Investigating the stratified efficacy and safety of pharmacological blood pressure-lowering: an overall protocol for individual patient-level data meta-analyses of over 300 000 randomised participants in the new phase of the Blood Pressure Lowering Treatment Trialists’ Collaboration (BPLTTC)

Introduction Previous research from the Blood Pressure Lowering Treatment Trialists’ Collaboration (BPLTTC) and others has shown that pharmacological blood pressure (BP)- lowering substantially reduces the risk of major cardiovascular events, including ischaemic heart disease, heart failure and stroke. In this new phase, the aim is to conduct individual patient-level data (IPD) meta-analyses involving eligible BP-lowering randomised controlled trials (RCTs) to address uncertainties relating to efficacy and safety of BP-lowering treatment. Methods and analysis RCTs investigating the effect of pharmacological BP-lowering, with a minimum of 1000 patient-years of follow-up in each trial arm, are eligible. Our systematic review identified 100 potentially eligible trials. We requested their investigators/sponsors to contribute baseline, follow-up and outcomes data. As of June 2018, the collaboration has obtained data from 49 trials (n=315 046 participants), with additional data currently in the process of being transferred from four RCTs (n=34 642 participants). In addition, data harmonisation has commenced. Scientific activities of the collaboration are overseen by the Steering Committee with input from all collaborators. Detailed protocols for individual meta-analyses will be developed and registered on public platforms. Ethics and dissemination Ethics approval has been obtained for this new and extended phase of the BPLTTC, the largest collaboration of de-identified IPD from RCTs. It offers an efficient and ethical manner of re-purposing existing data to answer clinically important questions relating to BP treatment as well as methodological questions relating to IPD meta-analyses. Among the immediate impacts will include reliable quantification of effects of treatment modifiers, such as baseline BP, age and prior disease, on both vascular and non-vascular outcomes. Analyses will further assess the impact of BP-lowering on important, but less well understood, outcomes, such as new-onset diabetes and renal disease. Findings will be published in peer-reviewed medical journals on behalf of the collaboration.


GENERAL COMMENTS
This manuscript describes the impressive recent activity of the Blood Pressure Lowering Treatment Trialists' Collaboration (BPLTTC) that aims to conduct individual patient-level data (IPD) meta-analyses of published BP lowering randomized controlled trials (RCTs) in order to further enhance our understanding of the efficacy and safety of BP lowering treatment. The investigators have already made substantial progress in obtaining data from 49 trials with over 315,000 participants in all. The novelty of this approach is that it will yield sufficient IPD to assess the effects of BP lowering as a whole and also BP lowering with specific drug classes on a large variety of clinical outcomes, including, in addition to major cardiovascular events, new-onset diabetes, peripheral vascular disease, atrial fibrillation, fractures, cancer, cognitive function decline and vascular dementia. The adverse effects of antihypertensive treatment are less well appreciated than the positive effects of BP lowering based on individual trial results; the proposed analysis will fill in the gaps unsatisfied by individual trial results and will have major impact on individual patient management, clinical decision making and antihypertensive treatment guidelines. The organization of the investigation and the quality of the investigators are first rate. There are no major weaknesses in the proposal.

GENERAL COMMENTS
The authors present an overall protocol (not a specific protocol or statistical analysis plan) of their third round of IPD meta-analyses of blood pressure lowering drugs. They present the study selection procedure (which has already been completed), the data collection and management procedures (which are ongoing), and list their three broad categories of primary outcomes, but they do not present detailed statistical analyses. Instead they write "For each of these objectives, at least one study protocol will be developed." The author team has a long tradition of conducting meaningful analyses based on IPD and I have only minor comments.

MINOR BUT ESSENTIAL POINTS
legal issues involved in collecting, managing and analyzing IPD? have access to patient identifiable information, our procedures are fully compliant with the Data Protection Act 1998." But how about the newer regulations such as EU's GDPR? And how about obtaining IPD from non-EU countries? Do they present particular difficulties? contracts team is well aware of legal requirements for data sharing and storage and all our procedures are fully compliant with these requirements." What are "these requirements"? The readers would appreciate more details and difficulties involved in these processes. details of analyses for specific outcomes but intend to write separate protocols for them. Otherwise the readers might assume that paper is such a protocol (as is usually the case for a systematic review protocol). Probably "An overall protocol" instead of simply "A protocol"? the social enterprise arm of The George Institute, has received investment to develop fixed dose combinations of aspirin, statin and blood pressure lowering drugs." Which "blood pressure lowering drugs"? MINOR AND DISCRETIONARY POINTS ded trials would involve many different drugs. Wouldn't the authors like to conduct network metaanalysis, and in particular IPD network meta-analysis, to compare different agents or classes of agents, and also to identify subgroups particularly suited or not-suited for particular agents?
MINOR POINTS policy of the journal.
-IPD as well?

Reviewer(s)' Comments to Author:
Reviewer: 1 Reviewer Name: Suzanne Oparil This manuscript describes the impressive recent activity of the Blood Pressure Lowering Treatment Trialists' Collaboration (BPLTTC) that aims to conduct individual patient-level data (IPD) metaanalyses of published BP lowering randomized controlled trials (RCTs) in order to further enhance our understanding of the efficacy and safety of BP lowering treatment. The investigators have already made substantial progress in obtaining data from 49 trials with over 315,000 participants in all. The novelty of this approach is that it will yield sufficient IPD to assess the effects of BP lowering as a whole and also BP lowering with specific drug classes on a large variety of clinical outcomes, including, in addition to major cardiovascular events, new-onset diabetes, peripheral vascular disease, atrial fibrillation, fractures, cancer, cognitive function decline and vascular dementia. The adverse effects of antihypertensive treatment are less well appreciated than the positive effects of BP lowering based on individual trial results; the proposed analysis will fill in the gaps unsatisfied by individual trial results and will have major impact on individual patient management, clinical decision making and antihypertensive treatment guidelines. The organization of the investigation and the quality of the investigators are first rate. There are no major weaknesses in the proposal.
Many thanks for appreciating the importance of the research aims and study design of the BPLTTC.

Reviewer: 2
Reviewer Name: Toshi A. Furukawa The authors present an overall protocol (not a specific protocol or statistical analysis plan) of their third round of IPD meta-analyses of blood pressure lowering drugs. They present the study selection procedure (which has already been completed), the data collection and management procedures (which are ongoing), and list their three broad categories of primary outcomes, but they do not present detailed statistical analyses. Instead they write "For each of these objectives, at least one study protocol will be developed." The author team has a long tradition of conducting meaningful analyses based on IPD and I have only minor comments.

MINOR BUT ESSENTIAL POINTS
Could the authors present more details about the ethical and legal issues involved in collecting, managing and analyzing IPD? Details about the governance, process of requesting data from data providers including information on the collection, handling, storage and analysis of the data are described in the protocol (page 7-9). We do not see any ethical issue (and we have obtained approval from the Institutional Review Board as described in the text on page 10, last paragraph). Data providers and the University of Oxford sign up to a Data Transfer Agreement which describes the conditions associated with the data transfer, storage and use by the Collaboration.
The authors write, "As we do not have access to patient identifiable information, our procedures are fully compliant with the Data Protection Act 1998." But how about the newer regulations such as EU's GDPR? And how about obtaining IPD from non-EU countries? Do they present particular difficulties?
The data that we receive from our collaborators are 'anonymised', therefore, not subject to GDPR (https://gdpr-info.eu/). The Data Transfer Agreement we have put in place required data providers to ensure that the data they share with us are anonymised and that the BPLTTC/analytic team at Oxford will not attempt to trace or identify any study participant. In this agreement, the data provider 'warrants that data have been obtained with the full consent and knowledge of the individual, including in respect of the proposed use and processing under and as envisaged by the agreement.' It is highly improbably that we can identify patients from the datasets we receive as we do not have access to the original data or linkage code.
We apply the same principles in our Data Transfer Agreement with investigators/data providers across EU and non-EU trials. We have not seen any difficulty in involving non-EU trials into the Collaboration. The more relevant issue usually involves tracing investigators or data custodians who are either deceased or whose contact details (e.g. email address no longer works) have changed. If the reviewer could put us in touch with some of the investigators or data custodians of trials whom we could not trace, we would greatly appreciate it.
The authors also write, "The University of Oxford's research contracts team is well aware of legal requirements for data sharing and storage and all our procedures are fully compliant with these requirements." What are "these requirements"? The readers would appreciate more details and difficulties involved in these processes.
The conduct of research at University of Oxford involves compliance to code of practice and procedures (https://researchsupport.admin.ox.ac.uk/governance/integrity) and to policies around research data handling and management (http://researchdata.ox.ac.uk/). To obtain further details about these policies and procedures, we now have added these website addresses in the text (page 10, last paragraph). Some difficulties we encounter would involve data providers or custodians who are not willing to share data with us.
The title should reflect the fact that the authors do not report details of analyses for specific outcomes but intend to write separate protocols for them. Otherwise the readers might assume that paper is such a protocol (as is usually the case for a systematic review protocol).
Probably "An overall protocol" instead of simply "A protocol"?
Many thanks for this suggestion. We have now modified the title as suggested to reflect the nature of this research protocol.
In COI statement, the authors write, "George Health Enterprises, the social enterprise arm of The George Institute, has received investment to develop fixed dose combinations of aspirin, statin and blood pressure lowering drugs." Which "blood pressure lowering drugs"? These drugs are a combination of generic blood pressure-lowering agents. We also updated and expanded the COI statement to reflect current status: "George Health Enterprises has submitted patents for low-dose blood pressure combinations on which AR is listed as one of the inventors. AR does not have a financial interest in these planned products." MINOR AND DISCRETIONARY POINTS I would assume that the included trials would involve many different drugs. Wouldn't the authors like to conduct network meta-analysis, and in particular IPD network meta-analysis, to compare different agents or classes of agents, and also to identify subgroups particularly suited or not-suited for particular agents?
This suggestion is very helpful. Network meta-analyses have largely been applied on aggregate data, but there are indeed methods for conducting IPD network meta-analyses. We will consider this approach as one of the possible analytical tools we could use. We now have mentioned this in the statistical analysis section.

MINOR POINTS
I don't seem to find the dates of the study, as required by the policy of the journal.
If the reviewer meant the dates of trials that we will consider in the meta-analyses, we are covering all studies from 1 January 1966 to 1 June 2018 (Page 6, middle paragraph). The conduct of the study, which has already begun, is dependent on available resources to achieve the proposed investigations. We therefore could not define when the current phase of the Collaboration will finish. Moreover, members of the Collaboration could propose new research projects which are beyond the scope the current project. In any case, each of these proposed investigations will require development and submission of a protocol with proposed timelines to aim for.
Perhaps the authors need to report the checklists for PRISMA-IPD as well We plan to report PRISMA-IPD when reporting the protocol for each planned investigation.

REVIEWER
Toshi Furukawa Kyoto University, Japan TAF reports personal fees from Meiji, Mitsubishi-Tanabe, MSD and Pfizer and a grant from Mitsubishi-Tanabe; TAF has a patent 2018-177688 pending.

GENERAL COMMENTS
The authors have responded adequately to all my comments.