Reliable evaluation of associations between Lp-PLA2 markers and the risk of cardiovascular outcomes
Lead Research Organisation:
University of Cambridge
Department Name: Institute of Public Health
Abstract
Heart attacks remain leading causes of death and disability in the UK and worldwide. Controlling known causes of heart disease (such as smoking, high blood pressure and raised cholesterol levels) substantially cuts the risk of disease. This success has encouraged the search for new causes which might further reduce risk, particularly if, like blood cholesterol levels, measuring or changing them can lead to improvements in disease prediction or prevention.
A blood enzyme known as Lp-PLA2 (?lipoprotein-associated phospholipase A2?) may play a direct role in narrowing the heart?s arteries and triggering heart attacks. Several studies have recently reported positive correlations between the amount (or activity) of Lp-PLA2 in the bloodstream and subsequent risk of heart disease. New medicines which almost completely block the activity of Lp-PLA2 (both in circulating blood and in arteries) have recently been invented and are being tested in early trials.
In 2004 the US Food and Drug Administration approved for use a test (known as ?PLAC?) which measures blood levels of Lp-PLA2. But this test has not been widely adopted because it is not yet reliably known whether (or to what extent) Lp-PLA2 measurements can lead to useful improvements in the early detection of heart attacks. It is also not clear to what extent blood levels of Lp-PLA2 are correlated with the future occurrence of heart attacks in different situations, such as in initially healthy adults compared with patients who have a history of heart disease or stroke. Such information is important in planning large trials of Lp-PLA2-inhibiting medicines.
To help provide answers to these and other key questions, we will pool original data from at least 27 long-term medical surveys which have already recorded initial Lp-PLA2 levels in a total of about 75,000 individuals, of whom about 15,000 have developed heart disease or strokes since monitoring. This unique database will encompass almost the entirety of the world?s available epidemiological knowledge on Lp-PLA2 levels and cardiovascular diseases. Analyses of it will rapidly yield precise, comprehensive and reliable findings that will help to determine: (i) whether or not Lp-PLA2 measurement merits incorporation into routine screening tests for heart disease and (ii) the best way to test new Lp-PLA2-inhibiting medicines in large trials (eg, how many people are likely to be required? with what initial characteristics?).
A blood enzyme known as Lp-PLA2 (?lipoprotein-associated phospholipase A2?) may play a direct role in narrowing the heart?s arteries and triggering heart attacks. Several studies have recently reported positive correlations between the amount (or activity) of Lp-PLA2 in the bloodstream and subsequent risk of heart disease. New medicines which almost completely block the activity of Lp-PLA2 (both in circulating blood and in arteries) have recently been invented and are being tested in early trials.
In 2004 the US Food and Drug Administration approved for use a test (known as ?PLAC?) which measures blood levels of Lp-PLA2. But this test has not been widely adopted because it is not yet reliably known whether (or to what extent) Lp-PLA2 measurements can lead to useful improvements in the early detection of heart attacks. It is also not clear to what extent blood levels of Lp-PLA2 are correlated with the future occurrence of heart attacks in different situations, such as in initially healthy adults compared with patients who have a history of heart disease or stroke. Such information is important in planning large trials of Lp-PLA2-inhibiting medicines.
To help provide answers to these and other key questions, we will pool original data from at least 27 long-term medical surveys which have already recorded initial Lp-PLA2 levels in a total of about 75,000 individuals, of whom about 15,000 have developed heart disease or strokes since monitoring. This unique database will encompass almost the entirety of the world?s available epidemiological knowledge on Lp-PLA2 levels and cardiovascular diseases. Analyses of it will rapidly yield precise, comprehensive and reliable findings that will help to determine: (i) whether or not Lp-PLA2 measurement merits incorporation into routine screening tests for heart disease and (ii) the best way to test new Lp-PLA2-inhibiting medicines in large trials (eg, how many people are likely to be required? with what initial characteristics?).
Technical Summary
Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an enzyme that circulates largely bound to low-density lipoprotein (LDL) and lies directly on the pathogenic sequence from localised inflammation to atherosclerotic lesion formation. The potential applications of Lp-PLA2 markers in the prediction and prevention of cardiovascular diseases have already been recognized by development of a US FDA-approved assay for its measurement, and by discovery (and development) of potent Lp-PLA2 inhibitors that lower enzyme activity in plasma and at vascular sites. But, despite publication of a number of studies generally reporting positive associations between Lp-PLA2 markers and cardiovascular outcomes, more detailed epidemiological evidence is needed in order to help determine reliably the relevance of Lp-PLA2 markers to coronary heart disease (CHD) and other vascular outcomes.
We will pool individual participant (ie, primary) data on Lp-PLA2 markers from at least 27 prospective studies, involving about 15,000 incident cardiovascular outcomes and about 60,000 non-cases in a prospectively designed, systematic meta-analysis. The combined database will also comprise at least 5000 individuals with serial Lp-PLA2 measurements and at least 40,000 individuals with measurements of both Lp-PLA2 mass and activity. The main analyses will involve regression models stratified by study and sex; studies provided as prospective cohort studies will be analysed using Cox?s proportional hazards model. Potential sources of diversity in associations between Lp-PLA2 markers and CHD risk will be explored.
Data emerging from this study will reliably: (i) quantify associations between Lp-PLA2 markers and CHD (and other vascular) outcomes under different circumstances (including characterisation of any dose-response relationships); (ii) determine the incremental predictive ability for CHD of these markers; (iii) clarify their distribution and values in various subgroups of the population; (iv) elucidate the degree of Lp-PLA2 biovariability in different situations; and (v) determine how well different Lp-PLA2 markers correlate with one another. These data should have potentially important and immediate clinical applications. There is a need to evaluate the utility of the FDA-approved Lp-PLA2 mass test (ie, the PLAC test produced by diaDexus, Inc) for CHD screening, which has been widely used in the studies contributing to the present collaboration. In addition, Lp-PLA2 is already a therapeutic target for several novel agents, including SB-480848 (a compound which has demonstrated the ability to reduce Lp-PLA2 activity in phase I and II trials), suggesting that these data may help to inform and optimize the design of planned phase III trials of such agents.
We will pool individual participant (ie, primary) data on Lp-PLA2 markers from at least 27 prospective studies, involving about 15,000 incident cardiovascular outcomes and about 60,000 non-cases in a prospectively designed, systematic meta-analysis. The combined database will also comprise at least 5000 individuals with serial Lp-PLA2 measurements and at least 40,000 individuals with measurements of both Lp-PLA2 mass and activity. The main analyses will involve regression models stratified by study and sex; studies provided as prospective cohort studies will be analysed using Cox?s proportional hazards model. Potential sources of diversity in associations between Lp-PLA2 markers and CHD risk will be explored.
Data emerging from this study will reliably: (i) quantify associations between Lp-PLA2 markers and CHD (and other vascular) outcomes under different circumstances (including characterisation of any dose-response relationships); (ii) determine the incremental predictive ability for CHD of these markers; (iii) clarify their distribution and values in various subgroups of the population; (iv) elucidate the degree of Lp-PLA2 biovariability in different situations; and (v) determine how well different Lp-PLA2 markers correlate with one another. These data should have potentially important and immediate clinical applications. There is a need to evaluate the utility of the FDA-approved Lp-PLA2 mass test (ie, the PLAC test produced by diaDexus, Inc) for CHD screening, which has been widely used in the studies contributing to the present collaboration. In addition, Lp-PLA2 is already a therapeutic target for several novel agents, including SB-480848 (a compound which has demonstrated the ability to reduce Lp-PLA2 activity in phase I and II trials), suggesting that these data may help to inform and optimize the design of planned phase III trials of such agents.