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Foundational Trials

COCA

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Publication

  • Title: Effect of Intravenous or Intraosseous Calcium vs Saline on Return of Spontaneous Circulation in Adults With Out-of-Hospital Cardiac Arrest: A Randomized Clinical Trial
  • Acronym: COCA (Calcium for Out-of-Hospital Cardiac Arrest)
  • Year: 2021
  • Journal published in: JAMA
  • Citation: Vallentin MF, Granfeldt A, Meilandt C, Povlsen AL, Sindberg B, Holmberg MJ, et al. Effect of intravenous or intraosseous calcium vs saline on return of spontaneous circulation in adults with out-of-hospital cardiac arrest: a randomized clinical trial. JAMA. 2021;326(22):2268-2276.

Context & Rationale

  • Background
    • Calcium had historically been recommended broadly during cardiac arrest, but later guidance restricted use to selected “special circumstances” (eg suspected hyperkalaemia, documented hypocalcaemia, calcium-channel blocker toxicity), largely on physiological rationale rather than high-certainty clinical evidence.
    • Observational studies were inconsistent and vulnerable to “resuscitation-time bias” (calcium preferentially given late in prolonged arrests), making harm/benefit signals difficult to interpret.
    • Two small double-blind randomised trials (1985) in refractory pulseless electrical activity (PEA) and asystole compared a single dose of calcium chloride with saline and did not demonstrate clear survival benefit; sample sizes were small and outcomes were short-term.
    • Biological plausibility existed in both directions: calcium may augment inotropy/membrane stability (especially in hyperkalaemia), yet calcium overload could worsen myocardial/neurological reperfusion injury and precipitate post-ROSC metabolic complications.
    • Despite uncertain evidence, calcium remained commonly available and variably used in practice, creating a compelling case for a modern placebo-controlled trial in out-of-hospital cardiac arrest (OHCA).
  • Research Question/Hypothesis
    • In adults with non-traumatic OHCA treated by emergency medical services (EMS) and receiving adrenaline, does early intravenous/intraosseous calcium chloride (vs saline) improve sustained return of spontaneous circulation (ROSC)?
    • Hypothesis (trialist): calcium administration during OHCA would increase ROSC and improve patient-centred outcomes (survival and favourable neurological status).
  • Why This Matters
    • If beneficial, calcium would represent a low-cost, widely implementable pharmacological adjunct in cardiac arrest care.
    • If harmful, discontinuing routine calcium would represent an immediately actionable patient-safety intervention, given its accessibility and historical use.
    • COCA specifically tested calcium in a contemporary ALS context, addressing an evidence gap left by decades-old trials and confounded observational literature.

Design & Methods

  • Research Question: In adult OHCA treated by EMS and receiving adrenaline, does calcium chloride (IV/IO) compared with saline placebo increase sustained ROSC (and improve survival and neurological outcomes)?
  • Study Type: Investigator-initiated, randomised, placebo-controlled, parallel-group, double-blind, superiority trial conducted in the prehospital setting (Central Denmark Region). 1
  • Population:
    • Setting: Prehospital EMS response to OHCA in the Central Denmark Region (multiple ambulance stations; standardised ALS care).
    • Key inclusion: Adults (≥18 years) with non-traumatic OHCA receiving CPR by participating EMS and receiving at least one dose of adrenaline during the arrest. 1
    • Key exclusions (pragmatic): Traumatic cardiac arrest; known/strongly suspected pregnancy; prior enrolment; adrenaline administered before arrival of prehospital personnel carrying study drug; clinical indication for calcium during the arrest (eg suspected hyperkalaemia/hypocalcaemia/calcium-channel blocker toxicity). 1
  • Intervention:
    • Calcium chloride 5 mmol (10 mL) administered IV or IO immediately after the first dose of adrenaline.
    • Second dose of calcium chloride 5 mmol (10 mL) administered after the second dose of adrenaline (maximum total calcium chloride 10 mmol). 1
  • Comparison:
    • 0.9% sodium chloride placebo (10 mL) administered IV or IO following the same schedule (after first and second adrenaline doses).
    • Otherwise identical standard ALS care according to contemporaneous guidelines.
  • Blinding: Double-blind (identical numbered ampoules in study kits; clinicians, participants/surrogates, and outcome assessors masked; unblinding only if clinically necessary). 1
  • Statistics:
    • Power calculation: A total of 674 patients were required to detect a 10% absolute increase in ROSC (from 16% to 26%) with 80% power at the 5% significance level (alpha 0.05). 1
    • Analysis: Primary analysis was a modified intention-to-treat including patients who received the first dose of trial drug and met eligibility criteria, analysed according to randomised allocation.
    • Interim monitoring: Independent data-monitoring committee (IDMC) planned safety reviews after 50, 200, and 400 participants; there were no formal statistical stopping criteria for harm or benefit, and the IDMC recommendation was based on overall assessment of safety/benefit balance. 1
  • Follow-Up Period: Outcomes assessed to 30 days (key secondary patient-centred outcomes) and to 90 days (tertiary outcomes), with registry-based follow-up and structured neurological/quality-of-life assessment in survivors.

Key Results

This trial was stopped early. The IDMC recommended discontinuation due to concern for harm after the planned interim analysis (at 383 participants); recruitment ceased after 397 were randomised, with 391 included in the primary analysis (planned sample size 674). 1

Outcome Calcium chloride Saline placebo Effect p value / 95% CI Notes
Sustained ROSC (≥20 minutes) (primary) 37/193 (19%) 53/198 (27%) RR 0.72 95% CI 0.49 to 1.03; P=0.09 Adjusted risk difference −7.6%; 95% CI −16.0 to 0.8; P=0.09
Survival at 30 days (key secondary) 10/193 (5.2%) 18/198 (9.1%) RR 0.57 95% CI 0.27 to 1.18; P=0.12 Direction favoured placebo; wide confidence interval
Survival at 30 days with favourable neurological outcome (mRS 0–3) (key secondary) 7/193 (3.6%) 15/198 (7.6%) RR 0.48 95% CI 0.20 to 1.12; P=0.12 Adjusted risk difference −4.0%; 95% CI −8.9 to 0.7
Survival at 90 days with favourable neurological outcome (mRS 0–3) (tertiary) 6/193 (3.1%) 15/198 (7.6%) RR 0.40 95% CI 0.17 to 0.91; P=Not reported No deaths occurred between 30 and 90 days
EQ-5D-5L index score at 30 days (survivors) 0.73 (0.07–0.89) 0.80 (0.60–0.94) Not reported Not reported Interpretation limited by very small survivor numbers
EQ VAS score at 30 days (survivors) 60 (41–75) 70 (56–85) Not reported Not reported Patient-reported; few respondents
Ionised calcium after ROSC (first measurement) 1.41 ± 0.15 mmol/L 1.17 ± 0.07 mmol/L Mean difference 0.23 95% CI 0.18 to 0.28 Demonstrated clear biological separation (persisted for ~12 hours)
Hypercalcaemia within 24 hours post-ROSC (ionised Ca >1.33 mmol/L) 26/35 (74%) 1/49 (2%) Not reported Not reported Among ROSC patients with ionised calcium measurement; mild 12/35 (34%) and moderate 14/35 (40%) vs mild 1/49 (2%) and moderate 0/49 (0%) 2
Tachyarrhythmia requiring treatment (post-ROSC) 8/37 (22%) 14/53 (26%) Not reported Not reported Among patients achieving ROSC 2
Dialysis during hospital admission (post-ROSC) 7/37 (19%) 3/53 (6%) Not reported Not reported Among patients achieving ROSC; small numbers 2
  • Point estimates for the primary outcome and both key secondary outcomes numerically favoured placebo (eg sustained ROSC 19% vs 27%; survival 5.2% vs 9.1%).
  • Clear biological separation was achieved: ionised calcium was higher after ROSC in the calcium group (1.41 ± 0.15 vs 1.17 ± 0.07 mmol/L; mean difference 0.23; 95% CI 0.18 to 0.28) and hypercalcaemia was common (74% vs 2% among measured post-ROSC patients). 2
  • Stopping early for potential harm leaves important residual uncertainty (wide confidence intervals) but is clinically consequential given the directionality across outcomes.

Internal Validity

  • Randomisation and allocation: 1:1 randomisation using permuted blocks (sizes 2/4/6) stratified by ambulance station; allocation list created by an independent statistician; trial drug provided as masked, numbered ampoules (allocation concealment at point of care). 1
  • Post-randomisation exclusions: 397 randomised; 391 included in the primary analysis; 6 were excluded from primary analysis because the arrest was ultimately categorised as traumatic (4 in calcium group; 2 in placebo group).
  • Selection/analysis set implications: Primary analysis used a modified intention-to-treat set (received first dose of trial drug and met eligibility); this improves biological interpretability but introduces potential for bias versus strict ITT (even if numerically small here).
  • Blinding integrity: Double-blinding is a major strength for performance/detection bias; however, post-ROSC laboratory hypercalcaemia could plausibly unblind in-hospital teams (clinical implication uncertain because primary outcome was prehospital ROSC and survival outcomes are objective).
  • Protocol adherence: Two trial-drug doses were administered in 144/197 (73%) in the calcium arm vs 147/200 (74%) in placebo; protocol deviations occurred in 9/197 (5%) vs 9/200 (5%).
  • Crossover/contamination: Calcium administered outside the trial protocol occurred in 4/197 (2%) vs 2/200 (1%) (small absolute difference).
  • Timing (dose delivery): Time from cardiac arrest to first dose of trial drug was 18 minutes (IQR 14–23) vs 18 minutes (IQR 14–24), consistent with similar exposure timing across groups.
  • Baseline comparability: Median age 68 vs 68 years; male 150/197 (76%) vs 156/200 (78%); witnessed arrest 152/197 (77%) vs 147/200 (74%); bystander CPR 154/197 (78%) vs 156/200 (78%).
  • Rhythm case-mix: VF/pVT 46/197 (23%) vs 53/200 (27%); PEA 75/197 (38%) vs 67/200 (34%); asystole 76/197 (39%) vs 80/200 (40%).
  • Co-interventions during arrest: Adrenaline doses were slightly higher in the calcium arm (median 3 [IQR 2–5] vs 2 [IQR 2–4]); use of amiodarone 41/197 (21%) vs 37/200 (19%); sodium bicarbonate 9/197 (5%) vs 9/200 (5%); magnesium 18/197 (9%) vs 9/200 (5%); mechanical chest compression 102/197 (53%) vs 107/200 (54%). 2
  • Separation of the variable of interest: Post-ROSC ionised calcium was higher in calcium recipients (1.41 ± 0.15 vs 1.17 ± 0.07 mmol/L; mean difference 0.23; 95% CI 0.18 to 0.28), demonstrating pharmacodynamic separation.
  • Outcome assessment: Sustained ROSC and survival outcomes are objective and less susceptible to ascertainment bias; neurological outcome (mRS) and EQ-5D are more vulnerable to response/proxy effects but were secondary/tertiary and limited by low survivor counts.
  • Statistical rigour: Planned sample size 674 was not reached due to early termination for potential harm; key outcomes were therefore underpowered with wide confidence intervals, increasing uncertainty around true effect magnitude.

Conclusion on Internal Validity: Moderate. Core trial conduct (double-blind randomisation, objective primary outcome, excellent follow-up) supports credibility, but early stopping for potential harm and the modified ITT analysis set introduce uncertainty and potential bias around effect size.

External Validity

  • Population representativeness: Trial participants were typical in age and rhythm distribution for adult OHCA, but occurred within a single regional EMS system with high bystander CPR (78% in both groups).
  • Important exclusions: Traumatic arrests, pregnancy, and patients with an overt clinical indication for calcium were excluded, limiting direct applicability to those clinically suspected of hyperkalaemia/hypocalcaemia or calcium-channel blocker toxicity.
  • Applicability to other systems: The intervention (two 10 mL boluses linked to adrenaline dosing) is feasible in most ALS systems; however, thresholds for adrenaline timing, termination of resuscitation, and transport practices vary internationally.
  • Hospital system dependence: Primary outcome (prehospital ROSC) is relatively system-agnostic; longer-term outcomes may be influenced by post-resuscitation care pathways, which differ across jurisdictions.

Conclusion on External Validity: Moderate. Findings are broadly applicable to adult non-traumatic OHCA managed with contemporary ALS, but less directly generalisable to cases with specific biochemical/toxicological indications for calcium or markedly different EMS systems.

Strengths & Limitations

  • Strengths:
    • Double-blind, placebo-controlled randomised design in the prehospital environment (rare for arrest pharmacology).
    • Objective primary endpoint (sustained ROSC) and registry-based survival follow-up with no loss to follow-up reported.
    • Clear pharmacodynamic separation (post-ROSC ionised calcium and hypercalcaemia patterns).
    • Pragmatic integration into standard ALS workflows (after first/second adrenaline doses) supporting implementability.
  • Limitations:
    • Stopped early for potential harm, resulting in lower-than-planned sample size and wide confidence intervals for key patient-centred outcomes.
    • Primary analysis used a modified ITT population; post-randomisation exclusions (traumatic arrests) were present.
    • Very small numbers of survivors limited interpretability of neurological and quality-of-life measures and reduced precision for safety outcomes conditional on ROSC.
    • Restriction away from cases with a clear clinical indication for calcium limits inference to the “routine empiric calcium” practice question, not targeted calcium for hyperkalaemia/toxicology.

Interpretation & Why It Matters

  • Clinical practice signal
    Routine empiric calcium chloride during adult OHCA did not improve sustained ROSC (19% vs 27%; RR 0.72; 95% CI 0.49 to 1.03) and showed numerically lower survival and favourable neurological outcomes.
  • Safety plausibility
    Calcium dosing achieved marked biochemical effects post-ROSC (hypercalcaemia 74% vs 2% among measured post-ROSC patients), supporting biological plausibility for harm rather than “inadequate exposure”. 2
  • Implementation implication
    For systems where calcium is intermittently administered “because it might help”, COCA supports restricting calcium to well-defined indications rather than routine use in undifferentiated OHCA.

Controversies & Subsequent Evidence

  • Early stopping and decision rule: The trial stopped early after an IDMC recommendation for potential harm, without a formal statistical stopping boundary; this improves patient safety but increases uncertainty and may exaggerate the apparent magnitude of harm. 1
  • Modified ITT vs strict ITT: Excluding randomised patients not meeting eligibility (eg traumatic arrests) can introduce bias even when the number is small (6/397), and it complicates comparisons with strictly ITT cardiac-arrest pharmacology trials.
  • Subgroup signal in PEA with ECG features: In patients with PEA and wide QRS/ischemic ECG patterns, ROSC appeared higher with calcium (8/39 [21%] vs 1/31 [3%]) but the estimate was imprecise and event-limited; a subsequent PEA-focused analysis explored this signal and emphasised the need for caution in over-interpreting subgroup effects. 4
  • Longer-term outcomes: A subsequent post hoc analysis of longer-term outcomes after calcium administration in COCA reported outcome patterns consistent with the index trial’s directionality, though absolute event counts remained small. 3
  • Systematic reviews/meta-analyses: Post-COCA syntheses conclude there is no high-certainty evidence of benefit for routine calcium during cardiac arrest and that the balance of evidence suggests possible harm; certainty remains limited because contemporary evidence is dominated by COCA plus small historical trials. 567
  • Guidelines: Contemporary international guidance continues to recommend against routine calcium administration during cardiac arrest and reserves calcium for specific indications (eg suspected hyperkalaemia/hypocalcaemia/calcium-channel blocker toxicity), aligning with COCA’s safety signal in undifferentiated OHCA. 8910

Summary

  • COCA tested routine IV/IO calcium chloride during adult non-traumatic OHCA (after first/second adrenaline doses) in a double-blind placebo-controlled RCT.
  • The trial stopped early for concern of harm; sustained ROSC was lower with calcium (19% vs 27%; RR 0.72; 95% CI 0.49 to 1.03).
  • Key patient-centred outcomes numerically favoured placebo (30-day survival 5.2% vs 9.1%; favourable neurological outcome 3.6% vs 7.6%), with wide uncertainty due to early stopping.
  • Biological separation was clear (post-ROSC hypercalcaemia common in calcium recipients), supporting plausibility of harm rather than inadequate dosing.
  • COCA supports avoiding routine calcium in undifferentiated adult OHCA and restricting its use to specific clinical indications.

Further Reading

Other Trials

Systematic Review & Meta Analysis

Observational Studies

Guidelines

Notes

  • Key secondary outcomes were 30-day survival and 30-day survival with favourable neurological outcome (mRS 0–3); early stopping limited precision for these patient-centred outcomes.
  • COCA addressed the “routine empiric calcium” question; it was not designed to test calcium for confirmed/suspected hyperkalaemia, hypocalcaemia, or calcium-channel blocker toxicity.

Overall Takeaway

In adult non-traumatic OHCA treated with contemporary ALS, routine IV/IO calcium chloride given after adrenaline did not improve sustained ROSC and showed numerically worse survival and neurological outcomes, prompting early trial termination for potential harm. COCA therefore shifts calcium away from an empiric “might help” arrest drug towards a targeted therapy reserved for specific indications.

Overall Summary

  • Routine calcium chloride during undifferentiated adult OHCA is not supported and may be harmful; restrict use to specific clinical indications.

Bibliography