Prediction of Myocardial Infarction by N-Terminal-Pro-B-Type Natriuretic Peptide, C-Reactive Protein, and Renin in Subjects With Cerebrovasc
http://www.100md.com
《循环学杂志》
St Vincent’s Institute of Medical Research (D.J.C., B.E.K.) and Department of Medicine (D.J.C., A.J.J., B.E.K.)
University of Melbourne, St Vincent’s Hospital, Fitzroy, Victoria; CSIRO Health Sciences and Nutrition (B.E.K.)
Parkville, Victoria; and The George Institute for International Health (M.W., J.P.C., S.A.C., B.C.N., A.P., S.W.M.)
University of Sydney, Camperdown, New South Wales, Australia.
Abstract
Background— B-type natriuretic peptide (BNP), C-reactive protein (CRP), and renin are elevated in persons at risk for cardiovascular disease. However, data that directly compare these markers in the prediction of myocardial infarction (MI) are limited.
Methods and Results— N-terminal-proBNP (NT-proBNP), CRP, and renin were measured in baseline blood samples from a nested case-control study of the 6105 participants of the Perindopril Protection Against Recurrent Stroke Study (PROGRESS), a placebo-controlled study of a perindopril-based blood pressure-lowering regimen among individuals with previous stroke or transient ischemic attack. Each of 206 subjects who experienced MI, either fatal or nonfatal, during a mean follow-up of 3.9 years was matched to 1 to 3 control subjects. Most MI cases (67%) occurred in subjects without a history of coronary heart disease. NT-proBNP, CRP, and renin each predicted MI; the odds ratio for subjects in the highest compared with the lowest quarter was 2.2 (95% CI, 1.3 to 3.6) for NT-proBNP, 2.2 (95% CI, 1.3 to 3.6) for CRP, and 1.7 (95% CI, 1.1 to 2.8) for renin. NT-proBNP and renin, but not CRP, remained predictors of MI after adjustment for all other predictors, including LDL and HDL cholesterol levels. Individuals with both NT-proBNP and renin in their highest quarters had 4.5 times the risk of MI compared with subjects with both biological markers in their lowest quarters.
Conclusions— NT-proBNP and renin, but not CRP, are independent predictors of MI risk after stroke or transient ischemic attack, providing information additional to that provided by classic risk factors, and may enable more effective targeting of MI prevention strategies.
Key Words: C-reactive protein ; myocardial infarction ; natriuretic peptides ; renin ; risk factors
Introduction
Although known risk factors account for 90% of the population-attributable risk for myocardial infarction (MI),1 the costs of prevention strategies have led to a targeted approach to prevention of coronary heart disease, whereby interventions are tailored to the estimated risk of the individual.2,3 To better identify individuals at highest risk, many different potential plasma markers have been assessed for prediction of MI risk, including C-reactive protein (CRP), B-type natriuretic peptides (BNP), and renin,4–14 and there has been recent debate about the magnitude of risk associated with elevated CRP levels.15,16 When measured after an acute coronary event, both BNP-related peptides and CRP, separately and together, predict mortality, MI, and heart failure.17–21 However, limited data are available that directly compare BNP-related peptides, CRP, and renin in stable persons at risk of MI, and it is unknown whether screening for >1 of these biological markers provides better prognostic information than screening for 1 marker.
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We evaluated the prognostic performance of N-terminal (NT)-proBNP, CRP, and renin in a population with cerebrovascular disease and increased risk of MI by conducting a nested case-control study of 206 subjects who developed MI and 412 control subjects who did not develop MI who were participants in the Perindopril Protection Against Recurrent Stroke Study (PROGRESS). PROGRESS was a multicenter, randomized, double-blind, placebo-controlled study designed to determine the effects of active therapy with a perindopril-based blood pressure-lowering regimen on the risks of stroke and other major vascular events among individuals with a stroke or transient ischemic attack (TIA) within the previous 5 years.22–24 This regimen substantially reduced the risk of stroke by 28%, major coronary events by 26%, congestive heart failure (CHF) by 26%, and nonfatal MI by 38%.22,24
Methods
Patients and Study Protocol
We conducted a prospective nested case-control analysis among PROGRESS participants, who were a predominantly elderly population with cerebrovascular disease and were at high risk of both coronary events and CHF.24 The design and major outcomes of PROGRESS have been described in detail elsewhere.22–24 Briefly, 6105 participants were recruited from 172 collaborating centers in 10 countries from Australasia, Europe, and Asia between 1995 and 1997. Participants were randomized to either placebo (n=3054) or active therapy (n=3051), comprising a flexible regimen based on the ACE inhibitor perindopril (4 mg daily) with the addition of the diuretic indapamide at the discretion of treating physicians. The institutional ethics committee of each collaborating center approved the trial, and all participants provided written, informed consent. Individuals were potentially eligible if they had a history of cerebrovascular disease (ischemic stroke, hemorrhagic stroke, or TIA but not subarachnoid hemorrhage) within the previous 5 years and no clear indication for or contraindication to ACE inhibitor treatment. There were no blood pressure criteria for entry, but it was recommended that the blood pressure of all hypertensive subjects be controlled with agents other than ACE inhibitors and angiotensin receptor blockers before entry into the study. CHF was a study exclusion criterion.
Before randomization, information was collected on history of vascular disease, other vascular risk factors, and current medications.22–24 The presence of coronary heart disease at baseline was based on a history of MI or coronary revascularization or a history of angina supported by documented ECG or angiographic evidence of coronary disease. Blood samples were collected (nonfasting, 10 mL into heparin and 10 mL into EDTA Vacutainer tubes) from 5918 of the 6105 subjects on enrollment before the run-in phase of the study, at which time none of the subjects was receiving ACE inhibitor or angiotensin receptor blocker therapy. After randomization, participants were scheduled to be seen on 5 occasions in the first year and every 6 months thereafter until the end of the scheduled follow-up period or death. Information on all serious adverse events, including those resulting from stroke, coronary heart disease, and CHF, were routinely recorded. All outcomes were coded according to the ninth revision of the International Classification of Diseases (ICD-9). The diagnosis of MI, either fatal (death within 28 days of MI) or nonfatal, was based on the combination of an appropriate clinical history supported by ECG changes and/or an elevation of cardiac enzymes or other biochemical markers of myocardial injury (ICD-9 code 410.0 to 410.9). Sudden deaths were excluded from this outcome because of uncertainty about the cause of death in this population with preexisting cerebrovascular disease, as were deaths resulting from other acute, subacute, or chronic forms of ischemic heart disease. An adjudication committee, blinded to study treatment allocation, reviewed source documentation for every potential MI, stroke, and all deaths recorded during the study follow-up period.
Biochemical Analyses
Coded blood samples were shipped at 4°C to the local laboratory, where they were centrifuged at 2000g for 10 minutes at 4°C, and the plasma was frozen in aliquots and stored at –80°C until assay. Lipids were measured on first-thaw EDTA plasma by automated direct-measurement assay (Olympus AU2700, Olympus America Inc). LDL cholesterol was calculated for those with triglycerides <4.5 mmol/L by use of Friedewald’s equation.25 Plasma levels of active renin were measured on first-thaw heparin plasma by immunoradiometric assay (Nichols Institute Diagnostics). NT-proBNP was measured by radioimmunoassay with an Elecsys instrument (Roche Diagnostics),26 and CRP was measured by high-sensitivity nephelometry (Dade Behring) on heparin plasma that had been thawed once or twice before assay. We previously showed that NT-proBNP and CRP are stable in plasma that was thawed twice (unpublished). Plasma samples from cases and controls were assayed for lipids, renin, NT-proBNP, and CRP in identical and masked fashion. The local laboratory at each study center measured plasma creatinine.
Statistical Methods
The base population for study was taken as all those who had plasma frozen and stored at baseline (n=5918). A nested case-control sample was selected from this base population. Cases (n=206) were anyone from the base population who developed MI during the mean follow-up of the PROGRESS trial of 3.9 years. By design, 412 (206x2) matched controls without MI during follow-up in the PROGRESS trial were sampled, giving a total of 618 cases and controls for biochemical analysis. For calculation of odds ratios, each case was matched with 1 to 3 controls randomly sampled from this group of 618 subjects who were alive and did not have an MI between randomization and the time of case ascertainment; anyone who became a case after the onset of MI in the index case was eligible for selection as a match, and controls could be matched for >1 case.27 Matching variables were age (within 5 years), gender, treatment allocated (perindopril based or placebo, monotherapy or dual therapy), region (Australia and New Zealand, China, Japan, France and Belgium, Italy, Sweden, United Kingdom, and Ireland), and most recent qualifying event (ischemic stroke or TIA, hemorrhagic stroke, stroke of unknown type) at randomization. If cases who acted as controls for other cases and controls who acted for multiple cases are included, 45 cases had 3 matched controls, 157 had 2 matched controls, and 4 had 1 matched control. Because no matched controls were available, 3 cases were matched on incomplete criteria: Two were not matched for region, and 1 was not matched for region and most recent qualifying event.
Baseline variables were compared between cases and controls by the use of 2, parametric, or nonparametric tests as appropriate.27 The case-control data were analyzed using 2 different conditional logistic regression models to obtain odds ratios for NT-proBNP, CRP, and renin, according to equal quarters of the distribution of each plasma marker in the total sample (cases and controls).27 Model 1 was unadjusted except for the matching variables. Model 2 was adjusted through matching and for all baseline predictors of MI: baseline systolic blood pressure, total cholesterol, HDL cholesterol, LDL cholesterol, and a history of coronary heart disease, valvular heart disease, and peripheral arterial disease. In addition, model 2 for NT-proBNP was adjusted for CRP and renin; model 2 for CRP was adjusted for NT-proBNP and renin; and model 2 for renin was adjusted for NT-proBNP and CRP. Continuous variables are shown as mean±SD, except for plasma levels of triglycerides, NT-proBNP, CRP, and renin, which were not normally distributed and are presented as median (interquartile range). Odds ratios are shown as mean (95% CI). All probability values were 2 tailed, and values of P<0.05 were considered to indicate statistical significance. All analyses were performed with SAS version 8.2 (SAS Institute Inc).
Results
The odds ratio for MI increased with increasing levels of baseline NT-proBNP, CRP, and renin. For subjects in the highest compared with the lowest quarter, the odds ratio was 2.2 (95% CI, 1.3 to 3.6) for NT-proBNP, 2.2 (95% CI, 1.3 to 3.6) for CRP, and 1.7 (95% CI, 1.1 to 2.8) for renin (Table 2). NT-proBNP and renin, but not CRP, remained independent predictors of MI in multivariable analysis (model 2, Table 2). Other variables that were predictors after multivariable analysis were HDL cholesterol and LDL cholesterol. Although there was a trend for MI cases to be more likely to be taking calcium channel blocker therapy, addition of this parameter to model 2 did not significantly change the calculated odds ratios. To examine why CRP failed to predict MI risk in multivariable analysis, we examined the effects of other variables in model 2. CRP predicted MI (P<0.05) when a history of coronary heart disease, valvular heart disease, and peripheral arterial disease, as well as total cholesterol, LDL cholesterol, and renin, were included in the model. However, when HDL cholesterol (P=0.20), systolic blood pressure (P=0.13), or NT-proBNP (P=0.12) was added separately to the model, CRP was no longer a statistically significant predictor of MI. The combination of NT-proBNP and renin had a multiplicative effect on the odds ratio for MI, so that individuals with both NT-proBNP and renin in their highest quarters had 4.5 times the risk of MI compared with subjects with both biological markers in their lowest quarters (the Figure).
Discussion
NT-proBNP and renin were independent predictors of MI risk, and each marker provided information additional to that obtained from established risk factors. Although CRP predicted MI risk in an analysis adjusted for the matching variables alone (model 1, Table 2), it did not predict MI in multivariable analysis including all other predictors (model 2, Table 2).
We found that NT-proBNP levels above the median of 17 pmol/L were associated with increased risk of MI. This median NT-proBNP level was within the normal range for NT-proBNP levels.28–30 Median NT-proBNP levels from population studies approximate 33 pmol/L,28,29 although a lower median of 16 to 19 pmol/L is reported for healthy subjects without a history or symptoms of heart disease or other chronic disease.29,30 We recently showed that similar levels of NT-proBNP were associated with increased risk of CHF in PROGRESS participants.31 Wang et al6 similarly found that BNP levels within a range currently regarded as normal were associated with an increased risk of death and first cardiovascular event, including heart failure, atrial fibrillation, and stroke or TIA in the Framingham Offspring Study. However, BNP did not predict coronary heart disease events in the Framingham Offspring Study.6 The difference between prediction of MI risk by NT-proBNP in PROGRESS participants and failure to predict coronary heart disease events by BNP in the Framingham Offspring Study may have been due to differences between the 2 study populations. PROGRESS participants had a mean age of 68 years, and all had established vascular disease, as evidenced by preceding stroke or TIA, whereas subjects in the Framingham Offspring Study were younger (mean age, 58 years), and most were free of cardiovascular disease at baseline. In addition, we used a narrower definition of coronary heart disease events than Wang et al.6
When measured after an acute coronary event, both BNP-related peptides and CRP, separately and together, predict mortality, MI, and heart failure.17–21 Other studies of stable subjects without acute coronary syndrome show that BNP and NT-proBNP predict all-cause mortality and cardiovascular events, although MI risk was not specifically examined in these studies.7–9 Plasma BNP level predicted dopamine-induced myocardial ischemia in patients with known or suspected coronary heart disease,32 suggesting that increased BNP levels may be associated with subclinical cardiac ischemia and therefore increased risk of MI. Our study provides additional new information by demonstrating that NT-proBNP predicts MI in stable patients, most of whom did not have a history of coronary heart disease. Elevated BNP and NT-proBNP levels may indicate ventricular strain,33 and release of BNP from ventricular myocytes may be an important compensatory response. BNP has beneficial effects in heart failure34 and is reported to reduce infarct size in experimental MI.35
CRP is an established risk factor for cardiovascular events, including MI,4,5 although there has been recent debate about the magnitude of risk associated with elevated CRP levels.15,16 Our finding that NT-proBNP was superior to CRP in the prediction of MI risk may be a result of CRP being a nonspecific marker of acute-phase response,36 whereas NT-proBNP is a cardiac-specific marker. Increased BNP and NT-proBNP levels are associated with a broad range of cardiac conditions,37 most of which relate to increased ventricular strain.33 NT-proBNP and CRP were independent predictors of risk of CHF in PROGRESS participants.31 It is of note that 78% of MI cases and 76% of controls without MI were receiving antiplatelet agents (Table 1), predominantly aspirin. Ridker et al4 showed that aspirin therapy attenuated prediction of risk of MI and stroke by CRP in the Physicians’ Health Study, and aspirin therapy may have similarly attenuated the prediction of MI risk by CRP in our study.
Our finding that renin predicted MI risk in subjects with cerebrovascular disease is in agreement with previous reports that renin predicted coronary heart disease in hypertensive subjects,10,12,14 although other studies failed to observe such an association in either normotensive or hypertensive subjects.11,13 Further evidence for an association between renin and cardiovascular disease is its association with increased urinary albumin excretion in essential hypertension.38 The relatively few studies of renin as a risk factor for cardiovascular disease may be due in part to the difficulties in measuring plasma renin activity. Our demonstration of renin as an independent predictor of MI risk using a simple immunoradiometric assay for active renin may lead to further assessment of the potential value of renin as a risk factor for cardiovascular disease.
A large body of data implicates angiotensin II in the pathogenesis of vascular disease,39 and angiotensin II may provide the link between increased renin levels and MI risk. However, it is also possible that increased renin levels are a marker of MI risk without playing a pathogenic role.13 For example, increased MI risk and increased renin levels may both be consequences of generalized vascular disease, including renovascular disease, which may cause increased renin secretion.40 Perindopril-based therapy reduced the incidence of major coronary events by 26% in PROGRESS participants; however, our study did not have sufficient statistical power to examine whether baseline plasma levels of NT-proBNP, CRP, or renin predicted benefit from this therapy.
The potential limitations of these data merit consideration. Our analyses were based on single baseline determinations that may not accurately reflect NT-proBNP, CRP, and renin levels over the mean follow-up of 3.9 years. This source of variability may have contributed to the failure of CRP to predict MI risk in multivariable analysis, but it cannot account for the observed associations between NT-proBNP, renin, and MI risk because any random misclassification would bias results toward the null hypothesis. Our definition of MI may have excluded cases of silent MI or those that resulted in sudden death; however, our MI cases did not include instances of death not caused by MI. In our nested case-control design, we matched for 5 baseline variables but were unable to match for all predictors of MI such as known cardiac disease because of difficulty in matching for >5 variables; however, we were able to adjust for these baseline predictors of MI in our multivariable analysis (model 2, Table 2).
What is the clinical value of measurement of NT-proBNP and renin; We have shown that NT-proBNP and renin provided prognostic information additional to that provided by classic risk factors, including systolic blood pressure, total cholesterol, HDL cholesterol, LDL cholesterol, and a history of coronary heart disease, valvular heart disease, and peripheral arterial disease. Moreover, MI cases and controls were matched for age, sex, region, qualifying event, and allocated treatment. Whereas measurement of NT-proBNP and renin is unlikely to influence management of individuals who already qualify for intensive strategies for prevention of cardiovascular disease, measurement of these markers may assist in the identification of individuals at increased risk of MI who may not otherwise be identified by classic risk factors.
In conclusion, we performed a head-to-head evaluation of a range of potential risk factors for MI, including classic risk factors, in subjects with previous stroke or TIA. We found that NT-proBNP and renin, but not CRP, independently predicted MI risk. The prognostic information provided by NT-proBNP and renin was additional to that provided by traditional cardiovascular risk factors and may enable more effective targeting of MI prevention strategies. Further studies are required to assess whether the use of NT-proBNP and renin levels to guide management improves patient outcomes.
Acknowledgments
This study was funded by grants from the NIH (5-R01-HL-071685), National Health and Medical Research Council of Australia, and National Heart Foundation of Australia. Drs Campbell and Neal are recipients of Career Development Awards, and Dr Jenkins is a recipient of a Clinical Research Fellowship from the National Heart Foundation of Australia. Dr Kemp is an Australian Research Council Federation Fellow. PROGRESS was funded by grants from Servier, the Health Research Council of New Zealand, and the National Health and Medical Research Council of Australia.
Disclosure
Dr Campbell has had research contracts with Solvay Pharmaceuticals and Novartis and has received consulting fees from Novartis during the past 5 years. Drs Chalmers and MacMahon hold research grants from Servier, as Chief Investigators for PROGRESS and ADVANCE, administered by the University of Sydney. Drs Chalmers, Patel, Neal, Woodward, and MacMahon have also received honoraria from Servier for speaking in relation to PROGRESS and/or ADVANCE at scientific meetings.
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University of Melbourne, St Vincent’s Hospital, Fitzroy, Victoria; CSIRO Health Sciences and Nutrition (B.E.K.)
Parkville, Victoria; and The George Institute for International Health (M.W., J.P.C., S.A.C., B.C.N., A.P., S.W.M.)
University of Sydney, Camperdown, New South Wales, Australia.
Abstract
Background— B-type natriuretic peptide (BNP), C-reactive protein (CRP), and renin are elevated in persons at risk for cardiovascular disease. However, data that directly compare these markers in the prediction of myocardial infarction (MI) are limited.
Methods and Results— N-terminal-proBNP (NT-proBNP), CRP, and renin were measured in baseline blood samples from a nested case-control study of the 6105 participants of the Perindopril Protection Against Recurrent Stroke Study (PROGRESS), a placebo-controlled study of a perindopril-based blood pressure-lowering regimen among individuals with previous stroke or transient ischemic attack. Each of 206 subjects who experienced MI, either fatal or nonfatal, during a mean follow-up of 3.9 years was matched to 1 to 3 control subjects. Most MI cases (67%) occurred in subjects without a history of coronary heart disease. NT-proBNP, CRP, and renin each predicted MI; the odds ratio for subjects in the highest compared with the lowest quarter was 2.2 (95% CI, 1.3 to 3.6) for NT-proBNP, 2.2 (95% CI, 1.3 to 3.6) for CRP, and 1.7 (95% CI, 1.1 to 2.8) for renin. NT-proBNP and renin, but not CRP, remained predictors of MI after adjustment for all other predictors, including LDL and HDL cholesterol levels. Individuals with both NT-proBNP and renin in their highest quarters had 4.5 times the risk of MI compared with subjects with both biological markers in their lowest quarters.
Conclusions— NT-proBNP and renin, but not CRP, are independent predictors of MI risk after stroke or transient ischemic attack, providing information additional to that provided by classic risk factors, and may enable more effective targeting of MI prevention strategies.
Key Words: C-reactive protein ; myocardial infarction ; natriuretic peptides ; renin ; risk factors
Introduction
Although known risk factors account for 90% of the population-attributable risk for myocardial infarction (MI),1 the costs of prevention strategies have led to a targeted approach to prevention of coronary heart disease, whereby interventions are tailored to the estimated risk of the individual.2,3 To better identify individuals at highest risk, many different potential plasma markers have been assessed for prediction of MI risk, including C-reactive protein (CRP), B-type natriuretic peptides (BNP), and renin,4–14 and there has been recent debate about the magnitude of risk associated with elevated CRP levels.15,16 When measured after an acute coronary event, both BNP-related peptides and CRP, separately and together, predict mortality, MI, and heart failure.17–21 However, limited data are available that directly compare BNP-related peptides, CRP, and renin in stable persons at risk of MI, and it is unknown whether screening for >1 of these biological markers provides better prognostic information than screening for 1 marker.
See p 9
We evaluated the prognostic performance of N-terminal (NT)-proBNP, CRP, and renin in a population with cerebrovascular disease and increased risk of MI by conducting a nested case-control study of 206 subjects who developed MI and 412 control subjects who did not develop MI who were participants in the Perindopril Protection Against Recurrent Stroke Study (PROGRESS). PROGRESS was a multicenter, randomized, double-blind, placebo-controlled study designed to determine the effects of active therapy with a perindopril-based blood pressure-lowering regimen on the risks of stroke and other major vascular events among individuals with a stroke or transient ischemic attack (TIA) within the previous 5 years.22–24 This regimen substantially reduced the risk of stroke by 28%, major coronary events by 26%, congestive heart failure (CHF) by 26%, and nonfatal MI by 38%.22,24
Methods
Patients and Study Protocol
We conducted a prospective nested case-control analysis among PROGRESS participants, who were a predominantly elderly population with cerebrovascular disease and were at high risk of both coronary events and CHF.24 The design and major outcomes of PROGRESS have been described in detail elsewhere.22–24 Briefly, 6105 participants were recruited from 172 collaborating centers in 10 countries from Australasia, Europe, and Asia between 1995 and 1997. Participants were randomized to either placebo (n=3054) or active therapy (n=3051), comprising a flexible regimen based on the ACE inhibitor perindopril (4 mg daily) with the addition of the diuretic indapamide at the discretion of treating physicians. The institutional ethics committee of each collaborating center approved the trial, and all participants provided written, informed consent. Individuals were potentially eligible if they had a history of cerebrovascular disease (ischemic stroke, hemorrhagic stroke, or TIA but not subarachnoid hemorrhage) within the previous 5 years and no clear indication for or contraindication to ACE inhibitor treatment. There were no blood pressure criteria for entry, but it was recommended that the blood pressure of all hypertensive subjects be controlled with agents other than ACE inhibitors and angiotensin receptor blockers before entry into the study. CHF was a study exclusion criterion.
Before randomization, information was collected on history of vascular disease, other vascular risk factors, and current medications.22–24 The presence of coronary heart disease at baseline was based on a history of MI or coronary revascularization or a history of angina supported by documented ECG or angiographic evidence of coronary disease. Blood samples were collected (nonfasting, 10 mL into heparin and 10 mL into EDTA Vacutainer tubes) from 5918 of the 6105 subjects on enrollment before the run-in phase of the study, at which time none of the subjects was receiving ACE inhibitor or angiotensin receptor blocker therapy. After randomization, participants were scheduled to be seen on 5 occasions in the first year and every 6 months thereafter until the end of the scheduled follow-up period or death. Information on all serious adverse events, including those resulting from stroke, coronary heart disease, and CHF, were routinely recorded. All outcomes were coded according to the ninth revision of the International Classification of Diseases (ICD-9). The diagnosis of MI, either fatal (death within 28 days of MI) or nonfatal, was based on the combination of an appropriate clinical history supported by ECG changes and/or an elevation of cardiac enzymes or other biochemical markers of myocardial injury (ICD-9 code 410.0 to 410.9). Sudden deaths were excluded from this outcome because of uncertainty about the cause of death in this population with preexisting cerebrovascular disease, as were deaths resulting from other acute, subacute, or chronic forms of ischemic heart disease. An adjudication committee, blinded to study treatment allocation, reviewed source documentation for every potential MI, stroke, and all deaths recorded during the study follow-up period.
Biochemical Analyses
Coded blood samples were shipped at 4°C to the local laboratory, where they were centrifuged at 2000g for 10 minutes at 4°C, and the plasma was frozen in aliquots and stored at –80°C until assay. Lipids were measured on first-thaw EDTA plasma by automated direct-measurement assay (Olympus AU2700, Olympus America Inc). LDL cholesterol was calculated for those with triglycerides <4.5 mmol/L by use of Friedewald’s equation.25 Plasma levels of active renin were measured on first-thaw heparin plasma by immunoradiometric assay (Nichols Institute Diagnostics). NT-proBNP was measured by radioimmunoassay with an Elecsys instrument (Roche Diagnostics),26 and CRP was measured by high-sensitivity nephelometry (Dade Behring) on heparin plasma that had been thawed once or twice before assay. We previously showed that NT-proBNP and CRP are stable in plasma that was thawed twice (unpublished). Plasma samples from cases and controls were assayed for lipids, renin, NT-proBNP, and CRP in identical and masked fashion. The local laboratory at each study center measured plasma creatinine.
Statistical Methods
The base population for study was taken as all those who had plasma frozen and stored at baseline (n=5918). A nested case-control sample was selected from this base population. Cases (n=206) were anyone from the base population who developed MI during the mean follow-up of the PROGRESS trial of 3.9 years. By design, 412 (206x2) matched controls without MI during follow-up in the PROGRESS trial were sampled, giving a total of 618 cases and controls for biochemical analysis. For calculation of odds ratios, each case was matched with 1 to 3 controls randomly sampled from this group of 618 subjects who were alive and did not have an MI between randomization and the time of case ascertainment; anyone who became a case after the onset of MI in the index case was eligible for selection as a match, and controls could be matched for >1 case.27 Matching variables were age (within 5 years), gender, treatment allocated (perindopril based or placebo, monotherapy or dual therapy), region (Australia and New Zealand, China, Japan, France and Belgium, Italy, Sweden, United Kingdom, and Ireland), and most recent qualifying event (ischemic stroke or TIA, hemorrhagic stroke, stroke of unknown type) at randomization. If cases who acted as controls for other cases and controls who acted for multiple cases are included, 45 cases had 3 matched controls, 157 had 2 matched controls, and 4 had 1 matched control. Because no matched controls were available, 3 cases were matched on incomplete criteria: Two were not matched for region, and 1 was not matched for region and most recent qualifying event.
Baseline variables were compared between cases and controls by the use of 2, parametric, or nonparametric tests as appropriate.27 The case-control data were analyzed using 2 different conditional logistic regression models to obtain odds ratios for NT-proBNP, CRP, and renin, according to equal quarters of the distribution of each plasma marker in the total sample (cases and controls).27 Model 1 was unadjusted except for the matching variables. Model 2 was adjusted through matching and for all baseline predictors of MI: baseline systolic blood pressure, total cholesterol, HDL cholesterol, LDL cholesterol, and a history of coronary heart disease, valvular heart disease, and peripheral arterial disease. In addition, model 2 for NT-proBNP was adjusted for CRP and renin; model 2 for CRP was adjusted for NT-proBNP and renin; and model 2 for renin was adjusted for NT-proBNP and CRP. Continuous variables are shown as mean±SD, except for plasma levels of triglycerides, NT-proBNP, CRP, and renin, which were not normally distributed and are presented as median (interquartile range). Odds ratios are shown as mean (95% CI). All probability values were 2 tailed, and values of P<0.05 were considered to indicate statistical significance. All analyses were performed with SAS version 8.2 (SAS Institute Inc).
Results
The odds ratio for MI increased with increasing levels of baseline NT-proBNP, CRP, and renin. For subjects in the highest compared with the lowest quarter, the odds ratio was 2.2 (95% CI, 1.3 to 3.6) for NT-proBNP, 2.2 (95% CI, 1.3 to 3.6) for CRP, and 1.7 (95% CI, 1.1 to 2.8) for renin (Table 2). NT-proBNP and renin, but not CRP, remained independent predictors of MI in multivariable analysis (model 2, Table 2). Other variables that were predictors after multivariable analysis were HDL cholesterol and LDL cholesterol. Although there was a trend for MI cases to be more likely to be taking calcium channel blocker therapy, addition of this parameter to model 2 did not significantly change the calculated odds ratios. To examine why CRP failed to predict MI risk in multivariable analysis, we examined the effects of other variables in model 2. CRP predicted MI (P<0.05) when a history of coronary heart disease, valvular heart disease, and peripheral arterial disease, as well as total cholesterol, LDL cholesterol, and renin, were included in the model. However, when HDL cholesterol (P=0.20), systolic blood pressure (P=0.13), or NT-proBNP (P=0.12) was added separately to the model, CRP was no longer a statistically significant predictor of MI. The combination of NT-proBNP and renin had a multiplicative effect on the odds ratio for MI, so that individuals with both NT-proBNP and renin in their highest quarters had 4.5 times the risk of MI compared with subjects with both biological markers in their lowest quarters (the Figure).
Discussion
NT-proBNP and renin were independent predictors of MI risk, and each marker provided information additional to that obtained from established risk factors. Although CRP predicted MI risk in an analysis adjusted for the matching variables alone (model 1, Table 2), it did not predict MI in multivariable analysis including all other predictors (model 2, Table 2).
We found that NT-proBNP levels above the median of 17 pmol/L were associated with increased risk of MI. This median NT-proBNP level was within the normal range for NT-proBNP levels.28–30 Median NT-proBNP levels from population studies approximate 33 pmol/L,28,29 although a lower median of 16 to 19 pmol/L is reported for healthy subjects without a history or symptoms of heart disease or other chronic disease.29,30 We recently showed that similar levels of NT-proBNP were associated with increased risk of CHF in PROGRESS participants.31 Wang et al6 similarly found that BNP levels within a range currently regarded as normal were associated with an increased risk of death and first cardiovascular event, including heart failure, atrial fibrillation, and stroke or TIA in the Framingham Offspring Study. However, BNP did not predict coronary heart disease events in the Framingham Offspring Study.6 The difference between prediction of MI risk by NT-proBNP in PROGRESS participants and failure to predict coronary heart disease events by BNP in the Framingham Offspring Study may have been due to differences between the 2 study populations. PROGRESS participants had a mean age of 68 years, and all had established vascular disease, as evidenced by preceding stroke or TIA, whereas subjects in the Framingham Offspring Study were younger (mean age, 58 years), and most were free of cardiovascular disease at baseline. In addition, we used a narrower definition of coronary heart disease events than Wang et al.6
When measured after an acute coronary event, both BNP-related peptides and CRP, separately and together, predict mortality, MI, and heart failure.17–21 Other studies of stable subjects without acute coronary syndrome show that BNP and NT-proBNP predict all-cause mortality and cardiovascular events, although MI risk was not specifically examined in these studies.7–9 Plasma BNP level predicted dopamine-induced myocardial ischemia in patients with known or suspected coronary heart disease,32 suggesting that increased BNP levels may be associated with subclinical cardiac ischemia and therefore increased risk of MI. Our study provides additional new information by demonstrating that NT-proBNP predicts MI in stable patients, most of whom did not have a history of coronary heart disease. Elevated BNP and NT-proBNP levels may indicate ventricular strain,33 and release of BNP from ventricular myocytes may be an important compensatory response. BNP has beneficial effects in heart failure34 and is reported to reduce infarct size in experimental MI.35
CRP is an established risk factor for cardiovascular events, including MI,4,5 although there has been recent debate about the magnitude of risk associated with elevated CRP levels.15,16 Our finding that NT-proBNP was superior to CRP in the prediction of MI risk may be a result of CRP being a nonspecific marker of acute-phase response,36 whereas NT-proBNP is a cardiac-specific marker. Increased BNP and NT-proBNP levels are associated with a broad range of cardiac conditions,37 most of which relate to increased ventricular strain.33 NT-proBNP and CRP were independent predictors of risk of CHF in PROGRESS participants.31 It is of note that 78% of MI cases and 76% of controls without MI were receiving antiplatelet agents (Table 1), predominantly aspirin. Ridker et al4 showed that aspirin therapy attenuated prediction of risk of MI and stroke by CRP in the Physicians’ Health Study, and aspirin therapy may have similarly attenuated the prediction of MI risk by CRP in our study.
Our finding that renin predicted MI risk in subjects with cerebrovascular disease is in agreement with previous reports that renin predicted coronary heart disease in hypertensive subjects,10,12,14 although other studies failed to observe such an association in either normotensive or hypertensive subjects.11,13 Further evidence for an association between renin and cardiovascular disease is its association with increased urinary albumin excretion in essential hypertension.38 The relatively few studies of renin as a risk factor for cardiovascular disease may be due in part to the difficulties in measuring plasma renin activity. Our demonstration of renin as an independent predictor of MI risk using a simple immunoradiometric assay for active renin may lead to further assessment of the potential value of renin as a risk factor for cardiovascular disease.
A large body of data implicates angiotensin II in the pathogenesis of vascular disease,39 and angiotensin II may provide the link between increased renin levels and MI risk. However, it is also possible that increased renin levels are a marker of MI risk without playing a pathogenic role.13 For example, increased MI risk and increased renin levels may both be consequences of generalized vascular disease, including renovascular disease, which may cause increased renin secretion.40 Perindopril-based therapy reduced the incidence of major coronary events by 26% in PROGRESS participants; however, our study did not have sufficient statistical power to examine whether baseline plasma levels of NT-proBNP, CRP, or renin predicted benefit from this therapy.
The potential limitations of these data merit consideration. Our analyses were based on single baseline determinations that may not accurately reflect NT-proBNP, CRP, and renin levels over the mean follow-up of 3.9 years. This source of variability may have contributed to the failure of CRP to predict MI risk in multivariable analysis, but it cannot account for the observed associations between NT-proBNP, renin, and MI risk because any random misclassification would bias results toward the null hypothesis. Our definition of MI may have excluded cases of silent MI or those that resulted in sudden death; however, our MI cases did not include instances of death not caused by MI. In our nested case-control design, we matched for 5 baseline variables but were unable to match for all predictors of MI such as known cardiac disease because of difficulty in matching for >5 variables; however, we were able to adjust for these baseline predictors of MI in our multivariable analysis (model 2, Table 2).
What is the clinical value of measurement of NT-proBNP and renin; We have shown that NT-proBNP and renin provided prognostic information additional to that provided by classic risk factors, including systolic blood pressure, total cholesterol, HDL cholesterol, LDL cholesterol, and a history of coronary heart disease, valvular heart disease, and peripheral arterial disease. Moreover, MI cases and controls were matched for age, sex, region, qualifying event, and allocated treatment. Whereas measurement of NT-proBNP and renin is unlikely to influence management of individuals who already qualify for intensive strategies for prevention of cardiovascular disease, measurement of these markers may assist in the identification of individuals at increased risk of MI who may not otherwise be identified by classic risk factors.
In conclusion, we performed a head-to-head evaluation of a range of potential risk factors for MI, including classic risk factors, in subjects with previous stroke or TIA. We found that NT-proBNP and renin, but not CRP, independently predicted MI risk. The prognostic information provided by NT-proBNP and renin was additional to that provided by traditional cardiovascular risk factors and may enable more effective targeting of MI prevention strategies. Further studies are required to assess whether the use of NT-proBNP and renin levels to guide management improves patient outcomes.
Acknowledgments
This study was funded by grants from the NIH (5-R01-HL-071685), National Health and Medical Research Council of Australia, and National Heart Foundation of Australia. Drs Campbell and Neal are recipients of Career Development Awards, and Dr Jenkins is a recipient of a Clinical Research Fellowship from the National Heart Foundation of Australia. Dr Kemp is an Australian Research Council Federation Fellow. PROGRESS was funded by grants from Servier, the Health Research Council of New Zealand, and the National Health and Medical Research Council of Australia.
Disclosure
Dr Campbell has had research contracts with Solvay Pharmaceuticals and Novartis and has received consulting fees from Novartis during the past 5 years. Drs Chalmers and MacMahon hold research grants from Servier, as Chief Investigators for PROGRESS and ADVANCE, administered by the University of Sydney. Drs Chalmers, Patel, Neal, Woodward, and MacMahon have also received honoraria from Servier for speaking in relation to PROGRESS and/or ADVANCE at scientific meetings.
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