Panel clarifies warnings for CHF medication

[Ace844]

Hello Everyone,

While doing some research and posting info for another thread I ran across this which i thought you all may be interested in reading.

Out Here,

ACE844

(Panel clarifies warnings for CHF medication

July 19 @ 2005)

Scios and the US Food and Drug Administration notified health care professionals on July 13, 2005, about the recommendations of an expert panel of cardiology and heart failure clinicians with regard to Natrecor (nesiritide). Recent questions raised about worsened renal function and mortality prompted the formation of the panel, which provided a consensus statement on each issue, provided advice on the ongoing and planned clinical development program, made recommendations about the appropriate use of the drug, and recommended an educational campaign to ensure that clinicians understand when the use of Natrecor is appropriate and when it is not.

In a letter addressed to health care professionals, California-based biopharmaceutical company Scios noted that the panel, led by Dr Eugene Braunwald, Distinguished Hersey Professor of Medicine, Harvard Medical School, reviewed the available data, including review of the original 2001 Natrecor product labeling that has described these risks. They endorsed the company's plan to conduct several clinical trials, including a large trial of clinical outcomes to further assess the benefits and risks of Natrecor. The panel also strongly encouraged Scios and investigators to continue enrollment of patients in current Natrecor trials (eg, Follow-up Serial Infusion of Nesiritide [FUSION] II) and in the planned Natrecor trials.

The panel also made recommendations about the appropriate use of Natrecor and encouraged the manufacturer to engage in a campaign to further educate clinicians about the drug. The panel made the following specific recommendations:

The use of Natrecor should be strictly limited to patients presenting to the hospital with acutely decompensated congestive heart failure (CHF) who have dyspnea at rest, as were the patients in the largest trial that led to approval of the drug (VMAC). Physicians considering the use of nesiritide should consider its efficacy in reducing dyspnea, the possible risks of the drug, and the availability of alternate therapies to relieve the symptoms of CHF.

Nesiritide should not be used to replace diuretics. Furthermore, because sufficient evidence is not currently available to demonstrate benefit for the applications listed below, nesiritide should not be used:

For intermittent outpatient infusion

For scheduled repetitive use

To improve renal function

To enhance diuresis

Scios should immediately undertake a proactive educational program to inform physicians regarding the conditions and circumstances in which nesiritide should and should not be used, as described above. Sponsor-supported communications, including review articles of nesiritide, should reflect the above recommendations. Scios should ensure that current and future marketing and sales activities related to nesiritide are consistent with this educational program.

Natrecor is indicated for the intravenous treatment of patients with acutely decompensated CHF who have dyspnea at rest or with minimal activity. In this population, the use of Natrecor reduced pulmonary capillary wedge pressure and improved dyspnea. The recommended dose of Natrecor is an intravenous bolus of 2 mcg/kg followed by a continuous infusion of 0.01 mcg/kg/min. Consistent with the clinical trials supporting its approval, the commercial use of Natrecor in clinical practice (noninvestigational) should be strictly limited to patients with acutely decompensated heart failure with a clinical presentation severe enough to warrant hospitalization. Natrecor should be administered in a clinical setting where blood pressure can be closely monitored. The drug should not be initiated at a dose higher than the recommended dose.

The prescribing information for Natrecor reflects data from 10 clinical trials including 941 patients with CHF (NYHA class II-III, 61%; class IV, 36%; mean age, 60 years; women, 28%). There were 5 randomized, multicenter, placebo- or active-controlled studies in which 772 patients with decompensated CHF received continuous infusions of Natrecor at doses ranging from 0.01 to 0.03 mcg/kg/min. Of these patients, the majority (70%) received the Natrecor infusion for at least 24 hours; 48% received Natrecor for 24 to 48 hours, and 22% received Natrecor for greater than 48 hours.

All of the patients participating in each of these trials required hospitalization for acutely decompensated heart failure. The study trials permitted entry at any point during the treatment course of acutely decompensated CHF, demonstrating that the use of Natrecor is safe and effective in a broad range of hospitalized patients. For example, the studies included patients in whom the study drug (either Natrecor or control) was started as the first intravenous vasoactive therapy before or after intravenous diuretics, as replacement therapy for patients not sufficiently responsive to another intravenous vasoactive therapy, or as add-on therapy in patients refractory to dobutamine or dopamine.

The VMAC trial, the largest relied on for the approval of the drug, was a randomized, double-blind study of 489 patients who required hospitalization for management of shortness of breath at rest or with minimal activity (eg, talking, eating, or bathing) due to acutely decompensated CHF. Patients with acute coronary syndrome, preserved systolic function, arrhythmia, and renal insufficiency were not excluded. The study compared the effects of Natrecor, placebo, and intravenous nitroglycerin when added to background therapy (intravenous and oral diuretics, nonintravenous cardiac medications, dobutamine, and dopamine). VMAC was designed to show primary efficacy comparisons between Natrecor and placebo. The nitroglycerin arm was included to show the relative safety and tolerability of Natrecor in comparison with a commonly used intravenous vasodilator.

The primary end points of VMAC were the change from baseline in patients' dyspnea and the change from baseline in pulmonary capillary wedge pressure (PCWP), evaluated after 3 hours. Patients receiving Natrecor reported greater improvement in dyspnea at 3 hours than patients receiving placebo plus standard care (P = .034). Natrecor led to a significant reduction in PCWP compared with placebo at 3 hours, when added to standard care (P < .001). There was a significant reduction in mean PCWP, relative to placebo, within 15 minutes of starting the Natrecor infusion, with most of the effect observed at 3 hours being achieved within the first 60 minutes of the infusion.

In its letter to health care professionals, Scios acknowledged that Natrecor is sometimes administered via intermittent and scheduled infusions to treat severely ill patients with CHF, particularly in the outpatient setting. Although a clinical development program is currently underway in this setting (FUSION II trial), Scios does not recommend Natrecor for this use at this time.

According to Scios, the only controlled clinical trial to assess the use of Natrecor for serial infusions in the outpatient setting is FUSION I. FUSION I was a pilot study (n = 210) and was not powered to adequately assess the effectiveness or safety of serial infusions of Natrecor. The size of the study, its design, and its findings provide an inadequate basis to recommend the routine use of intermittent, serial, or scheduled repetitive infusions of Natrecor.

In certain instances, Natrecor is also being used to replace diuretics, to improve renal function, or to enhance diuresis. To date, adequate clinical data that demonstrate clinically relevant diuretic properties or positive renal effects of Natrecor do not exist. The manufacturer does not recommend such use. Moreover, it is important to understand that clinical trial data show that the use of Natrecor was associated with a dose-dependent increase in serum creatinine. In VMAC, the serum creatinine level rose by more than 0.5 mg/dL above baseline in at least 1 blood draw in 7% of patients in the control groups and 8% in the nesiritide groups by 5 days, and by 21% and 28% respectively, by 30 days. Most of these increases occurred days after discontinuation of the drug.

Natrecor may cause hypotension. If hypotension occurs during the administration of Natrecor, the dose should be reduced or discontinued, and blood pressure should be monitored closely. At the recommended dose of Natrecor, the incidence of symptomatic hypotension (4%) was similar to that of intravenous nitroglycerin (5%). Asymptomatic hypotension occurred in 8% of patients treated with either drug. The mean duration of symptomatic hypotension was longer with Natrecor than intravenous nitroglycerin (2.2 vs 0.7 hours, respectively). Higher doses of Natrecor increased the risk of hypotension and elevated creatinine. In patients with severe heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with Natrecor may be associated with azotemia.

Other adverse events reported at a rate of at least 5% during the first 24 hours of infusion with either Natrecor plus standard care or intravenous nitroglycerin plus standard care therapy, respectively, included the following: ventricular tachycardia (3%, 5%), nonsustained ventricular tachycardia (3%, 5%), headache (8%, 20%), abdominal pain (1%, 5%), and nausea (4%, 6%). Natrecor should not be used in patients with systolic blood pressure <90 mm Hg or as primary therapy in patients with cardiogenic shock. Natrecor is not recommended for patients for whom vasodilating agents are not appropriate and should be avoided in patients with low cardiac filling pressures. In the 7 Natrecor clinical trials that collected mortality data through 30 days, 5.3% in the Natrecor treatment group died, compared with 4.3% in the group treated with other standard medications. In the 4 clinical trials in which mortality was collected through 180 days, 21.7% in the Natrecor treatment group died compared with 21.5% in the group treated with other standard medications. There are insufficient numbers of deaths to identify or exclude, with confidence, a moderate excess of risk to survival after treatment with Natrecor.

For more information about the use of Natrecor, call the Scios Medical Information department at 1-877-4-NATRECOR (1-877-462-8732) or visit www.natrecor.com.

[AZCEP]

This is some timely information, with the number of CHF related threads going on.

Atta Boy Ace!

Perhaps the clinician should take into consideration the wide range of possible responses that a medication can cause, shouldn't they? I guess that pathophysiology stuff is pretty important.

[Ace844]

This is some timely information, with the number of CHF related threads going on.

Atta Boy Ace!

Perhaps the clinician should take into consideration the wide range of possible responses that a medication can cause, shouldn't they? I guess that pathophysiology stuff is pretty important.

[fade:20711d095b]WHO KNEW?!?!!?!?! [/[/fade:20711d095b]b]