Out-of-hospital cardiac arrest (OHCA) due to ventricular fibrillation or pulseless ventricular tachycardia (VF/VT) is a catastrophic life event. Its course turns even more ominous when these rhythms prove to be shock-refractory. Antiarrhythmic drugs such as amiodarone or lidocaine in the United States and Europe and nifekalant in Japan, are often deployed in such circumstances in hope of restoring spontaneous circulation (ROSC) and to improve survival. Yet, even after many years of use, doubts linger over the efficacy and effectiveness of these drugs.,  Two recent reports in the Journal ask which antiarrhythmic drug (if any) is best for treating shock-refractory OHCA? In doing so, they raise an important additional question, namely what counts and what doesn’t when making such an assessment?

The first report, a meta-analysis, was drawn from 528 studies of amiodarone or lidocaine in cardiac arrest, which were ultimately culled to 3 randomized controlled clinical trials (RCTs) and 4 smaller observational studies. Its salient findings were that amiodarone and lidocaine improved the short-term success of resuscitation from OHCA, increasing rates of hospital admission, but disappointingly not survival to discharge. Of these outcomes, nearly all would agree that survival is what counts most. Yet, antiarrhythmic medications are administered in the acute setting primarily for their immediate effects, namely to terminate VF/VT, restore and stabilize an organized rhythm, promote ROSC and improve the likelihood of admission alive to hospital. Given this use, it is reassuring that such benefits from amiodarone and lidocaine were realized across virtually all the studies surveyed by the meta-analysis. However, carrying the benefits forward from hospital admission to discharge has proved to be more problematic and a conundrum that continues to haunt not only antiarrhythmic agents but virtually all pharmacologic interventions in OHCA., ,  In part this disparity arises because antiarrhythmic drugs are perhaps victims of their own success in promoting the successful resuscitation of sicker patients, many of whom might have otherwise died, and ultimately do. Other explanations include late-occurring drug-related toxicities that reverse the early benefits from treatment, uncontrolled imbalances in post-resuscitation hospital care after receipt of drugs and the timing of drug treatment itself.

Time-to-treatment plays a pivotal role in virtually all cardiovascular emergencies. For example, had thrombolysis in acute stroke been judged outside the context of time from symptom onset, its benefits might never have been realized. Similarly, CPR and defibrillation are known to be most beneficial when administered early in the course of OHCA, particularly when OHCA is witnessed.,  Distinguishing between a witnessed versus unwitnessed OHCA is important for many reasons, one of which is time measurement. Treatment intervals in OHCA are typically measured from the initial call activating the Emergency Medical Services (EMS) system (a time-stamped event that can be accurately documented), not from the time of collapse (which is seldom known with any degree of accuracy). A witnessed OHCA is taken to mean that the actual collapse was seen or heard, resulting in a presumably brief delay between the event and the call to EMS, whereas if unwitnessed the interval between the two may be much more protracted. Determining whether the OHCA was witnessed or unwitnessed can be made with reasonable confidence at the scene and is itself a powerful predictor of outcome, perhaps because of its association with the extent of organ damage that ensues between the time of collapse and start of treatment. Importantly, when OHCA has been witnessed, measured times from the initial EMS call to treatment may more closely represent the actual interval from collapse-to-treatment, whereas be significantly underestimated in unwitnessed cases.

In the Amiodarone, Lidocaine or Placebo Study (ALPS), the largest RCT reported in the meta-analysis, study drugs (amiodarone, lidocaine or placebo) were administered about 19?min after the initial call to EMS. Given the constraints of limited personnel on-scene, competing procedures and the need to establish vascular access (a prerequisite for drug administration), these measured treatment times are probably representative of how soon pharmacologic therapies can be deployed during EMS care. Realistically, antiarrhythmic drugs must work within this window of opportunity in order to save lives, but unfortunately in this trial (as in others) apparently failed to do so. Or did they actually fail … if taken from the perspective of time from collapse to treatment, rather than from call to treatment?

In ALPS, there was a statistically significant interaction between the witnessed status of OHCA and survival. That is, the pre-specified subgroup of patients with an unwitnessed OHCA, representing those with a presumably longer time interval between collapse and their measured time-to-drug, saw no effect from antiarrhythmic drugs on survival. Conversely, in the corresponding pre-specified subgroup of patients with a bystander-witnessed OHCA (in whom this interval between collapse and drug treatment was probably shorter and more closely approximated their measured treatment times), survival to hospital discharge significantly improved by an absolute margin of 5% over placebo with either amiodarone or lidocaine (Fig. 1). Furthermore, in the subgroup of patients in whom OHCA was EMS-witnessed, and whose actual time-to-drug-treatment was only 12?min from collapse, survival improved by an even greater absolute margin of 21.9% with amiodarone (p?=?0.01).

Fig. 1

The figure describes the absolute differences in survival to hospital discharge (with 95% confidence intervals) between amiodarone vs placebo and lidocaine vs placebo, stratified by whether the out-of-hospital cardiac arrest was bystander witnessed or unwitnessed in the Amiodarone, Lidocaine or Placebo Study (ALPS). The interaction between witnessed status of cardiac arrest and outcome was statistically significant (p for interaction 0.05).

Taken together, these findings suggest that from the perspective of time from collapse-to-treatment amiodarone and lidocaine each had a significant impact on survival from shock-refractory OHCA. In bystander-witnessed cases a survival benefit was realized within the time window that antiarrhythmic drugs were typically administered, with even stronger performance when the window was foreshortened. Seeing a more pronounced antiarrhythmic drug effect in earlier (but absent in later) stages of OHCA is consistent with the recognized time-dependence of interventions in other acute cardiovascular emergencies and is perhaps why the overall results of ALPS when taken without regard for time (that is, in the combined group of early and late-treated patients) did not achieve statistical significance. It would be interesting if findings from the other studies in the meta-analysis would corroborate this perspective when stratified in a similar manner.

A second Journal report focused on patients with OHCA who were treated with amiodarone or nifekalant (an amiodarone-like drug with comparatively less complex pharmacologic effects) in the hospital emergency department for refractory VF/VT. This study was derived from a database that collected strictly hospital-derived information from nearly all tertiary care facilities in Japan. Its strengths were in its large size, careful follow-up of all patients to hospital discharge, and its insight into outcomes within a care system that deferred administration of antiarrhythmic drug therapies in patients with OHCA until hospital arrival. The study found a higher hospital admission rate associated with nifekalant, but no differences in survival to hospital discharge between the two drugs, concluding that nifekalant may offer promise for improving OHCA outcomes.

What counts against these conclusions in this otherwise thoughtful and thorough analysis are its missing pieces. Missing are virtually all prehospital variables that are well-recognized predictors of survival after OHCA, such as the initial OHCA rhythm, whether the event was bystander witnessed, receipt of bystander CPR, and time-to-treatment intervals.,  While the investigators carefully adjusted outcome for basic demographics and variances in hospital care, the data void preceding hospital arrival prevents drawing meaningful conclusions about any association between drug treatment and outcome.,  This said, the study raises an important question of whether administration of antiarrhythmic drugs in patients with OHCA is best deferred until after hospital arrival?

The answer to this question falls back on the previous discussion. Amiodarone or lidocaine are likely to be effective in restoring rhythm and circulation in most settings. With early treatment they are also more likely to confer a survival benefit. But if, as in this instance, treatment is given late arguably no antiarrhythmic drug will change outcome, as suggested by the remarkable similarities in survival between this study and patients with an unwitnessed OHCA in ALPS (Fig. 1). From this perspective, a practice of deferring antiarrhythmic drug therapy until after hospital arrival is probably best seen as a lost opportunity. This perhaps is the best take-home message from each of these studies. What seems to count most in OHCA is not just a matter of giving the right treatment, but doing it at the right time.

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