- Email: [email protected]
Relation of Elevated Plasma Renin Activity at Baseline to Cardiac Events in Patients With Angiographically Proven Coronary Artery Disease
Relation of Elevated Plasma Renin Activity at Baseline to Cardiac Events in Patients With Angiographically Proven Coronary Artery Disease Joseph B. Muhlestein, MDa,b,*, Heidi T. May, PhDa, Tami L. Bair, BSa, Margaret F. Prescott, PhDc, Benjamin D. Horne, PhDa,b, Richard White, PhDd, and Jeffrey L. Anderson, MDa,b Plasma renin activity (PRA) is a measure of renin–angiotensin system activity and is associated with cardiovascular outcomes in patients with heart failure (HF). We conducted a prospective analysis to assess whether elevated baseline PRA is associated with cardiovascular outcomes in 1,165 patients with coronary artery disease (>70% stenosis on the coronary angiogram) enrolled in the Intermountain Heart Collaborative Study. The exclusion criteria included previous myocardial infarction (MI) or HF, ejection fraction <45%, and a discharge diagnosis of MI/-blocker treatment. Baseline PRA measurements were evaluated as risk categories (<0.50, 0.51 to 2.30, and >2.30 ng/ml/h) and as tertiles (<0.40, 0.41 to 1.90, and >1.90 ng/ml/h). Predefined cardiovascular outcomes were assessed for a minimum follow-up of 3 years (mean 6.4 ⴞ 3.2, maximum 14.6) using Cox regression analysis to adjust for the baseline characteristics. The mean patient age was 64.4 years; most patients were men (73.1%) and hypertensive (63.2%). Elevated baseline PRA (high vs low category; >2.30 vs <0.50 ng/ml/h) was associated with a significantly increased risk of 3-year cardiac morbidity/mortality (hazard ratio 1.96; p ⴝ 0.004), MI (hazard ratio 2.41; p ⴝ 0.02), HF hospitalization (hazard ratio 4.39; p ⴝ 0.03), and all-cause death (hazard ratio 1.80; p ⴝ 0.01). Elevated baseline PRA was also associated with longer-term HF hospitalization (hazard ratio 2.12; p ⴝ 0.004) and all-cause death (hazard ratio 1.56; p ⴝ 0.002). Similar results were observed for the PRA tertiles. The association of PRA with outcomes was observed after correction for hypertension, hyperlipidemia, diabetes, a family history of cardiovascular events, smoking, renal failure, and the use of statins. In conclusion, elevated baseline PRA is associated with cardiac morbidity and mortality in patients with coronary artery disease but normal left ventricular function and no previous MI or HF. © 2010 Elsevier Inc. All rights reserved. (Am J Cardiol 2010;106:764 –769) Plasma renin activity (PRA) was first associated with an increased risk of myocardial infarction (MI) in the early 1970s.1 Several major outcome studies have since provided evidence that PRA might be an independent predictor of cardiovascular morbidity and mortality across a broad range of patient groups.2–7 The Survival And Ventricular Enlargement (SAVE) study, conducted in 534 patients with coronary artery disease (CAD) and left ventricular dysfunction who had experienced an acute MI, showed that elevated a Intermountain Medical Center, Murray, Utah; bUniversity of Utah, Salt Lake City, Utah; cNovartis Pharmaceuticals Corporation, East Hanover, New Jersey; and dResearch Evaluation Unit, Oxford PharmaGenesis Ltd., Oxford, United Kingdom. Manuscript received January 21, 2010; manuscript received and accepted April 23, 2010. This study was supported by Novartis Pharmaceuticals Corporation, East Hanover, New Jersey. Dr. Muhlestein has served on speakers’ bureaux for Bristol-Myers Squibb, GSK, Merck, Novartis, and Sanofi-Aventis. Dr. Prescott is an employee of Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, and is thus eligible for Novartis stock and stock options. Dr. White is an employee of Oxford PharmaGenesis Ltd., which has received project funding from Novartis Pharmaceuticals Corporation, East Hanover, New Jersey. *Corresponding author: Tel: (801) 507-4701; fax: (801) 507-4789. E-mail address: [email protected] (J.B. Muhlestein).
0002-9149/10/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2010.04.040
PRA was associated with subsequent severe heart failure (HF) and combined cardiovascular events.6 A recent study of 699 patients with HF showed that PRA was associated with cardiovascular events despite treatment with an angiotensin-converting enzyme inhibitor and/or an angiotensin receptor blocker.5 We assessed the association between baseline PRA and the risk of cardiovascular events in a population of patients with CAD (ⱖ70% stenosis) but no history of MI or HF who had undergone coronary angiography and were followed up for long-term outcomes. This is the first study to assess the association between PRA and a first incident cardiovascular event (other than angina) in patients with CAD. Methods The study patients were drawn from the cardiac catheterization registry of the Intermountain Heart Collaborative Study, a cohort of patients undergoing coronary arteriography at the LDS Hospital (Salt Lake City, Utah). Patients were of unrestricted age and gender and gave written informed consent for a blood draw at angiography for use in confidential studies approved by the hospital’s institutional review board. A total of 1,165 patients with CAD, defined as the presence of one or more ⱖ70% obstructive lesions on the coronary artery angiogram, and who had been followed up for ⱖ3 years, were selected for the present study. The www.ajconline.org
Coronary Artery Disease/PRA and Cardiac Outcomes in CAD
assessment of CAD was made by review of the angiograms by the patient’s cardiologist and was performed with the reviewer blinded to the levels of PRA obtained from the blood collection. The clinical presentation of the patients included in the study was either stable angina pectoris (stable exertional symptoms only) or unstable angina pectoris (progressive symptoms or symptoms at rest). In addition to age and gender, the recorded baseline characteristics included a diagnosis of diabetes (fasting blood glucose level ⬎125 mg/dl, clinical diagnosis of diabetes mellitus, or the use of antidiabetic medication), hypertension (systolic blood pressure ⱖ140 mm Hg, diastolic blood pressure ⱖ90 mm Hg, or use of antihypertensive therapy), renal failure (clinical renal failure or calculated glomerular filtration rate of ⬍15 ml/min), and hyperlipidemia (total cholesterol ⱖ200 mg/dl, low-density lipoprotein cholesterol ⱖ130 mg/dl, or the use of cholesterol-lowering medication). A family history of cardiovascular outcomes was patient reported and defined as a first-order relative experiencing cardiovascular death, MI, or coronary revascularization before 65 years of age. Smoking status was patient reported and included active smokers and those with a ⬎10 pack-year history. Discharge medications were also recorded and included statins, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, calcium channel blockers, and diuretics. The goal of the present study was to evaluate patients with known CAD but without pre-existing left ventricular dysfunction. Therefore, those with a history of MI or a current diagnosis of acute MI (creatine kinase-MB ⬎6 mg/dl and creatine kinase-MB index ⬎3%), a history or current diagnosis of HF, or a left ventricular ejection fraction of ⱕ45% were excluded before sample testing. Patients who had been prescribed -blocker therapy at discharge were also excluded from the study a priori as an additional method of excluding patients with previous HF or MI. No information was available for drug treatment received by the patients before the baseline assessment or after discharge; hence, the study could have included patients who received -blocker therapy during long-term follow-up. Baseline PRA was measured from plasma obtained at coronary angiography and analyzed by Clinical Reference Laboratory Medinet (Lenexa, Kansas) using the DiaSorin PRA radioimmunoassay method (DiaSorin, Stillwater, Minnesota). Patients selected for inclusion had blood drawn when supine between 6 A.M. and 11:30 A.M. to minimize the confounding effects of posture and diurnal variation on the PRA levels. The blood samples were taken without washout of previously prescribed medications. The plasma was separated from whole blood within 4 hours of collection and stored at ⫺70°C until assayed in batches. The predefined cardiovascular outcomes were all-cause death, fatal and nonfatal MI, cardiac morbidity and mortality, HF hospitalization, and cerebrovascular accident (CVA), evaluated during the first 3 years of follow-up and for the entire follow-up duration. ●
MI was defined as a hospitalization in which the patient had a troponin I level of ⱖ0.4 ng/ml or a discharge diagnosis of an MI (International Statistical
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Classification of Disease and Related Health Problems, 9th ed., code 410). HF hospitalization was defined as a hospitalization in which a clinical diagnosis of HF was made or the patient had a discharge diagnosis of HF (International Statistical Classification of Disease and Related Health Problems, 9th ed., code 428). CVA was determined by the discharge diagnosis (International Statistical Classification of Disease and Related Health Problems, 9th ed., code 436). Deaths were determined by telephone survey, hospital records, the Utah State Health Department records, and the national Social Security death records. Patients not listed as deceased in any registry were considered to be alive.
All patients were followed up until death or the censoring date. For outcomes that assessed composite end points, patients who experienced both end points were censored after the occurrence of the first event to ensure they were counted only once. Our statistical approach can be summarized as follows. Patients were subdivided into low, moderate, or high baseline PRA using recursive partitioning analysis (a statistical technique that defines clinically meaningful PRA categories that predict cardiovascular risk) and by tertiles. The baseline, demographic, and clinical characteristics were compared across PRA categories to identify any significant differences associated with high PRA. The distribution of patients experiencing each predefined outcome across the PRA categories was evaluated using univariate analysis to determine whether patients with a particular outcome were more likely to have high PRA. A multivariate analysis of the relative increase in risk of outcomes with high PRA versus low PRA (adjusting for differences in baseline, demographic, and clinical characteristics) was performed to determine whether high PRA was associated with the predefined outcomes. Recursive partitioning resulted in the definition of low (ⱕ0.50 ng/ml/h), moderate (0.51 to 2.30 ng/ml/h), and high (⬎2.30 ng/ml/h) PRA categories. To validate the recursive partitioning method, the patients were also grouped into 3 approximately equal-sized tertiles (ⱕ0.40, 0.41 to 1.90, and ⬎1.90 ng/ml/h). The chi-square test was used to compare the baseline, demographic, and clinical characteristics across the PRA tertiles or categories and for univariate analysis of the association between PRA categories with the predefined cardiovascular outcomes. Multivariate Cox regression analysis was performed to determine the hazard ratios corrected for age, gender, hypertension, hyperlipidemia, diabetes, smoking, a family history of CAD, renal failure, clinical presentation (stable angina or MI), and discharge medications (statins, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and diuretics). The final models entered significant (p ⬍0.05) and confounding (10% change in -coefficient) covariables. Kaplan-Meier survival estimates and the log-rank test were used to compare the cumulative long-term incidence of the end points across the PRA categories. Two-tailed p values are presented, with p ⫽ 0.05 designated as nominally significant. Statistical analysis was per-
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Table 1 Patient demographic and disease characteristics by baseline plasma renin activity (PRA) category and baseline plasma renin activity (PRA) tertile Characteristic
Baseline PRA Tertile†
Baseline PRA Category*
Median plasma renin activity (ng/ml/h) Age (years)‡, mean ⫾ SD Men Hyperlipidemia Hypertension‡§ Diabetes mellitus‡§ Smoker Family history of cardiovascular disease Renal failure‡§ Left ventricular ejection fraction (%), mean ⫾ SD Angiotensin-converting enzyme inhibitor‡ Angiotensin receptor blocker Diuretic Statin‡§
Overall (n ⫽ 1,165)
Low (n ⫽ 470)
Moderate (n ⫽ 351)
High (n ⫽ 344)
Tertile 1 (n ⫽ 412)
Tertile 2 (n ⫽ 378)
Tertile 3 (n ⫽ 375)
0.30 65.5 ⫾ 11.2 353 (75.1%) 305 (64.9%) 284 (60.4%) 99 (21.1%) 99 (21.1%) 199 (42.3%) 6 (1.3%) 62.1 ⫾ 10.6
1.10 64.4 ⫾ 11.2 259 (73.8%) 221 (63.0%) 215 (61.3%) 90 (25.6%) 73 (20.8%) 157 (44.7%) 3 (0.9%) 63.5 ⫾ 9.9
5.40 63.0 ⫾ 11.6 242 (70.3%) 214 (62.2%) 237 (68.9%) 100 (29.1%) 85 (24.7%) 153 (44.5%) 12 (3.5%) 63.3 ⫾ 10.9
0.20 65.5 ⫾ 11.2 311 (75.5%) 269 (65.3%) 248 (60.2%) 82 (19.9%) 87 (21.1%) 173 (42.0%) 6 (1.5%) 62.4 ⫾ 10.5
0.90 64.4 ⫾ 11.2 278 (73.6%) 235 (62.2%) 232 (61.4%) 96 (25.3%) 78 (20.7%) 173 (45.7%) 3 (0.8%) 63.0 ⫾ 10.2
4.80 63.1 ⫾ 12.3 265 (70.6%) 236 (62.9%) 255 (68.1%) 111 (29.6%) 92 (24.4%) 164 (43.6%) 12 (3.1%) 63.4 ⫾ 10.8
0.80 64.4 ⫾ 11.6 852 (73.1%) 740 (63.5%) 735 (63.1%) 290 (24.9%) 256 (22.0%) 509 (43.7%) 21 (1.8%) 62.9 ⫾ 10.5
(n ⫽ 334) 5 (1.1%) 1 (0.2%) 7 (1.5%) 210 (44.7%)
(n ⫽ 256) 8 (2.3%) 4 (1.1%) 8 (2.3%) 158 (45.0%)
(n ⫽ 227) 11 (3.2%) 1 (0.3%) 9 (2.6%) 122 (35.5%)
(n ⫽ 288) 3 (0.7%) 1 (0.2%) 7 (1.7%) 182 (44.2%)
(n ⫽ 270) 9 (2.4%) 3 (0.8%) 7 (1.9%) 174 (46.2%)
(n ⫽ 259) 12 (3.1%) 2 (0.5%) 10 (2.6%) 134 (35.8%)
(n ⫽ 817) 24 (2.1%) 6 (0.5%) 24 (2.1%) 490 (42.1%)
Data are presented as n (%) unless otherwise stated. * Low recursive partitioning category: baseline PRA ⱕ0.50 ng/ml/h; moderate category: 0.51 to 2.30 ng/ml/h; high category ⬎2.30 ng/ml/h. † Tertile 1 baseline PRA ⱕ0.40 ng/ml/h; tertile 2 0.41 to 1.90 ng/ml/h; tertile 3 ⬎1.90 ng/ml/h. ‡ p ⬍0.05 for difference across categories (chi-square test). § p ⬍0.05 for difference across tertiles (chi-square test).
Proportion of patients with event (%)
25
Low PRA (≤ 0.50 ng/mL/h) Moderate PRA (0.51–2.30 ng/mL/h) High PRA (> 2.30 ng/mL/h)
20
15
*
* *
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Figure 1. Distribution of baseline PRA in patients who experienced a predefined cardiovascular outcome within 3 years of follow-up. Patients were divided into categories of baseline PRA by recursive partitioning. *p ⬍0.05, chi-square test.
formed using the SSPS, version 15.0 (SPSS, Chicago, Illinois). Results A total of 1,165 patients with CAD were included in the present study. The mean age was nearly 65 years, and almost 75% were men (Table 1). The median PRA was 0.80 ng/ml/h across the entire patient population. The patients with higher baseline PRA tended to be younger and to have a greater prevalence of hypertension, diabetes, and renal
failure. The rate of antihypertensive medication use at discharge was low. The average follow-up duration (mean ⫾ SD) after the baseline PRA measurement was 6.4 ⫾ 3.2 years (maximum follow-up 14.6). During the first 3 years of follow-up, 111 patients died, 40 had an MI (nonfatal for 26 patients), 19 were hospitalized for HF, and 14 had a CVA (nonfatal for 9 patients). During the entire follow-up period, 258 patients died, 215 had an MI, 96 were hospitalized for HF, and 67 had a CVA. Of the patients who experienced a predefined event within the first 3 years of follow-up, a greater proportion were in the moderate or high PRA categories (i.e., baseline PRA ⬎0.50 ng/ml/h) than in the low PRA category (ⱕ0.50 ng/ml/h). These differences were statistically significant (p ⬍0.05) for 3-year cardiac morbidity/mortality, MI, HF hospitalization, all-cause death, and all-cause death/HF (Figure 1). Similar results were found when patients were analyzed by tertiles (data not shown). The analysis of the 3-year outcomes showed that patients in the high baseline PRA category had a significantly increased risk of cardiac morbidity/mortality, MI, HF hospitalization, all-cause death, and all-cause death/HF compared with patients in the low baseline PRA category (Figure 2). The association between elevated PRA and outcomes was observed despite correction for hypertension, hyperlipidemia, diabetes, a family history of cardiovascular events, smoking, renal failure, and the use of statins. During the entire follow-up period (i.e., up to 14.6 years), PRA remained significantly associated with a longer-term increased risk of HF hospitalization, all-cause death, and allcause death/HF (Figure 2). High PRA was not significantly associated with MI during longer-term follow-up.
Coronary Artery Disease/PRA and Cardiac Outcomes in CAD
(a) 3-year outcomes Hazard ratio
Category Tertile Outcome Cardiac morbidity/ mortality MI HF hospitalization All-cause death All-cause death/HF CVA
0.1
Elevated PRA associated with reduced risk
HR (95% CI)
p value
1.96 (1.24, 3.10) 1.79 (1.13, 2.86) 2.41 (1.13, 5.12) 2.18 (1.01, 4.71) 4.39 (1.19, 16.20) 3.40 (0.92, 12.50) 1.80 (1.14, 2.86) 1.59 (1.00, 2.53) 1.89 (1.21, 2.96) 1.66 (1.06, 2.60) 0.94 (0.22, 3.90) 1.26 (0.29, 5.42)
0.004 0.013 0.017 0.047 0.027 0.066 0.010 0.049 0.005 0.028 0.925 0.758
1
Elevated PRA associated with increased risk
10
(b) Longer-term outcomes Hazard ratio
Category Tertile Outcome Cardiac morbidity/ mortality MI HF hospitalization All-cause death All-cause death/HF CVA
Elevated PRA associated with reduced risk 0.1
HR (95% CI)
p value
1.19 (0.92, 1.53) 1.18 (0.92, 1.53) 0.98 (0.71, 1.36) 0.97 (0.70, 1.34) 2.12 (1.26, 3.54) 2.12 (1.27, 3.54) 1.56 (1.17, 2.08) 1.41 (1.06, 1.88) 1.53 (1.17, 2.00) 1.44 (1.10, 1.89) 0.78 (0.42, 1.46) 0.85 (0.46, 1.58)
0.189 0.204 0.919 0.837 0.004 0.004 0.002 0.022 0.002 0.007 0.437 0.605
1
Elevated PRA associated with increased risk
10
Figure 2. Association between elevated baseline PRA and (A) 3-year and (B) longer-term cardiovascular outcomes. Elevated baseline PRA was calculated as highest versus lowest PRA tertile (tertile 3 vs tertile 1; baseline PRA ⬎1.90 versus ⱕ0.40 ng/ml/h) or category (high versus low; baseline PRA ⬎2.30 versus ⱕ0.50 ng/ml/h). Data are presented as hazard ratio (HR) (95% confidence interval [CI]) from multivariate analysis adjusted for hypertension, hyperlipidemia, diabetes, family history, smoking, and renal failure.
No statistically significant association between PRA and CVA was observed during intermediate or longer-term follow-up. For all outcomes, similar results were observed when patients were divided by the baseline PRA tertiles (Figure 2). Elevated baseline PRA was significantly associated with increased 3-year cardiac morbidity/mortality (log-rank p ⫽ 0.005; Figure 3) and MI (log-rank p ⫽ 0.031; Figure 3). Separation of the survival curves for cardiac morbidity/ mortality between patients in the moderate/high and low PRA categories was evident within 1 month (Figure 3) and persisted throughout the first 3 years of follow-up. Elevated PRA was also significantly associated with increased HF hospitalization (log-rank p ⫽ 0.03; Figure 3) and all-cause death (log-rank p ⫽ 0.007; Figure 3) during longer-term follow-up. Discussion This is the first study to evaluate the association between baseline PRA and cardiovascular morbidity and mortality in patients with CAD but with essentially normal left ventricular function and no history of MI or HF. We found that patients in the high PRA category had a significantly greater risk of short- to intermediate-term (3-year) cardiac morbid-
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ity/mortality (2.0-fold increase), MI (2.4-fold increase), and all-cause death (1.8-fold increase) compared with patients who had low PRA. Elevated baseline PRA was also significantly associated with an increased risk of longer-term (up to 14.6 years) HF hospitalization (2.1-fold increase) and all-cause death (1.6-fold increase). The association between PRA and outcomes was observed despite correction for hypertension, hyperlipidemia, diabetes, a family history of cardiovascular events, smoking, renal failure, and the use of statins. It was also independent of the methods used to define the baseline PRA subgroups or analyze the outcomes. Information on postdischarge medications was not available; hence, the association between PRA and outcomes was seen despite follow-up antihypertensive treatment. These findings add to the growing body of evidence that elevated baseline PRA is associated with cardiovascular morbidity and mortality across a broad range of patient groups and is a potential target for treatment. The present study has provided clear evidence that elevated baseline PRA is associated with hard clinical outcomes (death, MI, HF hospitalization, cardiac morbidity/ mortality) in patients with CAD. Previous studies have demonstrated that PRA might be associated with the risk of MI in patients with hypertension (Alderman et al worksite program3), increased risk of major cardiovascular events, cardiovascular death, all-cause death and HF in high-risk patients with vascular disease or diabetes but without left ventricular dysfunction or heart failure (Heart Outcomes Prevention Evaluation [HOPE] study7), progression to severe HF and combined cardiovascular events in post-MI patients (Sleep Apnea Cardiovascular Endpoints [SAVE] study6), and combined cardiovascular morbidity/mortality in patients with HF (Valsartan Heart Failure Trial [ValHeFT]4 and the study by Vergaro et al5). Overall, the current weight of evidence shows that PRA might be associated with the development of hard clinical outcomes across the cardiovascular disease continuum—from hypertension through to CAD and MI and then to the development of HF and subsequent HF-related cardiovascular events. Elevated baseline PRA was associated with approximately double the risk of HF hospitalization during longerterm follow-up. This is of major clinical importance because HF is a common long-term consequence of CAD progression, particularly in patients who have previously had an MI or have long-standing underlying ischemia (ischemic cardiomyopathy). Our results are consistent with the landmark SAVE study, in which elevated PRA doubled the risk of severe HF (relative risk 2.0, p ⫽ 0.002) during a 3-year period after acute MI in patients with CAD and documented left ventricular dysfunction.6 In the present study population of patients with CAD and normal baseline left ventricular function, the Kaplan-Meier survival curves for longer-term HF hospitalization showed clear and statistically significant separation of the moderate/high PRA categories from low PRA (p ⫽ 0.03), with most HF events occurring in the later years of follow-up. Together, these results indicate that elevated baseline PRA might be associated with the longterm development of HF in patients with CAD. An important observation from the Val-HeFT4 and Vergaro et al5 studies in patients with HF is that elevated PRA was significantly associated with clinical outcomes even
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(a) Cardiac morbidity/mortality
(b) MI
1.0
1.0
Low PRA (≤ 0.50 ng/mL/h) Moderate PRA (0.51–2.30 ng/mL/h) High PRA (> 2.30 ng/mL/h)
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0.8 Long-term log-rank p = 0.587
1.00
Event-free survival
Event-free survival
0.8
0.95
0.4 0.90
0.2
Low PRA (≤ 0.50 ng/mL/h) Moderate PRA (0.51–2.30 ng/mL/h) High PRA (> 2.30 ng/mL/h)
0.85
0.6
1.00 0.98
0.4
0.96 0.94
0.2
3-year log-rank p = 0.005
Long-term log-rank p = 0.554
0.92
3-year log-rank p = 0.031
0.90
0.80 0
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0
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14
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Time to cardiac morbidity/mortality (years) Number at risk
2.0
3.0
0.0
1165
1061
891
559
321
161
84
8
10
12
14
84
16
Time to MI (years) Number at risk
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(c) Longer-term HF hospitalization
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161
(d) Longer-term all-cause death Log-rank p = 0.026
1.00
Log-rank p = 0.007
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0.90 0.8 Cumulative survival
Event-free survival
0.80 0.70 0.60 0.50 0.40
Low PRA (≤ 0.50 ng/mL/h) Moderate PRA (0.51–2.30 ng/mL/h) High PRA (> 2.30 ng/mL/h)
0.30
0.6
0.4
Low PRA (≤ 0.50 ng/mL/h) Moderate PRA (0.51–2.30 ng/mL/h) High PRA (> 2.30 ng/mL/h)
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0.0
0.20 0
2
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Number at risk
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85
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Time to all-cause death (years)
Time to HF hospitalization (years) 85
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Number at risk
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1074
904
572
330
163
Figure 3. Association over time of baseline PRA with (A) cardiac morbidity and mortality throughout study period and (Inset) during the first 3 years, (B) MI throughout study period and (Inset) during the first 3 years, (C) HF hospitalization, and (D) all-cause death throughout study period. Graph shows Kaplan-Meier survival curves for patients divided into categories of baseline PRA by recursive partitioning. p Values were determined using log-rank test.
though most patients in both studies were receiving an angiotensin-converting enzyme inhibitor and/or an angiotensin receptor blocker.4,5 This supports the hypothesis that drug treatment to reduce PRA might improve the cardiovascular and renal outcomes beyond current optimal treatment. Although -blocker treatment reduces PRA, a study of the effects of carvedilol and metoprolol in patients with HF showed that reductions in PRA observed after 12 weeks were not sustained at 52 weeks.8 More will be known about the potential benefits of PRA reduction with the completion of the morbidity and mortality trials with direct renin inhibitors.9,10 The potential limitations of our study should be considered. The study, although prospective, was observational in nature and hence assessed associations but not causality per se. Although our multivariate analyses corrected for a broad range of baseline clinical, disease and demographic characteristics, residual confounding factors could not be excluded. Additional studies would be helpful to confirm the association between PRA and the risk of cardiac events and to assess the individual contribution of PRA to prognosis when considered jointly with other bi-
omarkers relevant to CAD (e.g., C-reactive protein, which we previously showed to be a predictor of mortality in patients with CAD and left ventricular dysfunction,11 and B-type natriuretic peptide, shown to be a potent prognostic marker for HF). Our finding that PRA was associated with 3-year, but not longer-term, MI or cardiac morbidity/mortality might reflect the fact that MI occurring after 3 years in patients with coronary stenosis is driven more by the underlying ischemic injury and other risk factors, such as hyperlipidemia. We assessed a relatively homogenous population of predominantly Northern European descent; the association between PRA and outcomes might or might not be similar in other racial and ethnic groups. Our analyses were done using a baseline PRA measurement, which might not adequately reflect PRA during longer-term follow-up. The absence of serial PRA measurements during the study period might explain the apparent loss over time of the association between PRA and the outcomes. Although discharge medication was recorded (and showed a low rate of antihypertensive drug use), we did not have information on individual drug therapy before baseline sampling or during longer-term follow-up. This is noteworthy because most of
Coronary Artery Disease/PRA and Cardiac Outcomes in CAD
our patients had hypertension, and most antihypertensive agents increase PRA.12–14 Additional studies are underway to investigate the influence of concomitant treatment on the association between elevated PRA and outcomes and to explore the relation between PRA and cardiovascular and renal outcomes in subgroups of patients with CAD and hypertension or diabetes at baseline.
6.
7.
8.
Acknowledgment: All authors participated in the development and writing of the report and approved the final report for publication. The authors take full responsibility for the content and thank Mark Rolfe (Oxford PharmaGenesis Ltd., Oxford, United Kingdom) for medical writing support, editorial assistance, and collation and incorporation of comments from all authors. 1. Brunner HR, Laragh JH, Baer L, Newton MA, Goodwin FT, Krakoff LR, Bard RH, Buhler FR. Essential hypertension: renin and aldosterone, heart attack and stroke. N Engl J Med 1972;286:441– 449. 2. Blumenfeld JD, Sealey JE, Alderman MH, Cohen H, Lappin R, Catanzaro DF, Laragh JH. Plasma renin activity in the emergency department and its independent association with acute myocardial infarction. Am J Hypertens 2000;13:855– 863. 3. Alderman MH, Ooi WL, Cohen H, Madhavan S, Sealey JE, Laragh JH. Plasma renin activity: a risk factor for myocardial infarction in hypertensive patients. Am J Hypertens 1997;10:1– 8. 4. Latini R, Masson S, Anand I, Salio M, Hester A, Judd D, Barlera S, Maggioni AP, Tognoni G, Cohn JN. The comparative prognostic value of plasma neurohormones at baseline in patients with heart failure enrolled in Val-HeFT. Eur Heart J 2004;25:292–299. 5. Vergaro G, Fontana M, Poletti R, Giannoni A, Iervasi AL, Masi L, Mammini C, Gabutti A, Passino C, Emdin M. Plasma renin activity is
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13. 14.
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an independent prognostic factor in chronic heart failure (abstract). Eur Heart J 2008;29 (Suppl 1):393. Rouleau JL, Packer M, Moye L, de Champlain J, Bichet D, Klein M, Rouleau JR, Sussex B, Arnold JM, Sestier F. Prognostic value of neurohumoral activation in patients with an acute myocardial infarction: effect of captopril. J Am Coll Cardiol 1994;24:583–591. Verma S, Gupta M, Holmes DT, Teoh H, Xu L, Yusuf S, Lonn EM. Plasma renin activity is associated with increased cardiovascular events and mortality in the HOPE study (abstract). Circulation 2009; 120:S453. Fung JW, Yu CM, Yip G, Chan S, Yandle TG, Richards AM, Nicholls MG, Sanderson JE. Effect of beta blockade (carvedilol or metoprolol) on activation of the renin-angiotensin-aldosterone system and natriuretic peptides in chronic heart failure. Am J Cardiol 2003;92:406 – 410. Sever PS, Gradman AH, Azizi M. Managing cardiovascular and renal risk: the potential of direct renin inhibition. J Renin Angiotensin Aldosterone Syst 2009;10:65–76. Parving HH, Brenner BM, McMurray JJ, de Zeeuw D, Haffner SM, Solomon SD, Chaturvedi N, Ghadanfar M, Weissbach N, Xiang Z, Armbrecht J, Pfeffer MA. Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE): rationale and study design. Nephrol Dial Transplant 2009;24:1663–1671. Ronnow BS, Reyna SP, Muhlestein JB, Horne BD, Allen Maycock CA, Bair TL, Carlquist JF, Kfoury AG, Anderson JL, Renlund DG. C-reactive protein predicts death in patients with non-ischemic cardiomyopathy. Cardiology 2005;104:196 –201. Azizi M, Menard J. Combined blockade of the renin-angiotensin system with angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists. Circulation 2004;109:2492– 2499. Lijnen P, Fagard R, Staessen J, Amery A. Effect of chronic diuretic treatment on the plasma renin-angiotensin-aldosterone system in essential hypertension. Br J Clin Pharmacol 1981;12:387–392. Colantonio D, Casale R, Desiati P, Giandomenico G, Bucci V, Pasqualetti P. Short-term effects of atenolol and nifedipine on atrial natriuretic peptide, plasma renin activity, and plasma aldosterone in patients with essential hypertension. J Clin Pharmacol 1991;31:238 – 242.
0002-9149/10/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2010.04.040
PRA was associated with subsequent severe heart failure (HF) and combined cardiovascular events.6 A recent study of 699 patients with HF showed that PRA was associated with cardiovascular events despite treatment with an angiotensin-converting enzyme inhibitor and/or an angiotensin receptor blocker.5 We assessed the association between baseline PRA and the risk of cardiovascular events in a population of patients with CAD (ⱖ70% stenosis) but no history of MI or HF who had undergone coronary angiography and were followed up for long-term outcomes. This is the first study to assess the association between PRA and a first incident cardiovascular event (other than angina) in patients with CAD. Methods The study patients were drawn from the cardiac catheterization registry of the Intermountain Heart Collaborative Study, a cohort of patients undergoing coronary arteriography at the LDS Hospital (Salt Lake City, Utah). Patients were of unrestricted age and gender and gave written informed consent for a blood draw at angiography for use in confidential studies approved by the hospital’s institutional review board. A total of 1,165 patients with CAD, defined as the presence of one or more ⱖ70% obstructive lesions on the coronary artery angiogram, and who had been followed up for ⱖ3 years, were selected for the present study. The www.ajconline.org
Coronary Artery Disease/PRA and Cardiac Outcomes in CAD
assessment of CAD was made by review of the angiograms by the patient’s cardiologist and was performed with the reviewer blinded to the levels of PRA obtained from the blood collection. The clinical presentation of the patients included in the study was either stable angina pectoris (stable exertional symptoms only) or unstable angina pectoris (progressive symptoms or symptoms at rest). In addition to age and gender, the recorded baseline characteristics included a diagnosis of diabetes (fasting blood glucose level ⬎125 mg/dl, clinical diagnosis of diabetes mellitus, or the use of antidiabetic medication), hypertension (systolic blood pressure ⱖ140 mm Hg, diastolic blood pressure ⱖ90 mm Hg, or use of antihypertensive therapy), renal failure (clinical renal failure or calculated glomerular filtration rate of ⬍15 ml/min), and hyperlipidemia (total cholesterol ⱖ200 mg/dl, low-density lipoprotein cholesterol ⱖ130 mg/dl, or the use of cholesterol-lowering medication). A family history of cardiovascular outcomes was patient reported and defined as a first-order relative experiencing cardiovascular death, MI, or coronary revascularization before 65 years of age. Smoking status was patient reported and included active smokers and those with a ⬎10 pack-year history. Discharge medications were also recorded and included statins, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, calcium channel blockers, and diuretics. The goal of the present study was to evaluate patients with known CAD but without pre-existing left ventricular dysfunction. Therefore, those with a history of MI or a current diagnosis of acute MI (creatine kinase-MB ⬎6 mg/dl and creatine kinase-MB index ⬎3%), a history or current diagnosis of HF, or a left ventricular ejection fraction of ⱕ45% were excluded before sample testing. Patients who had been prescribed -blocker therapy at discharge were also excluded from the study a priori as an additional method of excluding patients with previous HF or MI. No information was available for drug treatment received by the patients before the baseline assessment or after discharge; hence, the study could have included patients who received -blocker therapy during long-term follow-up. Baseline PRA was measured from plasma obtained at coronary angiography and analyzed by Clinical Reference Laboratory Medinet (Lenexa, Kansas) using the DiaSorin PRA radioimmunoassay method (DiaSorin, Stillwater, Minnesota). Patients selected for inclusion had blood drawn when supine between 6 A.M. and 11:30 A.M. to minimize the confounding effects of posture and diurnal variation on the PRA levels. The blood samples were taken without washout of previously prescribed medications. The plasma was separated from whole blood within 4 hours of collection and stored at ⫺70°C until assayed in batches. The predefined cardiovascular outcomes were all-cause death, fatal and nonfatal MI, cardiac morbidity and mortality, HF hospitalization, and cerebrovascular accident (CVA), evaluated during the first 3 years of follow-up and for the entire follow-up duration. ●
MI was defined as a hospitalization in which the patient had a troponin I level of ⱖ0.4 ng/ml or a discharge diagnosis of an MI (International Statistical
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Classification of Disease and Related Health Problems, 9th ed., code 410). HF hospitalization was defined as a hospitalization in which a clinical diagnosis of HF was made or the patient had a discharge diagnosis of HF (International Statistical Classification of Disease and Related Health Problems, 9th ed., code 428). CVA was determined by the discharge diagnosis (International Statistical Classification of Disease and Related Health Problems, 9th ed., code 436). Deaths were determined by telephone survey, hospital records, the Utah State Health Department records, and the national Social Security death records. Patients not listed as deceased in any registry were considered to be alive.
All patients were followed up until death or the censoring date. For outcomes that assessed composite end points, patients who experienced both end points were censored after the occurrence of the first event to ensure they were counted only once. Our statistical approach can be summarized as follows. Patients were subdivided into low, moderate, or high baseline PRA using recursive partitioning analysis (a statistical technique that defines clinically meaningful PRA categories that predict cardiovascular risk) and by tertiles. The baseline, demographic, and clinical characteristics were compared across PRA categories to identify any significant differences associated with high PRA. The distribution of patients experiencing each predefined outcome across the PRA categories was evaluated using univariate analysis to determine whether patients with a particular outcome were more likely to have high PRA. A multivariate analysis of the relative increase in risk of outcomes with high PRA versus low PRA (adjusting for differences in baseline, demographic, and clinical characteristics) was performed to determine whether high PRA was associated with the predefined outcomes. Recursive partitioning resulted in the definition of low (ⱕ0.50 ng/ml/h), moderate (0.51 to 2.30 ng/ml/h), and high (⬎2.30 ng/ml/h) PRA categories. To validate the recursive partitioning method, the patients were also grouped into 3 approximately equal-sized tertiles (ⱕ0.40, 0.41 to 1.90, and ⬎1.90 ng/ml/h). The chi-square test was used to compare the baseline, demographic, and clinical characteristics across the PRA tertiles or categories and for univariate analysis of the association between PRA categories with the predefined cardiovascular outcomes. Multivariate Cox regression analysis was performed to determine the hazard ratios corrected for age, gender, hypertension, hyperlipidemia, diabetes, smoking, a family history of CAD, renal failure, clinical presentation (stable angina or MI), and discharge medications (statins, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and diuretics). The final models entered significant (p ⬍0.05) and confounding (10% change in -coefficient) covariables. Kaplan-Meier survival estimates and the log-rank test were used to compare the cumulative long-term incidence of the end points across the PRA categories. Two-tailed p values are presented, with p ⫽ 0.05 designated as nominally significant. Statistical analysis was per-
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Table 1 Patient demographic and disease characteristics by baseline plasma renin activity (PRA) category and baseline plasma renin activity (PRA) tertile Characteristic
Baseline PRA Tertile†
Baseline PRA Category*
Median plasma renin activity (ng/ml/h) Age (years)‡, mean ⫾ SD Men Hyperlipidemia Hypertension‡§ Diabetes mellitus‡§ Smoker Family history of cardiovascular disease Renal failure‡§ Left ventricular ejection fraction (%), mean ⫾ SD Angiotensin-converting enzyme inhibitor‡ Angiotensin receptor blocker Diuretic Statin‡§
Overall (n ⫽ 1,165)
Low (n ⫽ 470)
Moderate (n ⫽ 351)
High (n ⫽ 344)
Tertile 1 (n ⫽ 412)
Tertile 2 (n ⫽ 378)
Tertile 3 (n ⫽ 375)
0.30 65.5 ⫾ 11.2 353 (75.1%) 305 (64.9%) 284 (60.4%) 99 (21.1%) 99 (21.1%) 199 (42.3%) 6 (1.3%) 62.1 ⫾ 10.6
1.10 64.4 ⫾ 11.2 259 (73.8%) 221 (63.0%) 215 (61.3%) 90 (25.6%) 73 (20.8%) 157 (44.7%) 3 (0.9%) 63.5 ⫾ 9.9
5.40 63.0 ⫾ 11.6 242 (70.3%) 214 (62.2%) 237 (68.9%) 100 (29.1%) 85 (24.7%) 153 (44.5%) 12 (3.5%) 63.3 ⫾ 10.9
0.20 65.5 ⫾ 11.2 311 (75.5%) 269 (65.3%) 248 (60.2%) 82 (19.9%) 87 (21.1%) 173 (42.0%) 6 (1.5%) 62.4 ⫾ 10.5
0.90 64.4 ⫾ 11.2 278 (73.6%) 235 (62.2%) 232 (61.4%) 96 (25.3%) 78 (20.7%) 173 (45.7%) 3 (0.8%) 63.0 ⫾ 10.2
4.80 63.1 ⫾ 12.3 265 (70.6%) 236 (62.9%) 255 (68.1%) 111 (29.6%) 92 (24.4%) 164 (43.6%) 12 (3.1%) 63.4 ⫾ 10.8
0.80 64.4 ⫾ 11.6 852 (73.1%) 740 (63.5%) 735 (63.1%) 290 (24.9%) 256 (22.0%) 509 (43.7%) 21 (1.8%) 62.9 ⫾ 10.5
(n ⫽ 334) 5 (1.1%) 1 (0.2%) 7 (1.5%) 210 (44.7%)
(n ⫽ 256) 8 (2.3%) 4 (1.1%) 8 (2.3%) 158 (45.0%)
(n ⫽ 227) 11 (3.2%) 1 (0.3%) 9 (2.6%) 122 (35.5%)
(n ⫽ 288) 3 (0.7%) 1 (0.2%) 7 (1.7%) 182 (44.2%)
(n ⫽ 270) 9 (2.4%) 3 (0.8%) 7 (1.9%) 174 (46.2%)
(n ⫽ 259) 12 (3.1%) 2 (0.5%) 10 (2.6%) 134 (35.8%)
(n ⫽ 817) 24 (2.1%) 6 (0.5%) 24 (2.1%) 490 (42.1%)
Data are presented as n (%) unless otherwise stated. * Low recursive partitioning category: baseline PRA ⱕ0.50 ng/ml/h; moderate category: 0.51 to 2.30 ng/ml/h; high category ⬎2.30 ng/ml/h. † Tertile 1 baseline PRA ⱕ0.40 ng/ml/h; tertile 2 0.41 to 1.90 ng/ml/h; tertile 3 ⬎1.90 ng/ml/h. ‡ p ⬍0.05 for difference across categories (chi-square test). § p ⬍0.05 for difference across tertiles (chi-square test).
Proportion of patients with event (%)
25
Low PRA (≤ 0.50 ng/mL/h) Moderate PRA (0.51–2.30 ng/mL/h) High PRA (> 2.30 ng/mL/h)
20
15
*
* *
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0
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ac rdi
y/ dit rbi lity mo orta m
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s ho
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Figure 1. Distribution of baseline PRA in patients who experienced a predefined cardiovascular outcome within 3 years of follow-up. Patients were divided into categories of baseline PRA by recursive partitioning. *p ⬍0.05, chi-square test.
formed using the SSPS, version 15.0 (SPSS, Chicago, Illinois). Results A total of 1,165 patients with CAD were included in the present study. The mean age was nearly 65 years, and almost 75% were men (Table 1). The median PRA was 0.80 ng/ml/h across the entire patient population. The patients with higher baseline PRA tended to be younger and to have a greater prevalence of hypertension, diabetes, and renal
failure. The rate of antihypertensive medication use at discharge was low. The average follow-up duration (mean ⫾ SD) after the baseline PRA measurement was 6.4 ⫾ 3.2 years (maximum follow-up 14.6). During the first 3 years of follow-up, 111 patients died, 40 had an MI (nonfatal for 26 patients), 19 were hospitalized for HF, and 14 had a CVA (nonfatal for 9 patients). During the entire follow-up period, 258 patients died, 215 had an MI, 96 were hospitalized for HF, and 67 had a CVA. Of the patients who experienced a predefined event within the first 3 years of follow-up, a greater proportion were in the moderate or high PRA categories (i.e., baseline PRA ⬎0.50 ng/ml/h) than in the low PRA category (ⱕ0.50 ng/ml/h). These differences were statistically significant (p ⬍0.05) for 3-year cardiac morbidity/mortality, MI, HF hospitalization, all-cause death, and all-cause death/HF (Figure 1). Similar results were found when patients were analyzed by tertiles (data not shown). The analysis of the 3-year outcomes showed that patients in the high baseline PRA category had a significantly increased risk of cardiac morbidity/mortality, MI, HF hospitalization, all-cause death, and all-cause death/HF compared with patients in the low baseline PRA category (Figure 2). The association between elevated PRA and outcomes was observed despite correction for hypertension, hyperlipidemia, diabetes, a family history of cardiovascular events, smoking, renal failure, and the use of statins. During the entire follow-up period (i.e., up to 14.6 years), PRA remained significantly associated with a longer-term increased risk of HF hospitalization, all-cause death, and allcause death/HF (Figure 2). High PRA was not significantly associated with MI during longer-term follow-up.
Coronary Artery Disease/PRA and Cardiac Outcomes in CAD
(a) 3-year outcomes Hazard ratio
Category Tertile Outcome Cardiac morbidity/ mortality MI HF hospitalization All-cause death All-cause death/HF CVA
0.1
Elevated PRA associated with reduced risk
HR (95% CI)
p value
1.96 (1.24, 3.10) 1.79 (1.13, 2.86) 2.41 (1.13, 5.12) 2.18 (1.01, 4.71) 4.39 (1.19, 16.20) 3.40 (0.92, 12.50) 1.80 (1.14, 2.86) 1.59 (1.00, 2.53) 1.89 (1.21, 2.96) 1.66 (1.06, 2.60) 0.94 (0.22, 3.90) 1.26 (0.29, 5.42)
0.004 0.013 0.017 0.047 0.027 0.066 0.010 0.049 0.005 0.028 0.925 0.758
1
Elevated PRA associated with increased risk
10
(b) Longer-term outcomes Hazard ratio
Category Tertile Outcome Cardiac morbidity/ mortality MI HF hospitalization All-cause death All-cause death/HF CVA
Elevated PRA associated with reduced risk 0.1
HR (95% CI)
p value
1.19 (0.92, 1.53) 1.18 (0.92, 1.53) 0.98 (0.71, 1.36) 0.97 (0.70, 1.34) 2.12 (1.26, 3.54) 2.12 (1.27, 3.54) 1.56 (1.17, 2.08) 1.41 (1.06, 1.88) 1.53 (1.17, 2.00) 1.44 (1.10, 1.89) 0.78 (0.42, 1.46) 0.85 (0.46, 1.58)
0.189 0.204 0.919 0.837 0.004 0.004 0.002 0.022 0.002 0.007 0.437 0.605
1
Elevated PRA associated with increased risk
10
Figure 2. Association between elevated baseline PRA and (A) 3-year and (B) longer-term cardiovascular outcomes. Elevated baseline PRA was calculated as highest versus lowest PRA tertile (tertile 3 vs tertile 1; baseline PRA ⬎1.90 versus ⱕ0.40 ng/ml/h) or category (high versus low; baseline PRA ⬎2.30 versus ⱕ0.50 ng/ml/h). Data are presented as hazard ratio (HR) (95% confidence interval [CI]) from multivariate analysis adjusted for hypertension, hyperlipidemia, diabetes, family history, smoking, and renal failure.
No statistically significant association between PRA and CVA was observed during intermediate or longer-term follow-up. For all outcomes, similar results were observed when patients were divided by the baseline PRA tertiles (Figure 2). Elevated baseline PRA was significantly associated with increased 3-year cardiac morbidity/mortality (log-rank p ⫽ 0.005; Figure 3) and MI (log-rank p ⫽ 0.031; Figure 3). Separation of the survival curves for cardiac morbidity/ mortality between patients in the moderate/high and low PRA categories was evident within 1 month (Figure 3) and persisted throughout the first 3 years of follow-up. Elevated PRA was also significantly associated with increased HF hospitalization (log-rank p ⫽ 0.03; Figure 3) and all-cause death (log-rank p ⫽ 0.007; Figure 3) during longer-term follow-up. Discussion This is the first study to evaluate the association between baseline PRA and cardiovascular morbidity and mortality in patients with CAD but with essentially normal left ventricular function and no history of MI or HF. We found that patients in the high PRA category had a significantly greater risk of short- to intermediate-term (3-year) cardiac morbid-
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ity/mortality (2.0-fold increase), MI (2.4-fold increase), and all-cause death (1.8-fold increase) compared with patients who had low PRA. Elevated baseline PRA was also significantly associated with an increased risk of longer-term (up to 14.6 years) HF hospitalization (2.1-fold increase) and all-cause death (1.6-fold increase). The association between PRA and outcomes was observed despite correction for hypertension, hyperlipidemia, diabetes, a family history of cardiovascular events, smoking, renal failure, and the use of statins. It was also independent of the methods used to define the baseline PRA subgroups or analyze the outcomes. Information on postdischarge medications was not available; hence, the association between PRA and outcomes was seen despite follow-up antihypertensive treatment. These findings add to the growing body of evidence that elevated baseline PRA is associated with cardiovascular morbidity and mortality across a broad range of patient groups and is a potential target for treatment. The present study has provided clear evidence that elevated baseline PRA is associated with hard clinical outcomes (death, MI, HF hospitalization, cardiac morbidity/ mortality) in patients with CAD. Previous studies have demonstrated that PRA might be associated with the risk of MI in patients with hypertension (Alderman et al worksite program3), increased risk of major cardiovascular events, cardiovascular death, all-cause death and HF in high-risk patients with vascular disease or diabetes but without left ventricular dysfunction or heart failure (Heart Outcomes Prevention Evaluation [HOPE] study7), progression to severe HF and combined cardiovascular events in post-MI patients (Sleep Apnea Cardiovascular Endpoints [SAVE] study6), and combined cardiovascular morbidity/mortality in patients with HF (Valsartan Heart Failure Trial [ValHeFT]4 and the study by Vergaro et al5). Overall, the current weight of evidence shows that PRA might be associated with the development of hard clinical outcomes across the cardiovascular disease continuum—from hypertension through to CAD and MI and then to the development of HF and subsequent HF-related cardiovascular events. Elevated baseline PRA was associated with approximately double the risk of HF hospitalization during longerterm follow-up. This is of major clinical importance because HF is a common long-term consequence of CAD progression, particularly in patients who have previously had an MI or have long-standing underlying ischemia (ischemic cardiomyopathy). Our results are consistent with the landmark SAVE study, in which elevated PRA doubled the risk of severe HF (relative risk 2.0, p ⫽ 0.002) during a 3-year period after acute MI in patients with CAD and documented left ventricular dysfunction.6 In the present study population of patients with CAD and normal baseline left ventricular function, the Kaplan-Meier survival curves for longer-term HF hospitalization showed clear and statistically significant separation of the moderate/high PRA categories from low PRA (p ⫽ 0.03), with most HF events occurring in the later years of follow-up. Together, these results indicate that elevated baseline PRA might be associated with the longterm development of HF in patients with CAD. An important observation from the Val-HeFT4 and Vergaro et al5 studies in patients with HF is that elevated PRA was significantly associated with clinical outcomes even
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(a) Cardiac morbidity/mortality
(b) MI
1.0
1.0
Low PRA (≤ 0.50 ng/mL/h) Moderate PRA (0.51–2.30 ng/mL/h) High PRA (> 2.30 ng/mL/h)
0.6
0.8 Long-term log-rank p = 0.587
1.00
Event-free survival
Event-free survival
0.8
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0.4 0.90
0.2
Low PRA (≤ 0.50 ng/mL/h) Moderate PRA (0.51–2.30 ng/mL/h) High PRA (> 2.30 ng/mL/h)
0.85
0.6
1.00 0.98
0.4
0.96 0.94
0.2
3-year log-rank p = 0.005
Long-term log-rank p = 0.554
0.92
3-year log-rank p = 0.031
0.90
0.80 0
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Time to cardiac morbidity/mortality (years) Number at risk
2.0
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559
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84
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16
Time to MI (years) Number at risk
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(c) Longer-term HF hospitalization
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(d) Longer-term all-cause death Log-rank p = 0.026
1.00
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Event-free survival
0.80 0.70 0.60 0.50 0.40
Low PRA (≤ 0.50 ng/mL/h) Moderate PRA (0.51–2.30 ng/mL/h) High PRA (> 2.30 ng/mL/h)
0.30
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Low PRA (≤ 0.50 ng/mL/h) Moderate PRA (0.51–2.30 ng/mL/h) High PRA (> 2.30 ng/mL/h)
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Time to all-cause death (years)
Time to HF hospitalization (years) 85
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Number at risk
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1074
904
572
330
163
Figure 3. Association over time of baseline PRA with (A) cardiac morbidity and mortality throughout study period and (Inset) during the first 3 years, (B) MI throughout study period and (Inset) during the first 3 years, (C) HF hospitalization, and (D) all-cause death throughout study period. Graph shows Kaplan-Meier survival curves for patients divided into categories of baseline PRA by recursive partitioning. p Values were determined using log-rank test.
though most patients in both studies were receiving an angiotensin-converting enzyme inhibitor and/or an angiotensin receptor blocker.4,5 This supports the hypothesis that drug treatment to reduce PRA might improve the cardiovascular and renal outcomes beyond current optimal treatment. Although -blocker treatment reduces PRA, a study of the effects of carvedilol and metoprolol in patients with HF showed that reductions in PRA observed after 12 weeks were not sustained at 52 weeks.8 More will be known about the potential benefits of PRA reduction with the completion of the morbidity and mortality trials with direct renin inhibitors.9,10 The potential limitations of our study should be considered. The study, although prospective, was observational in nature and hence assessed associations but not causality per se. Although our multivariate analyses corrected for a broad range of baseline clinical, disease and demographic characteristics, residual confounding factors could not be excluded. Additional studies would be helpful to confirm the association between PRA and the risk of cardiac events and to assess the individual contribution of PRA to prognosis when considered jointly with other bi-
omarkers relevant to CAD (e.g., C-reactive protein, which we previously showed to be a predictor of mortality in patients with CAD and left ventricular dysfunction,11 and B-type natriuretic peptide, shown to be a potent prognostic marker for HF). Our finding that PRA was associated with 3-year, but not longer-term, MI or cardiac morbidity/mortality might reflect the fact that MI occurring after 3 years in patients with coronary stenosis is driven more by the underlying ischemic injury and other risk factors, such as hyperlipidemia. We assessed a relatively homogenous population of predominantly Northern European descent; the association between PRA and outcomes might or might not be similar in other racial and ethnic groups. Our analyses were done using a baseline PRA measurement, which might not adequately reflect PRA during longer-term follow-up. The absence of serial PRA measurements during the study period might explain the apparent loss over time of the association between PRA and the outcomes. Although discharge medication was recorded (and showed a low rate of antihypertensive drug use), we did not have information on individual drug therapy before baseline sampling or during longer-term follow-up. This is noteworthy because most of
Coronary Artery Disease/PRA and Cardiac Outcomes in CAD
our patients had hypertension, and most antihypertensive agents increase PRA.12–14 Additional studies are underway to investigate the influence of concomitant treatment on the association between elevated PRA and outcomes and to explore the relation between PRA and cardiovascular and renal outcomes in subgroups of patients with CAD and hypertension or diabetes at baseline.
6.
7.
8.
Acknowledgment: All authors participated in the development and writing of the report and approved the final report for publication. The authors take full responsibility for the content and thank Mark Rolfe (Oxford PharmaGenesis Ltd., Oxford, United Kingdom) for medical writing support, editorial assistance, and collation and incorporation of comments from all authors. 1. Brunner HR, Laragh JH, Baer L, Newton MA, Goodwin FT, Krakoff LR, Bard RH, Buhler FR. Essential hypertension: renin and aldosterone, heart attack and stroke. N Engl J Med 1972;286:441– 449. 2. Blumenfeld JD, Sealey JE, Alderman MH, Cohen H, Lappin R, Catanzaro DF, Laragh JH. Plasma renin activity in the emergency department and its independent association with acute myocardial infarction. Am J Hypertens 2000;13:855– 863. 3. Alderman MH, Ooi WL, Cohen H, Madhavan S, Sealey JE, Laragh JH. Plasma renin activity: a risk factor for myocardial infarction in hypertensive patients. Am J Hypertens 1997;10:1– 8. 4. Latini R, Masson S, Anand I, Salio M, Hester A, Judd D, Barlera S, Maggioni AP, Tognoni G, Cohn JN. The comparative prognostic value of plasma neurohormones at baseline in patients with heart failure enrolled in Val-HeFT. Eur Heart J 2004;25:292–299. 5. Vergaro G, Fontana M, Poletti R, Giannoni A, Iervasi AL, Masi L, Mammini C, Gabutti A, Passino C, Emdin M. Plasma renin activity is
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