Nitroglycerin Shortage: Giving Nesiritide Another Look

National drug shortages are presenting a new and unique way of considering alternative drug therapies for various disease states. Of note, the most recent drug shortage impacting EDs and sparking new debate and rehashing of old data is intravenous nitroglycerin.
IV Nitro is used ubiquitously in EDs and pre-hospital settings primarily for acute coronary syndromes and acute decompensated heart failure/acute pulmonary edema.  While other dosage forms of nitroglycerin exist, and can be applied (both practically, and literally in the case of nitropaste) [see previous post for dosing] in these clinical scenarios, there are few alternative drug therapies that offer the same titratability and reliable response as IV nitro.  Thinking back a few years, an old, albeit controversial drug comes to mind – nesiritide.
Nesiritide is a recombinant B-type natriuretic peptide (BNP) that was approved back in 2001 for intravenous treatment of patients with acutely decompensated congestive heart failure who have dyspnea at rest or with minimal activity. This approval was largely based on the outcomes from the VMAC trial which found that nesiritide reduced pulmonary capillary wedge pressure and improved dyspnea compared to nitroglycerin or placebo (although there were trends toward a longer LOS in patients treated with nesiritide compared with NTG and in 30-day mortality).1 But because of later review of data submitted to the FDA and meta-analysis, findings of a trend toward increased 30 day mortality, and increased incidence of renal impairment (defined as an increase in SCr of > 0.5mg/dL during the study period), critics questioned the role of nesiritide given lack of clearly defined clinical benefit and higher cost.2,3  On the other hand, controversy as to the clinical relevance of an increase in SCr of > 0.5mg/dL during the study period, increase in a poorly defined ‘medical intervention’ required for renal impairment while incidence of dialysis remained the same and temporal relationship between nesiritide infusion and onset of renal injury vs cardio-renal syndrome.
As a result of this controversy, and need for additional efficacy and safety data, the ASCEND-HF trial was created and published in 2011.4 The study set out to answer some of these heavily debated questions by analyzing two co-primary endpoints of the change in self-reported dyspnea 6 and 24 hours after study-drug initiation and the composite end point of re-hospitalization for heart failure and death from any cause during the period from randomization to day 30.
This study randomized patients to nesiritide (with or without a bolus dose) plus standard therapy (diuretics, morphine, other vasoactive meds, including ntg) or placebo. These patients must have been hospitalized for heart failure occurring within 24 hours prior to their first IV treatment for HF or if they had been diagnosed with acute decompensated HF within 48 hours of hospitalization for another cause but still 24 hours prior to first IV treatment for HF. These patients also must have exhibited defined signs/symptoms/lab/radiologic evidence of acute CHF. However, patients were excluded if they had an SBP < 100 mmHg or 110 mmHG with IV NTG use, had other contraindications to vasodilators, had been treated with dobutamine, milrinone or levosimendan within 30 days, ACS, severe pulmonary disease, ESRD with renal replacement therapy.
The study analyzed 7007 patients and found no difference between the distribution of patient-reported assessments of dyspnea at 6 and 24 hours. Importantly, there was no difference in the composite of rehospitalization or death within 30 days: nesiritide, 321 (9.4%); placebo 345 (10.1%), 95% CI, −2.1 to 0.7; P = 0.31. In addition, individually analyzing the components of the composite similarly found no difference between the groups.  But despite showing no difference between the groups again with respect to new renal impairment, more patients who received nesiritide had an episode of hypotension and symptomatic hypotension (7.2% vs. 4.0%; P<0.001 for symptomatic).
Considering that nesiritide (with standard therapy including nitroglycerin) is no better than placebo (standard therapy including nitro as well) there was no rush back to starting nesiritide over NTG on our acute HF patients, largely due to significantly higher drug cost, and lack of evidence of clinical superiority (or at least cutting LOS) despite greater safety evidence.  So nesiritide was shelved, and appropriately so.
But the issue is now resurfacing, but in a different perspective: if there IS no nitro, is nesiritide an appropriate alternative? Or should we look towards other supportive measures or fast-tracking pipeline drugs like serelaxin?
Related links for Nitroglycerin Shortage: Giving Nesiritide Another Look
Nitroglycerin Shortage: Giving Nesiritide Another Look Reference:
1. Publication Committee for the VMAC Investigators (Vasodilation in the Management of Acute CHF). Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure: a randomized controlled trial. JAMA. 2002;287:1531-1540
2. Sackner-Bernstein JD, Kowalski M, Fox M, Aaronson K. Short-term Risk of Death After Treatment With Nesiritide for Decompensated Heart Failure A Pooled Analysis of Randomized Controlled Trials. JAMA. 2005;293:1900-1905
3. Sackner-Bernstein JD, Skopicki HA, Aaronson KD. Risk of worsening renal function with nesiritide in patients with acutely decompensated heart failure.Circulation. 2005; 111: 1487–1491
4. O’Connor CM, Starling RC, Hernandez AF, et al. Effect of nesiritide in patients with acute decompensated heart failure.
N Engl J Med 2011;365:32-43