risk factors on, the onset of cardiovascular disease between women and men. While blood pressure-lowering with antihypertensive drugs are effective in reducing cardiovascular disease risk in both women and men, detailed comparsions between the sexes on the effects of blood pressure-lowering treatment and of specific antihypertensive drug classes on cardiovascular disease is less investigated. Existing evidence based on tabular meta-analyses is limited as such studies are unable stratify by sex at an individual level. We aim to investigate the effects of pharmacological blood pressure-lowering on cardiovascular disease risk, and compare the effects of different antihypertensive drug classes on this risk between women and men.
Blood pressure-lowering is an established strategy for preventing micro-and macrovascular events in people with type 2 diabetes but its role in the prevention of diabetes itself is unclear. 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. We will conduct an individual participant meta-analysis of randomised controlled trials of blood pressure-lowering drug treatment effects on subsequent risk of type 2 diabetes. Then, we will complement this planned analysis with Mendelian randomisation experiments by using genetic variants associated with blood pressure and those associated with genes that encode the therapeutic target of each antihypertensive drug class as instruments in the analysis.
Blood pressure-lowering is an established strategy for preventing micro-and macrovascular events in people with type 2 diabetes but it remains unclear if there are treatment thresholds that should be considered nor there are differential effects across antihypertensive drug classes. Single trials may not have the statistical power to address these questions reliably, and aggregate meta-analyses are unable to stratify the analysis according to type 2 diabetes history. In this project, we will conduct an individual participant-level meta-analysis of trials on blood pressure-lowering treatment for the prevention of cardiovascular disease in people with and without type 2 diabetes, and examine these results across a wide range of baseline blood pressure levels. Moreover, we will compare any variation in the effects by antihypertensive drug classess in these participant subgroups.
The third cycle of the BPLTTC offers an opportunity to investigate, in more detail, the effects of pharmacologic lowering on long-term blood pressure across a number of patient groups. 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 long-term blood pressure overall and across patient subgroups, and to quantify these effects using different methods that include simply comparing blood pressure difference between treatment arms to methods that also account for between and within-person variability.
The evidence for the benefits of antihypertensive medication in the reduction of cardiovascular disease is clear, some studies raised the possibility of some adverse effects, such as the risk of developing cancer. There is no clear mechanism why we expect to see this increase in risk, as the hypothesised pathway is linked to the drug class (addressed in the project below) but not on BP-lowering effects. However, these suggested associations have been based on observational studies, hence, we examine this association using randomised evidence of BP-lowering trials.
Several guidelines, including the 2017 American College of Cardiology (ACC)/American Heart Association (AHA) BP guideline and the 2018 European Society of Hypertension/European Society of Cardiology BP guideline, recommend measuring BP outside of the office setting and withholding the initiation and intensification of antihypertensive medication among those with white coat hypertension and white coat effect, respectively, and initiating and intensifying treatment among those with masked hypertension and masked uncontrolled hypertension, respectively. However, there are no data from large randomized outcomes trials testing whether initiating antihypertensive medication among adults with white coat hypertension and masked hypertension and intensifying treatment among those with white coat effect and masked uncontrolled hypertension reduces the risk for cardiovascular disease (CVD) or all-cause mortality. Adopting a published algorithm to define hypertension phenotypes, we will investigate these questions using the BPLTTC resource
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 and disease, and examine any differential effects by drug class and baseline blood pressure. 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.
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.
There have been observations that both low and high blood pressure may be associated with higher risk of peripheral vascular disease, particularly those involving lower extremities. Other have suggested that use of antihypertensive drugs may worsen existing leg ischaemia in people with known peripheral artery disease. Large-scale trials to examine the effects of pharmacologic lowering of blood pressure in those with and without this vascular condition is limted. This project wil examine the effects of blood pressure-lowering treatment on subsequent risk of peripheral vascular disease in people with and without this condition at baseline.
It has been observed that hypertension is associated with some level of impairment of cognitive function. It has been hypothesised that elevated blood pressure contributes to ischaemic damage of cerebral tissues particularly white matter regions that play a role in cognitive function. Over time, persistently elevated blood pressure may promote cognitive decline and increase the risk of dementia. Many of these studies have been based on observational studies, and evidence from intervention trials are limited and show conflicting results. To harness the strength of the collaboration, we will pool data across several trials with relevant data, and address questions on the impact of blood pressure-lowering treatment on cognitive function and risk of dementia.
Antihypertensive drug classes are thought to be similarly effective in lowering BP, but differences in their effects on the degree of dispersion of BP readings at follow-up visits suggest that some drug classes may control elevated blood pressure more effectively at higher levels than at lower levels of baseline blood pressure, thereby reducing dispersion, whereas others lower BP independently of baseline level, leaving dispersion unchanged. We will explore the class-specific effects on various indices of blood pressure dispersion and the dependence of reductions in dispersions on mean and maximum blood pressure level at baseline.
Antihypertensive drugs are effective in reducing blood pressure and consequently reduce the risk of cardiovascular disease. Others have also suggested that intra-individual variability in blood pressure is predictive of adverse cardiovascular outcomes. However, there is limited randomised evidence on the impact of antihypertensive treatment on blood pressure variability, and how this variability could influence subsequent cardiovascular disease risk. This investigation will answer these questions, and explore the consistency of these effects in people with different characteristics as defined by their age, sex and other factors.
As previously indicated, atrial fibrillation (AF) is the most common clinically significant cardiac arrhythmia and its incidence and prevalence are rising globally. 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.
Decisions to initiate pharmacotherapy to lower blood pressure has been commonly based on baseline blood pressure level reaching a certain threshold, typically, 140 mmHg systolic and/or 90 diastolic blood pressure or higher. Recent findings from this collaboration showed that the relative reduction in cardiovascular risk is consistent across baseline levels, even at systolic blood pressure below 120 mmHg. It is unclear if treatment should be given to all even in this group which tend to have a low level of absolute cardiovascular disease risk. Earlier findings from the collaboration have also shown that an alternative, and potentially more effective, approach would be to assess predicted cardiovascular risk at baseline to guide treatment decisions. As the collaboration has currently accumulated a greater number of participants and cardiovascular events, we plan to investigate the relative and absolute effects of blood pressure reduction according to predicted cardovascular risk at baseline, and compare these effects based baseline blood pressure levels.
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.
With > 360,000 participants included in the 52 collaborating trials, 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 (European Lacidipine Sudy on Atherosclerosis) 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) HDFP (Hypertension Detection Follow-up Program) 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 Intervention Trial) PREVENT (Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial) PROFESS (Prevention Regimen for Efectively Avoiding Second Strokes) Perindopril Protection Against Recurrent Stroke Study) 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)
Blood Pressure Lowering Treatment Trialists’ Collaboration.
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Emma Copland, Dexter Canoy, Milad Nazarzadeh, Zeinab Bidel, Rema Ramakrishnan, Mark Woodward, John Chalmers, Koon K Teo, Carl J Pepine, Barry R Davis, Sverre Kjeldsen, Johan Sundström, Kazem Rahimi; Blood Pressure Lowering Treatment Trialists’ Collaboration.
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