The Clinical Significance of N‐terminal Pro‐brain Natriuretic Peptide in Detecting the Residual Cardiovascular Risk in Hypertension and Other Clinical Conditions and in Predicting Future Cardiovascular Events

It has been clinically demonstrated that hypertensive patients, even with controlled blood pressure (BP), have a higher incidence of cardiovascular events than normotensive patients.1 This has been attributed to an underlying residual cardiovascular risk (RCR) and is due to the fact that treatment of hypertension cannot completely reverse the sustained vascular damage as well as other cardiovascular morbid conditions.1 Therefore, some researchers have investigated several biomarkers that better predict the cardiovascular consequences of the RCR.2 Of all biomarkers used, the best predictor has been the brain natriuretic peptide (BNP) and its inactive fragment N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) in hypertension and other disease states.3, 4 Increased levels of RCR have been associated with a 50% increased risk of future cardiovascular events not only in controlled hypertensive patients, but also in patients with other cardiovascular diseases.5 Therefore, the baseline measurement of blood levels of NT‐proBNP in either newly diagnosed untreated or pretreated hypertensive patients is important for the evaluation of RCR and its predictive value for future cardiovascular events. In order to get a better perspective of the current status of RCR and its predictive significance, a Medline search of the English language literature was conducted from 2010 to 2015 and 14 pertinent papers were selected. The findings from these studies together with collateral literature will be discussed in this commentary.

Clinical Diagnostic Significance of NT‐proBNP

The brain (B‐type) natriuretic peptide (BNP) is a 32‐amino acid polypeptide secreted by ventricular myocytes in response to the stretching effect of pressure or volume overload of the left ventricle, and its levels correlate with the degree of left ventricular dysfunction (LVD). Circulating levels of BNP and its inactive metabolite NT‐proBNP are very low in healthy individuals, but they increase significantly in response to myocardial stress.4, 6 Therefore, the measurement of BNP and especially NT‐proBNP, as a result of its long half‐life, have been used for the early detection of LVD secondary to hypertension, myocardial ischemia, and heart failure (HF). Several studies have shown good correlation between the levels of NT‐proBNP and stage of LVD. Consequently, NT‐proBNP has been used for the detection of RCR and the prediction of future cardiovascular events in the general population and in patients with hypertension, cardiovascular disease (CVD), coronary heart disease (CHD), and HF. The measurement of NT‐proBNP has been used effectively for the diagnosis of subclinical LVD and HF in primary care and is cost‐effective in that it replaced the use of echocardiography.7, 8 An NT‐proBNP level <180 pg/mL ruled out major LVD and avoided the use of echocardiography and the referral to specialized centers in 38% and 23% of the cases, respectively.7 In another study, NT‐proBNP levels ≤400 pg/mL or ≤300 pg/mL for initial evaluation and sequential follow‐up reduced the use of echocardiography by 33% to 36% and 28% to 29%, respectively. This corresponded to a yearly cost reduction of 2 to 5 million euros/million inhabitants.8 The data from studies indicating the usefulness of NT‐proBNP for the detection of RCR and its predictive value for future cardiovascular events in patients with various disease states are summarized in 1.

Table 1.

Usefulness of NT‐proBNP in the Detection of Cardiovascular Residual Risk and Its Prediction for Future Cardiovascular Events in Various Diseases

First Author	Study Design	Study Population	Patients, No.	Age, y	Peptide Type	Follow‐Up, y	Outcome
Di Angelantonio4	Rev	PC	87,474	41–86	BNP, NT‐proBNP	4–12	CVD HR, 2.82
Wannamethee9	PC	GP	3649	60–79	NT‐proBNP	9	CVD HR, 1.49
Nadir10	PC	GP	300	64	BNP	3.3	cTOD +
Linssen11	PC	GP	8383	49	NT‐proBNP	7.5	CVD HR, 1.37
Welsh12	Rand	HC	6595	55	NT‐proBNP	15	CVD HR, 1.34
Price3	P‐C	DM	1066	68	NT‐proBNP	4	CVD HR, 1.39
Paget13	PC	HTN	684	52	NT‐proBNP	6	Death HR, 2.33
Welsh14	Rand	HTN	6549	65	NT‐proBNP	5.5	CVD OR, 1.24

Abbreviations: +, positive effect; cTOD, cardiac target organ damage; CVD, cardiovascular disease; DM, diabetes mellitus; GP, general population; HC, high cholesterol; HTN, hypertension; HR, hazards ratio; OR, odds ratio; PC, prospective cohort study; Rand, randomized; Rev, review; RR, relative risk.

Studies Demonstrating the Value of BNPs for the Detection of Residual Cardiovascular Risk

Several studies have tested the significance of B‐type natriuretic peptides (BNP and NT‐proBNP) for the detection of RCR and its value in predicting future cardiovascular events in several clinical conditions with good success. In a large review and meta‐analysis of 40 long‐term studies, Di Angelantonio and colleagues4 demonstrated the value of baseline levels of BNP and NT‐proBNP. The relative risk (RR) for those in the upper tertile of BNP and NT‐proBNP levels was 2.82 (95% confidence interval [CI], 2.40–3.33) for the incidence of CVD and 2.03 (95% CI, 1.54–2.66) and 1.93 (95% CI, 1.58–2.37) for CHD for stroke, respectively, after adjusting for several risk factors. Similar results have been reported by Wannamethee and colleagues9 from a prospective study of older patients. In this study, NP‐pro BNP levels were significantly associated with the incidence of cardiovascular outcomes after adjusting for cardiovascular risk factors. The hazard ratio (HR) for those with and without preexisting CVD was 1.52 (95% CI, 1.33–1.75) and 1.49 (95% CI, 1.33–1.65), respectively. Nadir and coworkers10 used BNP and high‐sensitivity cardiac troponin to identify silent cardiac target organ damage (cTOD) in a primary prevention population. In this study, 34% developed cTOD and BNP screening was better than cardiac troponin in identifying silent cTOD. In a similar study, Linssen and colleagues11 used NT‐proBNP for the prediction of future cardiovascular morbidity and mortality in the general population from the Renal and Vascular End‐Stage Disease (PREVEND) study. After adjusting for age, sex, and other cardiovascular risk factors, a doubling of NT‐proBNP levels was associated with a 22% increased risk in all‐cause mortality and a 16% increase in cardiovascular events. Welsh and associates12 also used NT‐proBNP for the prediction of cardiovascular events from the West of Scotland Coronary Prevention Study (WOSCOPS). In this study, 35.2% of patients experienced cardiovascular events, and NT‐proBNP was associated with more fatal than nonfatal cardiovascular events (HR, 1.34 [95% CI, 1.19–1.52] and 1.17 [95% CI, 1.10–1.24]), respectively, after adjusting for classical risk factors plus C‐reactive protein. The addition of NT‐proBNP to traditional risk factors improved the c‐index (+0.013). Similarly, Price and colleagues3 used NT‐proBNP to predict cardiovascular events in older patients with type 2 diabetes from the prospective Edinburgh Type 2 Diabetes Study. In this study, NT‐proBNP was associated with subsequent risk of coronary artery disease independently of traditional risk factors (HR, 1.48 [95% CI, 1.10–1.98]). Paget and colleagues13 examined the predictive value of NT‐proBNP for future cardiovascular events in hypertensive patients with no history or symptoms of HF at baseline. After adjusting for several risk factors, including ambulatory BP, the risk for all‐cause mortality more than doubled with each increment of 1 log of NT‐proBNP (HR, 2.33 [95% CI, 1.36–3.96]). The risk of death with the highest NT‐proBNP tertile (≥133 pg/mL) was 3.3 times higher than the lowest tertile (<50.8 pg/mL) (HR, 3.30; 95% CI, 10.90–12.29). Similar findings have been reported by Welsh and colleagues14 in hypertensive patients free of CHD at baseline from the Anglo‐Scandinavian Cardiac Outcomes Trial (ASCOT). This study showed that NT‐proBNP predicted CVD risk independently of BP variation (odds ratio [OR], 1.24; 95% CI, 1.06–1.45). Furthermore, a 1 mm Hg increase in standard deviation (SD) of BP was associated with 2% higher NT‐proBNP in a multivariate regression analysis. Interestingly, atenolol‐based treatment resulted in a 69.6% increase in NT‐proBNP levels compared with a 36.5% decrease with amlodipine‐based treatment. In addition, amlodipine‐treated patients who achieved a 6‐month NT‐proBNP level <61 pg/mL were at lower risk for CVD (OR, 0.58; 95% CI, 0.37–0.91) than those who did not. These findings suggest that in addition to predicting cardiovascular risk, NT‐proBNP could also help to assess the efficacy of specific antihypertensive regimens.

Treatment of Residual Cardiovascular Risk

The findings from the studies presented suggest that the RCR is present in various cardiovascular conditions such as LVD, CVD, HF, diabetes mellitus, and hypertension. It is also a good predictor of future cardiovascular events, and BNP and NT‐proBNP are useful tools in its detection. In addition, BNP and NT‐proBNP are not only useful for their diagnostic potential but also for their rates of follow‐up and adherence to treatment. The best treatment regimen for RCR is not clear at present. In a recent brief review, Struthers and George15 suggest that the addition of β‐blockers to a baseline regimen based on renin‐angiotensin system (RAS) inhibitors will prevent future cardiovascular events if the levels of BNP or NT‐proBNP are elevated. Their recommendations are heavily based on the findings of the NT‐proBNP Selected Prevention of Cardiac Events in a Population of Diabetic Patients Without a History of Cardiac Disease (PONTIAC) study.16 In this study, 300 type 2 diabetic patients, with a mean age of 67.5±9 years who were free of cardiac disease at baseline but who had elevated systolic BP and NT‐proBNP levels, were randomized to usual care or to intensified care with maximum tolerated doses of RAS inhibitors plus β‐blockers. After 2 years of follow‐up, the intensified treatment group had a significant reduction in primary endpoints (hospitalizations or death) from cardiac causes (HR, 0.35; 95% CI, 0.13–0.98) compared with the usual care group. Systolic BP decreased equally with treatment in both groups, but there was no reduction in NT‐proBNP. The findings of the PONTIAC study are at variance with the findings of the much larger ASCOT study, in which the β‐blocker–based regimen (atenolol) resulted in a significant increase (69.6%) in NT‐proBNP levels compared with a significant decrease (36.5%) with the calcium channel blocker–based (amlodipine) regimen.14 The increased NT‐proBNP levels with β‐blockers has been attributed to the increased diastolic filling time and to left ventricular stretch. In addition, the selection of the β‐blocker used in the PONTIAC study is questionable because of its adverse effects in glucose regulation. However, it should be stated that β‐blockers are useful drugs in patients with CHD and HF, but not as useful in hypertensive patients with LVH.

Conclusions

The take‐home message from these studies include several points. Residual cardiovascular risk is present in various clinical and subclinical cardiovascular conditions, and the RCR is a good predictor for future cardiovascular events. BNP or NT‐proBNP are useful for the detection of RCR and should be included in the baseline evaluation of different cardiovascular conditions, including hypertension, and their follow‐up to detect nonadherence to treatment. Measurement of BNP and NT‐pro‐BNP is cost‐effective and replaces more expensive tests. Treatment of RCR should be based on the good control of each individual condition, including coexisting risk factors using appropriate treatment regimens, mostly regimens based on RAS blockers with the addition of other drugs including β‐blockers, if indicated. Future studies are needed to compare several treatment regimens to find the most effective treatment for RCR.