Without evidence of benefit, an intervention should not be presumed to be beneficial or safe.

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Nifekalant versus lidocaine for in-hospital shock-resistant ventricular fibrillation or tachycardia


ResearchBlogging.org

Also posted over at Paramedicine 101 (now at EMS Blogs) and at Research Blogging. Go check out the excellent material at these sites.

This is an interesting study for several reasons. One is the ability of the authors to act out parts of Through the Looking-Glass.[1] VF and VT are Ventricular Tachycardia and Ventricular Fibrillation.

If life-threatening VF or VT persists despite repeated defibrillation shocks, an additional antiarrhythmic drug is required.[2]

The next paragraph points out that there is no requirement according to ACLS.

The American Heart Association guideline for advanced cardiac life support (ACLS) states that when VF/pulseless VT persists after two to three shocks plus CPR and administration of a vasopressor, the physician should consider administering an anti-arrhythmic such as amiodarone, and lidocaine may be considered if amiodarone is unavailable.1 [2]

Believing that should consider administering is the same as an additional antiarrhythmic drug is required requires the same lack of illogic as used by the Queen, when instructing Alice to practice believing impossible things.

Then there are the obvious questions. Why compare nikefelant with lidocaine? Why not compare nikefelant with amiodarone? Why not compare nikefelant with an antiarrhythmic that is more effective than amiodarone – procainamide, sotalol, or ajmaline?

Lidocaine is probably used because the IRB (Institutional Review Board) would consider it unethical to have a placebo group. Lidocaine is the placebo, but with less safety than the placebo.

It was by comparing amiodarone with lidocaine that ACLS ended up including amiodarone for VT/VF (Ventricular Tachycardia/Ventricular Fibrillation) cardiac arrests. That was a huge boon for Wyeth. We were told that the improved survival to admission was important. We were told that survival studies – the only studies that matter in resuscitation – were being done. We have had only silence since then.

We should conclude that amiodarone does not improve survival.

No. That is not the right conclusion. If amiodarone produced survival as good as placebo, then that study would have been published and used to justify giving amiodarone. At least we are doing something! That is what people want to believe in.

The only reasonable conclusion is that Wyeth did not publish the results because the survival in the amiodarone group was significantly worse than in the placebo group, or Wyeth stopped the study early, because it was trending toward statistically significant harm from amiodarone.

If the study never reaches statistical significance, they can always rely on there being no proof of harm. That is what we have now and there are plenty of people claiming that no proof of harm means obvious benefit.


Original cartoon

We have a lot of ignorant/willfully ignorant people encouraging us to just give drugs because we cannot prove that these drugs are harmful. We cannot provide evidence that the drugs are harmful, because it is almost impossible to approve a placebo-controlled study to find out. The IRBs claim that it would be unethical to deprive patients of the Standard Of Care, no matter how harmful that Standard Of Care may be. If the IRBs approve a study, the politicians oppose the study.[3]

There were some interesting differences between the lidocaine and nikefalant groups.

The number of shocks before study-drug administration did not differ between the two arms, although epinephrine use before study-drug administration was significantly higher in the lidocaine arm (Table 2).[2]

Epinephrine use
Nikefalant   6 out of 27 = 22.2%
Lidocaine   20 out of 28 = 71.4%
With a p value of <0.001

According to ACLS, an antiarrhythmic should not be considered until after a pressor is considered.

Patients with nifekalant were more likely to have ROSC compared with patients with lidocaine (Table 3). However, there was no difference in 1-month survival or survival to hospital discharge between the nifekalant arm and the lidocaine arm.[2]

The overall outcome, such as survival rate, of patients with shock-resistant VF or VT is poor regardless of the pharmacological intervention. Nevertheless, termination of VF or VT and recovery of ROSC by nifekalant is important in the initial stage of resuscitation, because we cannot rescue the patients unless VF or VT is converted.[2]

They assume that the VF/VT will not be converted without a drug.

They assume that converting more VF/VT will lead to more survival even though there continues to be absolutely no evidence to support this hope.

It is reasonable to assume that the short-term thrill of conversion of VF/VT to a better rhythm comes at the expense of long-term harm to the patient.

We need to stop falling for feel good endpoints that encourage us to harm our patients.

If others are NOT helping their patients with these drugs, we want to be NOT helping our patients, too!

Footnotes:

[1] Through the Looking-Glass
by Lewis Carroll
The Millennium Fulcrum Edition 1.7
CHAPTER V. Wool and Water

‘I can’t believe THAT!’ said Alice.

‘Can’t you?’ the Queen said in a pitying tone. ‘Try again: draw a long breath, and shut your eyes.’

Alice laughed. ‘There’s no use trying,’ she said: ‘one CAN’T believe impossible things.’

‘I daresay you haven’t had much practice,’ said the Queen. ‘When I was your age, I always did it for half-an-hour a day. Why, sometimes I’ve believed as many as six impossible things before breakfast.

[2] Nifekalant versus lidocaine for in-hospital shock-resistant ventricular fibrillation or tachycardia.
Shiga T, Tanaka K, Kato R, Amino M, Matsudo Y, Honda T, Sagara K, Takahashi A, Katoh T, Urashima M, Ogawa S, Takano T, Kasanuki H; Refractory VT/VF, Prospective Evaluation to Differentiate Lidocaine Efficacy from Nifekalant (RELIEF) Study Investigators.
Resuscitation. 2010 Jan;81(1):47-52. Epub 2009 Nov 13.
PMID: 19913983 [PubMed – indexed for MEDLINE]

[3] Effect of adrenaline on survival in out-of-hospital cardiac arrest: A randomised double-blind placebo-controlled trial
Jacobs IG, Finn JC, Jelinek GA, Oxer HF, Thompson PL.
Resuscitation. 2011 Sep;82(9):1138-43. Epub 2011 Jul 2.
PMID: 21745533 [PubMed – in process]

Free Full Text PDF Download from reanimacion.net
 

This study was designed as a multicentre trial involving five ambulance services in Australia and New Zealand and was accordingly powered to detect clinically important treatment effects. Despite having obtained approvals for the study from Institutional Ethics Committees, Crown Law and Guardianship Boards, the concerns of being involved in a trial in which the unproven “standard of care” was being withheld prevented four of the five ambulance services from participating.

In addition adverse press reports questioning the ethics of conducting this trial, which subsequently led to the involvement of politicians, further heightened these concerns. Despite the clearly demonstrated existence of clinical equipoise for adrenaline in cardiac arrest it remained impossible to change the decision not to participate.

Shiga, T., Tanaka, K., Kato, R., Amino, M., Matsudo, Y., Honda, T., Sagara, K., Takahashi, A., Katoh, T., Urashima, M., Ogawa, S., Takano, T., & Kasanuki, H. (2010). Nifekalant versus lidocaine for in-hospital shock-resistant ventricular fibrillation or tachycardia Resuscitation, 81 (1), 47-52 DOI: 10.1016/j.resuscitation.2009.09.027

Jacobs IG, Finn JC, Jelinek GA, Oxer HF, & Thompson PL (2011). Effect of adrenaline on survival in out-of-hospital cardiac arrest: A randomised double-blind placebo-controlled trial. Resuscitation, 82 (9), 1138-43 PMID: 21745533

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Comments

  1. update :

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4126999/pdf/540_2013_Article_1775.pdf

    J Anesth. 2014 Aug;28(4):587-92. doi: 10.1007/s00540-013-1775-5. Epub 2014 Jan 5.
    Comparison of nifekalant and amiodarone for resuscitation of out-of-hospital cardiopulmonary arrest resulting from shock-resistant ventricular fibrillation.
    Harayama N1, Nihei S, Nagata K, Isa Y, Goto K, Aibara K, Kamochi M, Sata T.

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