Author + information
- G. Michael Felker, MD, MHS∗ ( and )
- Tariq Ahmad, MD, MPH
- ↵∗Reprint requests and correspondence:
Dr. G. Michael Felker, Duke Clinical Research Institute, DUMC Box 3850, Durham, North Carolina 27710.
“For the execution of the journey to the Indies I did not make use of intelligence, mathematics or maps.”
— El Libro de las Profecías, Christopher Columbus (1)
Prevention of cardiovascular disease remains the “undiscovered country” of cardiology, and is the focus of substantial efforts in the domains of research and public policy (2,3). The successful implementation of a cardiovascular disease prevention strategy depends on 2 distinct aspects: 1) identification of the optimal target population; and 2) the appropriate intervention for mitigating risk. To date, efforts aimed at identifying at-risk populations for primary prevention interventions have largely focused on patients with lipid abnormalities, elevated high-sensitivity C-reactive protein (hs-CRP), or diabetes mellitus. The natriuretic peptides, B-type natriuretic peptide (BNP) and N-terminal pro–B-type natriuretic peptide (NT-proBNP), are increasingly recognized as powerful tools for global risk prediction in cardiovascular disease. While the initial discovery and development of these biomarkers was focused on heart failure, it is now clear that these markers can provide quantitative information about the state of cardiovascular health across the spectrum of cardiovascular disease, ranging from the general population, to acute and chronic ischemic heart disease, to heart failure (4–7).
Natriuretic peptide levels across a broad range of values, from slightly high to extremely elevated, are independently predictive of future cardiovascular events and death (8). Given that these markers are readily measured using widely available and relatively inexpensive assays, their use to target at-risk populations for primary prevention is inherently attractive.
Two recent randomized studies have evaluated the use of natriuretic peptides to identify high-risk patients for implementation of cardiovascular prevention interventions. The recently published STOP-HF (St. Vincent's Screening To Prevent Heart Failure Study) trial randomized 1,374 asymptomatic patients with at least 1 risk factor for cardiovascular disease to BNP guided therapy versus usual care (9). Those in the “BNP-guided arm” had plasma levels measured annually, with specialized cardiology consultation for any BNP values >50 pg/ml. After a mean follow-up period of 4.2 years, 8.7% of patients in the control group and 5.3% of patients in the “biomarker” group met the primary endpoint of asymptomatic left ventricular dysfunction or incident heart failure (odds ratio: 0.55; 95% confidence interval: 0.37 to 0.82; p ≤ 0.003). This issue of the Journal includes a report of the results of a natriuretic peptide guided trial for primary prevention of cardiovascular disease in patients with type 2 diabetes mellitus (10). The PONTIAC (NT-proBNP Selected PreventiOn of cardiac eveNts in a populaTion of dIabetic patients without A history of Cardiac disease) study randomized 300 patients with type 2 diabetes mellitus, NT-proBNP levels greater than >125 pg/ml and no known cardiac disease, to a biomarker guided “intensified” group and a “control group.” All patients were treated at diabetes care units where guideline based therapies were pursued; those in the “intensified” group were additionally treated at a cardiology outpatient clinic for individualized up-titration of renin-angiotensin system (RAS) antagonists and beta-blockers. After 2 years, randomization to the biomarker-guided group was associated with a remarkable 65% reduction in risk of the primary endpoint of hospitalization or death due to cardiac disease (p = 0.04). The presumed mechanism for this treatment effect was the use and intensity of neurohormonal blockade: more patients in the intensified arm were using RAS antagonists and beta-blockers, and a greater percentage were at target doses. Notably, the event rates in the “intensified” group were identical to patients who had NT-proBNP levels <125 pg/ml at study onset and were not included in the study, but followed for cardiovascular outcomes.
Several aspects of these results deserve careful consideration. The primary difference in process of care between the 2 treatment groups was specialized cardiology referral, and guideline based care was mandated in both groups. It is notable that the low percentage of patients in the control arm on neurohormonal therapy remained largely unchanged at 12 months despite fairly frequent outpatient follow-up and a mandate for use and uptitration of guideline-based therapies. Even without the help of biomarker guidance, one can envision more aggressive use of therapies, especially because intolerance seems to have been exceedingly rare, with few reported side effects of therapy despite aggressive up-titration. Also, it is notable that despite the major reduction in cardiovascular risk, there were no differences in measured blood pressures between the intervention and control groups over the course of the study. These findings raise the question of the mechanisms through which the intervention studied in the PONTIAC study produced such a striking difference in outcomes. Finally, given that natriuretic peptide levels track closely with risk and are lowered by neurohormonal antagonism in heart failure, it is unusual that greater use of these therapies led to major improvements in outcomes without effecting natriuretic peptide levels.
In considering how these results could be applied in clinical care, several other questions remain: What is the optimal target population? Are the findings unique to diabetics? Are certain therapeutic interventions such as RAS antagonists preferred over others? Is use of this strategy cost-effective and safe when applied more broadly? What are the optimal cutpoints for natriuretic peptide levels? Finally, given the relatively small number of events and short follow-up period of the PONTIAC study, further validation of these findings will be required.
How do we interpret the results of the PONTIAC study in context of previous efforts in primary prevention of cardiovascular disease? First, the magnitude of treatment effect seen in PONTIAC is similar or greater to that of related studies using similar interventions. Both the HOPE (Heart Outcomes Prevention Evaluation) and STENO-2 studies previously showed substantial and similar risk reduction by using angiotensin-converting enzyme inhibitor therapy in patients with diabetes, although these studies had substantial proportions of patients with pre-existing cardiovascular disease (11,12). Second, PONTIAC follows on the heels of the JUPITER (Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin) trial that showed dramatic benefits of using a biomarker that signifies subclinical cardiovascular disease to guide therapy. JUPITER patients were apparently healthy, without known diabetes, and normal low-density lipoprotein cholesterol (<130 mg/dl), but elevated hs-CRP (>2.0 mg/l) levels; statin use led to a 44% reduction in risk of major cardiovascular events (13).
Are the results presented here enough to elevate natriuretic peptides to the elite cadre of “post–low-density lipoprotein” primary prevention biomarkers such as hs-CRP? Certainly, the biological argument is sound. Clinically silent processes in the cardiovascular system can gradually shift the homeostatic balance from health to disease far before an index cardiac event. Many of the pathologic processes known to be precursors of cardiovascular disease can increase natriuretic peptide levels. Cartesian reductionism suggests that identifying and targeting these undesirable processes would translate to improvements in cardiovascular health. Although this seems self-evident, the literature is replete with examples of primary prevention failures despite strong biologic plausibility, such as hormone replacement therapy among others (14). Clearly, the results of PONTIAC must be replicated before they can be considered to be practice changing. To underscore the relative size of the current study in the primary prevention literature, there were more primary events in the JUPITER (393) than total patients enrolled in the PONTIAC study (300).
The results of the PONTIAC study can be viewed in light of a larger movement, particularly in heart failure, toward “biomarker guided” therapy. The concept of titrating therapy for chronic diseases based on a biomarker of disease activity (such as HbA1C for diabetes or viral load for HIV) is commonplace in medicine, but the results of applying this paradigm to heart failure management have been mixed. Several randomized trials have examined strategies of natriuretic peptide guided therapy for heart failure with varied results; however, meta-analyses have suggested the possibility of substantial clinical benefits from this approach (15,16). A large National Institutes of Health funded multicenter trial, the GUIDE-IT (GUIDing Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure) study (NCT01685840), is currently underway to provide more definitive data on the efficacy and safety of natriuretic peptide guided therapy in heart failure. As this approach is validated for advanced phenotypes, it seems likely that it will continue to move “upstream” to progressively earlier stages of disease.
Studies such as PONTIAC that use a single biomarker to target or modify treatment are likely the tip of an iceberg representing a shift toward a more nuanced view of the diagnoses and treatment of cardiovascular disease. The last decade has seen an exponential expansion in the landscape of cardiovascular biomarkers, which now include innumerable genetic variants, microRNAs, novel proteins, and metabolites (17,18). A new view of disease explains it in terms of aberrancies in interconnected biological networks, and therapeutic interventions cause perturbations in the system's dynamic behavior in order to restore normal function from a dysfunctional state (19). These responses can be predicted based on integration of data from several sources: genetic, biochemical, cellular, physiological, and clinical (20). Based on this view of medicine, it seems naive to expect detailed understanding of a complex disease process via measurement of individual biomarkers alone. Indeed, the explosion of increasingly robust and sensitive biomarkers will require an ongoing refinement of the very concept of disease and prevention, as perturbations of the cardiovascular system are recognizable and potentially amenable to intervention at far earlier stages. Preliminary work using simplified multimarker strategies involving markers of various pathologic processes (inflammation, fibrosis, ischemia, myocardial wall stress) have already been shown to improve risk prediction over individual markers (21). It remains to be seen whether such approaches may be helpful to target specific subsets of the overall population at risk.
The results of the PONTIAC study suggest that natriuretic peptide focused therapy may be an important new avenue for targeting at-risk populations for primary prevention strategies. Moving forward, a wide array of novel molecular strategies will be able to detect risk at progressively earlier stages of disease, and therapeutics could be tailored for specific defects. Future studies will be required to refine these approaches such that they provide efficacious, safe, and cost effective cardiovascular disease prevention. Although Christopher Columbus may have relied primarily on gut instinct, contemporary cardiovascular prevention may be able to depend on increasingly sophisticated Google maps.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Dr. Felker has a relationship with Roche Diagnostics. Dr. Ahmad has reported that he has no relationships relevant to the contents of this paper to disclose.
- American College of Cardiology Foundation
- West DC Kling A.
- Buse J.B.,
- Ginsberg H.N.,
- Bakris G.L.,
- et al.
- Schocken D.D.,
- Benjamin E.J.,
- Fonarow G.C.,
- et al.
- Morrow D.A.
- Talwar S.
- Daniels L.B.,
- Maisel A.S.
- Maisel A.S.,
- Daniels L.B.
- Huelsmann M.,
- Neuhold S.,
- Resl M.
- Vasan R.S.
- Braunwald E.
- Loscalzo J.
- Wang T.J.,
- Wollert K.C.,
- Larson M.G.,
- et al.