BNP-Guided Heart Failure Prevention

Abstract & Commentary

By Andrew J. Boyle, MBBS, PhD

Assistant Professor of Medicine, Interventional Cardiology, University of California, San Francisco

Dr. Boyle reports no financial relationships relevant to this field of study. This article originally appeared in the September 2013 issue of Clinical Cardiology Alert.

Synopsis: The authors conclude that among patients at risk of heart failure (HF), BNP-based screening and collaborative care reduced the combined rates of left ventricular systolic dysfunction, diastolic dysfunction, and HF.

Source: Ledwidge M, et al. Natriuretic peptide-based screening and collaborative care for heart failure. The STOP-HF randomized trial. JAMA 2013;310:66-74.

Heart failure (hf) is associated with a high mortality rate, debilitating symptoms, impaired quality of life, and major financial costs. As our society ages, the prevalence of HF is increasing. Current treatments for HF are imperfect and prevention of HF is the best possible option. In this study, the authors target patients at risk for developing HF and study a strategy of using serum brain-type natriuretic peptide (BNP) measurement in the primary care setting to guide referral and therapy aids in preventing left ventricular (LV) dysfunction and HF. The study recruited patients from 39 primary care practices in Ireland.

Patients were referred from primary care to the study if they were older than 40 years and had one or more risk factors for developing HF, including hypertension, hyperlipidemia, obesity (body mass index > 30), vascular disease (coronary, peripheral, or cerebral), diabetes, arrhythmia requiring treatment, or moderate/severe valvular disease. Exclusion criteria were the presence of established LV dysfunction or prior HF, or any other cause of limited life expectancy. Patients were randomized 1:1 to intervention (BNP-driven collaborative care between the primary care physician [PCP] and specialist cardiovascular center; n = 697) or control (routine PCP management; n = 677) groups. All patients had BNP testing but the results were only available to the PCP in the intervention group. The control group received advice on lifestyle modification and risk factor intervention as determined by their PCP. In the intervention group, BNP results were made available to the PCP, with protocol-driven echocardiography, referral to a cardiologist, and further lifestyle counseling and management if the BNP was > 50 ng/L. Those with BNP < 50 ng/L received usual care. Patients and treating physicians could not be blinded, but at study completion all patients underwent echocardiography and clinical evaluation by a blinded cardiologist. The primary endpoint was development of LV systolic or diastolic dysfunction with or without HF. Secondary endpoints included emergency hospitalization for arrhythmia, transient ischemic attack, stroke, myocardial infarction, peripheral or pulmonary thrombosis/embolus, or HF.

Patients were followed for 4.2 1 1.2 years. A total of 263 patients (41.6%) in the intervention group had at least one BNP reading of 50 pg/mL or higher. The primary endpoint of LV dysfunction with or without HF occurred in 59 of 677 (8.7%) in the control group and 37 of 697 (5.3%) in the intervention group (odds ratio [OR] 0.55; P = 0.003). Asymptomatic LV dysfunction was found in 6.6% of control patients and 4.3% of intervention-group patients (OR 0.57; P = 0.01). Heart failure occurred in 2.1% of controls and 1.0% of intervention-group patients (OR 0.48; P = 0.12). The incidence rates of emergency hospitalization for major cardiovascular events were 40.4 per 1000 patient-years in the control group vs 22.3 per 1000 patient-years in the intervention group (incidence rate ratio, 0.60; P = 0.002). The intervention group underwent more cardiovascular investigations (control group, 496 per 1000 patient-years vs intervention group, 850 per 1000 patient-years; incidence rate ratio, 1.71; P < 0.001) and received more renin-angiotensin-aldosterone system (RAAS) inhibitors (control group, 49.6%; intervention group, 56.5%; P = 0.01). Blood pressure reductions were similar in the control and intervention groups. In patients with BNP < 50 ng/L, there was no change in BNP level over the 4.2-year follow-up. However, in those with BNP > 50 ng/L, the BNP level increased over the study period, but the increase was significantly attenuated in the intervention group. The authors conclude that among patients at risk of HF, BNP-based screening and collaborative care reduced the combined rates of LV systolic dysfunction, diastolic dysfunction, and HF.

COMMENTARY

This study is an interesting and important one. First, it confirms that BNP measurement in patients at risk of HF can predict the development of future LV dysfunction. Second, this strategy also reduces emergency admissions to the hospital from a variety of cardiovascular causes. Unfortunately, though, there was no prespecified intervention in this study, so we are left to ponder what it was that resulted in the better outcomes in the intervention group. Was it the increased use of RAAS inhibition? Was it the extra patient counseling that improved compliance? Was it engagement of the patients with the specialist care and the extra diagnostic testing that facilitated a more tailored pharmacological management of these patients? These should all be tested in prospective studies.

Several limitations of this study should be noted. First, it was performed in a small area of Ireland and the results may not be generalizable to other populations. Second, because the participants could not be blinded, there is a possibility of some confounding, which would likely but not definitely create bias toward a negative result. Third, new onset HF was defined as requiring hospitalization for HF. This definition would have missed HF that was treated as an outpatient. Despite these limitations, BNP-guided therapy for patients at risk for HF seems to be a reasonable strategy. I hope we will see a formal cost-effectiveness analysis from this dataset, as the intervention group had higher rates of diagnostic testing but lower rates of hospitalization, and the overall effect on health care budgets remains unknown.

Trametinib Tablets (Mekinist)

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD

Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA

Drs. Elliott and Chan report no financial relationships relevant to this field
of study.

A third kinase inhibitor, trametinib dimethyl sulfoxide, has been approved by the FDA for the treatment of metastatic BRAF V600 mutation-positive melanoma. Trametinib follows vemurafenib and dabrafenib in this category. The latter two are BRAF inhibitors while trametinib is a mitogen-activated extracellular signal regulated kinase (MEK) 1 and 2 inhibitor. BRAF activates MEK1 and MEK2 along the signaling pathway. Trametinib is marketed by GlaxoSmithKline as Mekinist.

Indications

Trametinib is indicated for the treatment of unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test.¹It is not indicated for use in patients with prior BRAF inhibition therapy.

Dosage

The recommended dose is 2 mg orally once daily. It should be taken at least 1 hour before or at least 2 hours after a meal. Trametinib is available as 0.5 mg, 1 mg, and 2 mg tablets.

Potential Advantages

Cutaneous squamous-cell carcinoma, a side effect of BRAF inhibitors, was not reported with trametinib in the clinical trial.² Trametinib improved progression-free survival (PFS) compared to chemotherapy with dacarbazine or paclitaxel.¹ Trametinib is indicated for BRAF V600E or V600K mutations while both vemurafenib and dabrafenib are indicated for the V600E mutation. Trametinib does not appear to have any clinically important drug interactions involving CYP350, P-gp, organic anion transporting polypeptides, or breast cancer resistant protein (BCRP) transporter.¹

Potential Disadvantages

Serious adverse events in clinical trials included cardiomyopathy, retinal pigment epithelial detachment, retinal vein occlusion, interstitial lung disease pneumonitis, embryofetal toxicity, and serious skin toxicity.¹ Common adverse events include rash (57%), diarrhea (43%), lymphedema (32%), dermatitis acneiform (19%), stomatitis (15%), and hypertension (15%).¹ Trametinib may be less effective than BRAF inhibitors (e.g., vemurafenib), although there has been no direct comparison to date.^2,3

Comments

BRAF mutation leads activation of MEK1 and MEK2 promoting tumor growth. The efficacy and safety of trametinib was studied in a randomized, open-label, active-controlled study of 322 subjects.⁴ These subjects had BRAF V600E or V600K mutation-positive, unresectable, or metastatic melanoma with no more than one prior chemotherapy regimen and no prior ipilimumab, BRAF, or MEK inhibitor treatment. Subjects were randomized (2:1) to trametinib (2 mg daily; n = 214), or dacarbazine (1000 mg/m² every 3 weeks), or paclitaxel (175 mg/m² every 3 weeks; n = 108). The primary efficacy endpoint was PFS and secondary, confirmed tumor response. Subjects on chemotherapy were allowed to crossover to trametinib at the time of disease progression. PFS (disease progression or death) occurred in 55% of those treated with trametinib and 71% with chemotherapy (HR 0.47; 95% CI, 0.34, 0.65; P < 0.0001). Median time to PFS was 4.8 (4.3, 4.5) months compared to 1.5 (1.4, 2.7) months. Objective response was 2% complete and 20% partial response compared to 0% and 8%, respectively. Median duration of follow-up was 4.9 months for trametinib and 3.1 months for placebo. At 6 months, survival was 81% with trametinib and 67% in the chemotherapy group, even with the crossover (HR, 0.54; 95% CI, 0.32, 0.63; P < 0.01).² Dose interruption occurred in 35% of subjects and dose reduction in 27%. Approximately 2% discontinued therapy completely. Trametinib does not appear to be effective in patients with metastatic BRAF mutation previously treated with a BRAF inhibitor.^1,3

Clinical Implications

Approximately 45% of patients with metastatic melanoma have mutations. Current therapy includes high-dose IL2, ipilimumab as non-targeted regimens, and BRAF inhibitors (vemurafenib, dabrafenib) as targeted regimens. These are the preferred regimens recommended by the National Comprehensive Cancer Network. Trametinib is recommended for patients who are intolerant to BRAF inhibitors but not for those who have progressed.⁵ There may be some benefit to combining an MEK with a BRAF inhibitor. This is being evaluated in an ongoing clinical trial where trametinib is combined with dabrafenib compared to dabrafenib alone.⁶ The cost of trametinib is $8700 for 30 days.

References

Mekinist Prescribing Information. Research Triangle Park, NC: GlaxoSmithKline; May 2013.
Flaherty KT, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med 2012;367:107-114.
Jang S, Atkins MB. Which drug, and when, for patients with BRAF-mutant melanoma? Lancet Oncol 2013;14: e60-69.
Kim KB, et al. Phase II study of the MEK1/MEK2 inhibitor trametinib in patients with metastatic BRAF-mutant cutaneous melanoma previously treated with or without a BRAF inhibitor. J Clin Oncol 2013;31:482-489.
http://www.nccn.org/professionals/physician_gls/pdf/melanoma.pdf. Accessed October 5, 2013.
http://clinicaltrials.gov/show/NCT01584648. Accessed October 5, 2013.