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/β-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 ± 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 = 0.004), MI (hazard ratio 2.41; p = 0.02), HF hospitalization (hazard ratio 4.39; p = 0.03), and all-cause death (hazard ratio 1.80; p = 0.01). Elevated baseline PRA was also associated with longer-term HF hospitalization (hazard ratio 2.12; p = 0.004) and all-cause death (hazard ratio 1.56; p = 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.
Plasma renin activity (PRA) was first associated with an increased risk of myocardial infarction (MI) in the early 1970s. 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. 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 PRA was associated with subsequent severe heart failure (HF) and combined cardiovascular events. 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. We assessed the association between baseline PRA and the risk of cardiovascular events in a population of patients with CAD (≥70% 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 ≥70% obstructive lesions on the coronary artery angiogram, and who had been followed up for ≥3 years, were selected for the present study. The 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 ≥140 mm Hg, diastolic blood pressure ≥90 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 ≥200 mg/dl, low-density lipoprotein cholesterol ≥130 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 ≤45% were excluded before sample testing. Patients who had been prescribed β-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 β-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.
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MI was defined as a hospitalization in which the patient had a troponin I level of ≥0.4 ng/ml or a discharge diagnosis of an MI ( International Statistical Classification of Disease and Related Health Problems , 9th ed., code 410).
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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).
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CVA was determined by the discharge diagnosis ( International Statistical Classification of Disease and Related Health Problems , 9th ed., code 436).
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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 (≤0.50 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 (≤0.40, 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 β-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 performed 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).
| Characteristic | Baseline PRA Category ⁎ | Baseline PRA Tertile † | 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) | ||
| Median plasma renin activity (ng/ml/h) | 0.30 | 1.10 | 5.40 | 0.20 | 0.90 | 4.80 | 0.80 |
| Age (years) ‡ , mean ± SD | 65.5 ± 11.2 | 64.4 ± 11.2 | 63.0 ± 11.6 | 65.5 ± 11.2 | 64.4 ± 11.2 | 63.1 ± 12.3 | 64.4 ± 11.6 |
| Men | 353 (75.1%) | 259 (73.8%) | 242 (70.3%) | 311 (75.5%) | 278 (73.6%) | 265 (70.6%) | 852 (73.1%) |
| Hyperlipidemia | 305 (64.9%) | 221 (63.0%) | 214 (62.2%) | 269 (65.3%) | 235 (62.2%) | 236 (62.9%) | 740 (63.5%) |
| Hypertension ‡ § | 284 (60.4%) | 215 (61.3%) | 237 (68.9%) | 248 (60.2%) | 232 (61.4%) | 255 (68.1%) | 735 (63.1%) |
| Diabetes mellitus ‡ § | 99 (21.1%) | 90 (25.6%) | 100 (29.1%) | 82 (19.9%) | 96 (25.3%) | 111 (29.6%) | 290 (24.9%) |
| Smoker | 99 (21.1%) | 73 (20.8%) | 85 (24.7%) | 87 (21.1%) | 78 (20.7%) | 92 (24.4%) | 256 (22.0%) |
| Family history of cardiovascular disease | 199 (42.3%) | 157 (44.7%) | 153 (44.5%) | 173 (42.0%) | 173 (45.7%) | 164 (43.6%) | 509 (43.7%) |
| Renal failure ‡ § | 6 (1.3%) | 3 (0.9%) | 12 (3.5%) | 6 (1.5%) | 3 (0.8%) | 12 (3.1%) | 21 (1.8%) |
| Left ventricular ejection fraction (%), mean ± SD | 62.1 ± 10.6 | 63.5 ± 9.9 | 63.3 ± 10.9 | 62.4 ± 10.5 | 63.0 ± 10.2 | 63.4 ± 10.8 | 62.9 ± 10.5 |
| (n = 334) | (n = 256) | (n = 227) | (n = 288) | (n = 270) | (n = 259) | (n = 817) | |
|---|---|---|---|---|---|---|---|
| Angiotensin-converting enzyme inhibitor ‡ | 5 (1.1%) | 8 (2.3%) | 11 (3.2%) | 3 (0.7%) | 9 (2.4%) | 12 (3.1%) | 24 (2.1%) |
| Angiotensin receptor blocker | 1 (0.2%) | 4 (1.1%) | 1 (0.3%) | 1 (0.2%) | 3 (0.8%) | 2 (0.5%) | 6 (0.5%) |
| Diuretic | 7 (1.5%) | 8 (2.3%) | 9 (2.6%) | 7 (1.7%) | 7 (1.9%) | 10 (2.6%) | 24 (2.1%) |
| Statin ‡ § | 210 (44.7%) | 158 (45.0%) | 122 (35.5%) | 182 (44.2%) | 174 (46.2%) | 134 (35.8%) | 490 (42.1%) |
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