Thursday, February 27, 2014

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?

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

Tuesday, February 25, 2014

Preparedness for Mass Casualty Events

The blackout of the Eastern United States and Canada in August 2003. Hurricane Sandy in October 2012. The horrific events of the Boston Marathon in April 2013.

What do all of these events have in common?

These mass casualty events affected numerous individuals, and institutions in these affected areas had to suddenly respond to patients impacted by these events in addition to handling patients who had already been hospitalized at the time that these events happened. Most patients affected by such events usually went to the most ideal place of the hospital in order to receive prompt care- the emergency department.

Unfortunately, across the globe, these events are seemingly becoming an everyday occurrence.

In my very first post on this blog, I discussed the concept that pharmacists practicing in the emergency department need to be able to anticipate care for patients in a such a manner that even being a few steps ahead of the physicians and ready to hand off medications that were likely to be needed for patients was the most ideal. I also made the point that after having seen something occur so frequently, it becomes somewhat of a rote process, and almost second nature. This skill does not necessarily develop overnight, but does take time to cultivate as practice becomes more and more refined.

In some ways, I think trauma resuscitations are beautiful. Now, I know that may sound a bit unusual, but hear me out on this one. Yes, the situation in and of itself for the patient is indeed awful, but everyone responding to the trauma- the trauma surgeon, residents, nurses, critical care technicians, pharmacists, and other ancillary support- know exactly what their role is. So much so that even the locations around the bed or stretcher of the patient in which the responders position themselves is well-defined. Several articles have addressed the role of the pharmacist in trauma resuscitations, and even when it comes time for us to hand off medications that the patient may need in such a situation, we may have already drawn everything up and have it prepared and ready to go before it is requested. It is almost as if we have simulated the situation so many times that in the midst of all the chaos, it is organized. And there is beauty in that.

No doubt that there is literature published on mass casualty events that fall under the categories of chemical, biological, radiological, and nuclear (CBRN) disasters. We are aware of the importance of decontamination and maintaining a “chempack” of antidotes and antimicrobial agents in the event of such disasters, and some of us may be involved in ensuring that adequate supply of these agents are maintained.

However, here is my question: What about events that do not fall under the categories of CBRN? That is, is there literature out there to guide pharmacists on how to respond to mass casualty events such as those listed in the examples above? What do we do then?

To put it quite simply, there is little to guide us, which is somewhat disheartening, as the likelihood of events outside of CBRN occurring is a bit higher than those that fall under CBRN. More and more tragic situations are impacting us, some occurring in our own backyards, but we are ill-equipped with guidance from national organizations on how to prepare for such events. For any guidance that is provided, the oft-made statement of “refer to your local emergency preparedness plan” may be seen with any of the reference manuals that you may flip through in your research. And yes, that reference manual may be in a remote location on your institutional Intranet that you may not be able to access in such a situation.

When it comes to situations like this, an “all hands on deck” approach is an absolute must. However, in such disasters, it is also important to consider practical questions that may arise; preferably, those questions should be addressed before such an event.

For example, how will you be able to assemble, organize, and delegate tasks to personnel in providing medications to victims during such events? Is your staff trained to respond to such events? How will you relay and communicate information to the staff in the setting of such an event?

What sorts of medications and quantities need to be maintained in stock in the event of such a disaster? We need to think beyond medications that are in chempacks, and begin to think about those medications that we commonly use in trauma resuscitations. Especially as drug shortages plague our day-to-day activities, is there a mechanism in place for alternative medications to be retrieved in a timely fashion? How will you ensure that your supply is adequate to not only treat patients directly impacted by such events, but also inpatients and members of the community?

More importantly, how will you mobilize medications to those patients? Say that the electricity is out, and your employee badge to access the area of medications is not functioning, and you cannot access patient care areas nor the automated dispensing cabinets within the institution. What happens then?

These are just some questions that may arise, and I am sure there are many more. As this may be the tip of the iceberg and this may be considered to be an “alligator sky” to some, concerted efforts need to take place with support from both governmental agencies and national pharmacy organizations to ensure that pharmacy personnel are prepared to respond to such events.

Selected References:

Pedersen CA, Canaday BR, Ellis WM, et al. Pharmacists' opinions regarding level of involvement in emergency preparedness and response. J Am Pharm Assoc 2003; 43:694-701.

Austin Z, Martin JC, Gregory PA. Pharmacy practice in times of civil crisis: The experience of SARS and the blackout in Ontario, Canada. Res Social Adm Pharm 2007; 3:320-335.

Hogue MD, Hogue HB, Lander RD, et al. The nontraditional role of pharmacists after hurricane Katrina: process description and lessons learned. Public Health Rep 2009; 124:217-223.

Erickson K. An emergency department pharmacist's experience at the Boston Marathon. Am J Health Syst Pharm 2013; 70:1652,1654.

Duncan EA, Colver K, Dougall N, et al. Consensus on items and quantities of clinical equipment required to deal with a mass casualties big bang incident: a national Delphi study. BMC Emerg Med 2014; 14:5.

“Where was I when the rockets came to life,
And carried you away into the alligator sky?
Even though I’ll never know what’s up ahead;
I’m never letting go, I’m never letting go.”
--“Alligator Sky” by Owl City

Thursday, February 20, 2014

A Pharmacists Guide Medication Safety On Earth

Lately I’ve been on a kick of nurturing my inner Canadian by reading a few books by notable figures from the Great White North.  The first was the latest autobiography of Dr. David Suzuki (any respectable Canadian should need no explanation of who he is) and the second was a book (An Astronauts Guide To Life On Earth) written by a Canadian astronaut, Dr. Chris Hadfield, about his journey to becoming the first Canadian to execute a space walk and the first Canadian to be commander of the International Space Station.  During his time as commander he used something we’re all familiar with in the FOAMed universe, Twitter and other social media forms, to engage others’ interest in space exploration.

While it was no doubt, an inspiring read, one particular point of his astronaut training at NASA stood out to me as a pharmacist. To understand that point, you have to look at adverse drug event, medication error and other medical error reporting in hospitals.  If you’ve ever sat in on, or been a member of a pharmacy and therapeutics committee, or medication safety committee, you’ll be familiar with the analogy of open reporting of errors in the aviation industry to ADR/Med error reporting within a hospital.  The thought is that we (as a hospital) should encourage all errors and near-miss errors to be reported in a non-punitive fashion in order to identify sentinel events before they happen, and in the event of a serious error, identify the failure in the system rather than individual finger pointing.  While attempting to use this system in health care is in theory nice, it is vastly over-simplified and doesn’t work as well as the prototypical aviation industry version. It is also, inherently flawed – you have to wait for an error or near miss to occur before action is taken.

Consider now, how an astronaut trains (if you need to queue up the Apollo 13 scene where Tom Hanks is sitting in a simulation Lunar Landing Module, be my guest).  Astronauts spend months, if not years, simulating every task they will likely be performing while in space. Importantly, they don’t just simulate the standard operating procedure (and do so repeatedly until they can perform the task flawlessly), they simulate such procedures in every conceivable situation/condition/malfunctioning equipment/pending alien invasion/etc.  Again they sim and sim and sim and sim until they get it perfect.  Dr. Hadfield used the example of a situation where if x happened during launch, he had 5 seconds to determine whether to abort and save the crews’ life of continue the mission.  That’s 5 seconds to interpret a given alarm/data point, consider all options and execute the necessary procedure. There is no way this could be done if you hadn’t already simulated that (or a similar) scenario.

Now back to pharmacy. Most hospitals in the USA employ some sort of computerized physician order entry system as well as various computers charting and documenting for nurses and pharmacists. However, these systems are often fraught with incomplete order screens where potential for error increases dramatically.  But rather than anticipating errors and bugs and perfecting the system before implementation, we’re constantly playing pretend aviators, trying to catch up after an error occurs.  It is certainly a tremendous amount of work to perform an up front check, but it is inherently our job and responsibility to prevent errors from occurring and trying to avoid setting up others for such errors.

It may be an ideological dream, but certainly an astronauts guide to life on earth makes more sense than our current practice.

Monday, February 10, 2014

The Combination of PDE-5 Inhibitors and Nitrates: What to Do in the Critically Ill Patient?

Let us say that you have a 50-year-old female patient who presents to the emergency department with a history of pulmonary arterial hypertension and signs and symptoms consistent with acute decompensated heart failure. The patient presents with acute shortness of breath and is in severe respiratory distress. Vital signs include blood pressure of 182/90 and heart rate of 110. A beside ultrasound is performed, confirming the presence of significant pulmonary congestion. Non-invasive ventilation is initated and you would like to order a nitroglycerin drip for this patient. However, upon reviewing her medication list, you notice that is on sildenafil as an outpatient for her pulmonary arterial hypertension.

You recall that the combination of PDE-5 inhibitors and nitrates is a "no-no"; this movie scene may even come to mind:

Even knowing about this interaction you ponder about this some more, and you really and truly believe that nitroglycerin can benefit your patient. So what are you going to do?

Phosphodiesterase-5 (PDE-5) inhibitors are often recommended for the treatment of pulmonary arterial hypertension. These agents act by inhibiting the hydrolysis of cyclic guanosine monophosphate (cGMP) to gunosine monophosphate (GMP), which allows for selective relaxation of the pulmonary vasculature. This thereby reduces pulmonary vascular resistance and increase functional capacity in patients with pulmonary arterial hypertension. We all know how these agents work in the more common indication that these agents are utilized for (erectile dysfunction), but to review briefly, in the setting of sexual stimulation, PDE-5 inhibitors augment the effects of nitric oxide through inhibition of the breakdown of cGMP, which allows for smooth muscle relaxation in the corpus cavernosum.

Nitroglycerin (and other organic nitrates) form free nitric oxide radicals that activate guanylate cyclase, which catalyzes the synthesis of cGMP, leading to smooth muscle relaxation. Using PDE-5 inhibitors in the setting of organic nitrates could potentiate the vasodilatory effects of the latter, leading to profound and potentially life-threatening systemic hypotension.

There have been very few studies that have evaluated the safety of the use of organic nitrates in the setting of concomitant PDE-5 inhibitors. One small study evaluated the safety of intravenous nitroglycerin in 34 patients with a history of coronary artery disease who had ingested 100 mg of sildenafil or placebo. After 45 minutes, nitroglycerin was initiated, and the dose was titrated upward every ten minutes to a maximum of 160 mcg/min. The investigators found that at doses between 5 and 80 mcg/min, the decrease in systolic blood pressure (SBP) decrease was 4 to 6 mmHg higher with sildenafil compared to placebo. However, as doses escalated upward, only 25% of the patients were able to tolerate the maximum dose due to the incidence of adverse events.

In addition, investigators of a case series of three patients demonstrated that the use of an extended course of systemic oral nitrates in three patients in combination with sildenafil can effectively reduce pulmonary arterial pressure in the setting of pulmonary arterial hypertension and advanced heart failure. None of the patients in the case series manifested any complications associated with this combination therapy.

So going back to our patient…will you be starting that nitroglycerin infusion after all? Granted, if the situation was a bit different and the patient presented with an acute coronary syndrome instead, I would be a bit more cautious in reaching for the nitroglycerin infusion and utilize other standard therapies for relieving the ischemia associated with such an event for that very reason- that is, we do have other therapies available that may provide the patient with some relief without placing the patient at unnecessary risk for a potentially life-threatening event secondary to a drug interaction. However, the scenario described above is a somewhat relatively unique combination of diseases in a critically ill patient that may present to your emergency department. You may not be able to push and/or escalate the dose of the nitroglycerin infusion as high or as quickly as you would like, but provided that you have the dedicated resources, equipment, and personnel available to closely monitor such a patient in whom you believe this therapy might provide some benefit, it may be considered an option.

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