Trials and guidelines in critical care cardiology

Of the historical cardiology questions from the CICM Second Part Exam, those that have not been straightforward ECG interpretation exercises have focused mainly on the management of heart failure, arrhythmias, and acute cardiac ischaemia. To guide the end-stage exam candidates this compilation of trials and guidelines hopes to fill a space in the exam revision process that had previously been occupied by doing the past papers, but which has become more vacant in the recently changing exam process. For consistency this has been composed mainly using Critical Care Reviews and The Bottom Line; wherever possible, the original paper is linked from the name of the study, and the Bottom Line review is linked from the year of publication.

ICU trainees are reminded that many of these trials and guidelines are not specifically relevant to ICU patients. In particular, the trial data that informs these guidelines was generally collected from a very different, much healthier population. On the other hand, ICU patients also happen to have ischaemic heart disease, heart failure, and arrhythmias. It therefore follows that ICU trainees should be familiar with the guidelines, inasmuch as they apply to the critically ill population; but it is less important to be familiar with the trials that have shaped those guidelines, as they are not "ICU trials" and could not possibly be asked about in an ICU exam paper. 

With this rationale, the following compendium deemphasises the interpretation of trial data and presents only a small selection of RCTs. These have been picked mainly because they address questions frequently encountered in the ICU (eg. "should I give frusemide as an infusion or not") or because they represent some kind of foundational bedrock of or practice (eg. DAPT for ACS) in which case it might be fun to look at what the effect size was. For the interested reader, summaries of the other papers can be explored at lmtrials.com.

Heart failure trials

Afterload reduction:

• CONSENSUS - 1987 - enalapril in severe CHF; n=253. Mortality at 6 months improved from 44% to 26%.
• Val-HEFT - 2001 - valsartan; n=5,010. 13.2% lower incidence of composite endpoint.
• A-HEFT - 2004 - hydralasizine and isosorbide dinitrate; n=1050 specifically among African Americans who have reduced RAAS activity. Huge benefit (43% reduction in the risk of death), stopped early to keep people from dying of placebo. 
• Paradigm-HF - 2014 - sacubitril+valsartan vs enalapril; n=8442. Composite endpoint much improved (21.8% vs 26.5%). AHA and ESC now recommend this combo instead of ARB or ACE-I, wherever it is tolerated.

Beta blockers 

• CIBIS-II - 1999 - bisoprolol; n=2647. Mortality better (11.8% vs 17.3%) 
• MERIT-HF- 1999 - metoprolol; n=3991. Composite endpoint risk reduction by 19%.
• COPERNICUS - 2002 - carvedilol;  n=2289. Composite endpoint risk reduction by 27%.
• AHA and ESC don't seem to care which of these you choose, even though authors claim to have found a difference between them (eg. Liu et al, 2023, found bisoprolol superior)

Diuretics

• RALES - 1999 - spironolactone; n=1663. Stopped early because there was a 30% reduction in the risk of death.
• DRAIN - 2019 - frusemide as continuous infusion, or boluses? n=80 in Italy. Infusion was better: 47.5% were free from congestion after 72 hrs, vs. 25%.

Flozins

• DAPA-HF - 2019 - dapagliflozin; n=4744. Composite outcome much better (16.3% vs 21.2%)
• EMPEROR - 2020 - empagliflozin; n=3730. Composite outcome 19.4% vs 24.7%
• AHA and ESC don't care which one you choose.

Ischaemic heart disease trials

Which blood thinners?

Théroux et al - 1988 - Unstable angina: aspirin, heparin, or both? n=479 in Canada. Incidence of MI was 3% with aspirin, 0.8% with heparin, and 1.6% with both (whereas with placebo it was 12%). 

Eikelboom et al - 2000 - meta-analysis of heparin infusion for ACS; n=17,157. Heparin halved the risk of re-MI and death in the first 7 days.

CURE - 2001 -  aspirin and clopidogrel for NSTEMI? n=12,562 all over the world. DAPT much better: 9.3% vs. 11.4% at 12 months (composite of death, nonfatal MI or stroke).

TRITON-TIMI 38 - 2007 - prasugrel vs clopidogrel; n=13,608. Prasugrel was better at preventing cardiac composite badness (9.9% vs 12.1%) but also caused more bleeding.

PLATO - 2009 - ticagrelor vs clopidogrel; n=18,624 all over the world.  Composite badness occurred in fewer ticagrelor patients (9.8% vs 11.7%) but again more bleeding.

When to angio the NSTEMI or unstable angina?

TIMACS - 2009 - angio within 24 hrs? n=3031. Not much difference in composite outcome (9.6% vs 11.3%) or death (4.8% vs. 5.9%), except in the highest risk category (GRACE score > 140) where the difference was considerable (13.9% vs 21.0%). 

After 80 - 2016 - Early angio vs. conservative management, for NSTEMI/UA in the over-80s? n=457 in Norway. Composite outcome much better with angio (40.6% vs. 61.4%) but only because of reduced MI (17 vs 30%); mortality unchanged (25% vs 27%).

(but what if they had a cardiac arrest?)

Specific drugs in the acute phase?

COMMIT - 2005 - metoprolol for acute STEMI; n=45,852.  Less reinfarction (2.0% vs 2.5%), less VF (2.5% vs 3.0%), but more cardiogenic shock (5.0% vs 3.9%). Moral of the story, don't give a negative inotrope to unstable people on day 0 after their infarct.

Arrhythmia trials 

AFFIRM - 2002 - n=4,060; rhythm control or rate control in AF? Well, they are both crap. Mortality 23.8% vs 21.3%. Rate control is slightly better.

REVERT - 2015 - if SVT, what if Valsalva but with your legs up in the air for 15 seconds? n=433, in the UK. Get those legs up: SR conversion rate 43%, vs 17%.

AMIO-AQUEOUS - 2002 - amiodarone vs. lignocaine for refractory VT storms. n=29 in the US. Amiodarone was much better (33% drug failure rate, vs 91%).

PROCAMIO - 2016 - procainamide vs amiodarone for VT. n=74 in Spain. Major cardiac adverse events much better with procainamide (9% vs. 41%); but pointless for CICM candidates to know this, because this awesome drug is not available in Australia.

Cardiology guidelines

Heart failure

• 2023 ESC guidelines for cardiomyopathies
• 2023 ESC focused update on heart failure - an update of their 2021 guideline
• 2022 AHA guidelines for heart failure
• 2022 ESC guidelines for pulmonary hypertension
• 2021 AHA guideline for the management of valvular heart disease
• 2021 ESC guideline for the management of valvular heart disease
• 2020 AHA guidelines for HOCM
• 2019 AHA classification and management guidelines for cardiorenal syndrome

Ischaemic heart disease

• 2023 ESC guidelines for acute coronary syndromes 
• 2023 AHA guidelines for chronic IHD
• 2021 AHA guidelines for coronary artery revascularisation
  • And the IACST response to the protectionist downgrade of CABG recommendations is also worth reading
• 2016 AHA update on the duration of DAPT
• 2014 AHA STEMI guidelines

Antihypertensives

• 2018 AHA guideline on hypertension - for CICM exam candidate probably the most relevant section would be 11.2, Hypertensive Crises 
• 2018 ESC guideline on hypertension - again the hypertensive emergency section is the best part

Various rhythm disturbances

• 2023 Scandinavian SSAI guidelines for new-onset AF in the ICU 
• 2022 ESC guidelines for ventricular arrhythmias
• 2020 Canadian (CCS) guidelines for AF
• 2020 ESC guidelines for AF
• 2019 AHA update on AF - based on their old 2014 AF guidelines
• 2019 ESC guidelines on SVT
• 2018 AHA guideline for bradycardia and heart blocks
• 2017 AHA guideline for VT/VF including AICD recommendations
• 2015 AHA guideline for SVT including WPW

Anticoagulation for various cardiac things

• 2022 AHA guidelines for LV thrombus