Patients with ACS and Elevated Levels of Natriuretic Peptides: Results from AVANT GARDE-TIMI 43
Biomarkers are increasingly recognized as an important tool for risk stratifying patients with a variety of cardiac conditions, including myocardial infarction and heart failure. The first step in demonstrating utility of a marker is its ability to identify high risk patients and provide independent predictive power compared to ones currently available.(1) A more difficult task is the ability to accurately select patients for treatment that will reduce their risk. Unfortunately, the list of successful biomarkers is small (e.g. LDL lowering and statins, troponin and use of glycoprotein IIb/IIIa antagonists.(2) Even less data exists on following changes in a biomarker to alter treatment, although a recent meta-analysis suggests that natriuretic peptides achieve this.(3)
In this regard the AVANT GARDE TIMI 43 Trial(4) was designed to test the hypothesis that complete renin blockade will reduce cardiovascular events in patients with acute coronary syndrome (STEMI 59%, NSTEMI 28%, UA 13%) who have elevated levels of natriuretic peptides. Patients were randomized to placebo or one of three different treatment arms: valsartan, direct rennin blockade with aliskiren, or dual blockade with both valsartan and aliskiren. Patients with active heart failure (although a history of heart failure was allowed) or EF <40% were excluded.
The two groups that included treatment aliskiren were associated with a greater decrease in rennin activity than the other two arms. Interestingly, blood pressure increased in all treatment arms by 8 weeks, although the increase in the placebo arm was about double that of the 3 treatment arms (7.7 vs 2.8-4.2 mmHg, p<0.02 for all comparisons)
Somewhat surprisingly, although NT-proBNP was reduced significantly, the reduction was similar and not significantly different among the 4 treatment arms, with an average 36-44% reduction. In addition, there was no difference in the proportion of patients who achieved a NT-proBNP level <200 pg/ml. Concordant with the lack of difference in NT-proBNP levels among groups, there was no significant difference in clinical events (varying combinations of death, MI and CHF) during the 8 weeks of follow-up.
The results of the trial are disappointing, although not surprising. In the absence of heart failure and systolic dysfunction, event rates will be low, especially over the short study time period and relatively small numbers of patients included in each group, limiting the ability to demonstrate outcome differences. Patient risk was likely further reduced given the excellent ancillary guideline treatment, as almost 90% received beta-blockers, statins and aspirin, and more than 80% received theinopyridines. The potential treatment effect would have been further reduced as approximately 15-20% also received concomitant renin blockade with either ACE-inhibitors, angiotensin blockers or aldosterone blockade, and likely the majority had revascularization performed.
Unfortunately, as this trial demonstrates, despite the many biomarkers available, few are sufficiently robust so that they can be used to select appropriate treatment. Although biomarker selection for treatment in oncology has resulted in successful “personalized medicine,” we are still awaiting similar advances in cardiology.
- Vasan RS. Biomarkers of cardiovascular disease: molecular basis and practical considerations. Circulation 2006 May 16;113:2335-62.
- Newby LK, Ohman EM, Christenson RH, Moliterno DJ, Harrington RA, White HD, Armstrong PW, Van De Werf F, Pfisterer M, Hasselblad V, Califf RM, Topol EJ. Benefit of glycoprotein IIb/IIIa inhibition in patients with acute coronary syndromes and troponin t-positive status: the paragon-B troponin T substudy. Circulation 2001;103:2891-6.
- Porapakkham P, Porapakkham P, Zimmet H, Billah B, Krum H. B-type natriuretic peptide-guided heart failure therapy: A meta-analysis. Arch Intern Med 2010;170:507-14.
- Scirica BM, Morrow DM, Bode C, et al. patients with acute coronary syndromes and elevated levels of natriuretic peptides: the results of the AVANT GARDE-TIMI 43 Trial. Eur Heart J 2010; Jul 1.
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