Prof. Dr. Sundeep Mishra reviews three major studies presented at this year's European Society of Cardiology (ESC) 2019 Congress and provides key takeaways for Indian Cardiologists.

Another one bites the dust

PARAGON-HF shows that ARNI fails in Heart Failure with Preserved Ejection Fraction

Heart failure with preserved ejection fraction (HFpEF) aka diastolic heart failure is a heterogenous disease entity which comprises nearly ½ of all heart failures. While for heart failure with reduced ejection fraction (HFrEF) many therapies (beta-blockers, ACE-I / ARBs, ARNI MRAs) are known to reduce mortality, in sharp contrast trials of various therapies have remained inconclusive in HFpEF and till date, no therapy has been found to reduce mortality in HFpEF. However, some trials TOPCAT for the aldosterone inhibitor spironolactone and CHARM-Preserved for candesartan, an ARB revealed some benefits in patients with HFpEF which extended to patients with mid-range LVEF (HFmEF).

PARAGON-HF was a randomised controlled trial (RCT) which assigned 4822 patients with NYHA class II to IV heart failure, EF ≥ 45%, elevated level of natriuretic peptides, and structural heart disease to receive sacubitril–valsartan (ARNI) - target dose, 97 mg of sacubitril with 103 mg of valsartan twice daily or valsartan - target dose, 160 mg twice daily. It revealed that ARNI did not result in a significantly lower rate of total hospitalisations in HFpEF patients (P=0.06). However, HFpEF is a heterogenous population and some secondary findings indeed seem encouraging for ARNI Population:

1. 45% more improvement in NYHA class with ARNI (CI, 1.13 to 1.86)
2. 50% less worsening in renal function with ARNI (CI, 0.33 to 0.77)
3. 27 % in primary end point (total hospitalisations for heart failure and death from cardiovascular causes ) with ARNI In women (CI 0.59 - 0.90)
4. 22% benefit with ARNI in patients with lower EF (45% - 57%) within the HFpEF population (0.64 - 0.95).
5. 30% improvement in >5 point improvement in KCCQ clinical summary score in patients receiving ARNI (1.04 - 1.61)

Prasugrel lands a Knock out Punch to Ticagrelor in ACS

ISAR REACT-5 trial

For long, there has been a debate about which is a better anti-thrombotic agent; Ticagrelor or Prasugrel? Prasugrel seems more potent but ticagrelor seems safer. Most studies are available with ticagrelor because it is believed that this molecule strikes the right balance between efficacy and safety. However, acute coronary syndrome (ACS) is one situation where ischaemic risk is higher than stable disease and it is thus possible that requirement of anti-thrombotic efficacy is higher, at least in initial days. In earlier trials; PLATO, ticagrelor was found beneficial (over clopidogrel) in patients with ACS. On the other hand prasugrel was not found superior (TRIOLOGY ACS) to clopidogrel in patients who had ACS without STEMI and did not undergo revascularisation.

ISAR-REACT 5 was an open-label trial to assess whether ticagrelor was superior to prasugrel in patients with ACS using a planned invasive strategy. The trial randomly assigned 4018 patients with ACS at 21 centers in Germany and 2 centers in Italy (who were about to undergo coronary angiography) to receive therapy with prasugrel or ticagrelor. Close to half of the patients had a suspected diagnosis of non-STEMI (46.2%). Both the drugs were loaded in the usual way (pre-procedure if they had STEMI but prasugrel loaded only if they were due for angioplasty post-coronary evaluation in non STEMI patients).

At 1 year, the primary composite endpoint occurred in 9.3% in the ticagrelor group and 6.8% in the prasugrel group (P = .006). The lower incidence of the composite endpoint was primarily driven by fewer myocardial infarctions in the prasugrel group than in the ticagrelor group, and the benefit of fewer ischaemic events with prasugrel did not occur at the expense of an increased risk of bleeding. The rate of death from any cause was 4.5% vs 3.7%, the rate of MI was 4.8% vs 3.0%, and the rate of stroke was 1.1% vs 1.0% for patients in the ticagrelor vs. prasugrel groups, respectively. The rate of definite stent thrombosis was also lower in patients in the prasugrel group (0.6% vs. 1.1%, respectively).

Living on a Prayer

Oxygen therapy again fails for ACS in NZOTACS trial

Since more than century oxygen has been considered a lifesaving modality, used in a variety of clinical situations, particularly in cases with medical emergency, where its use has practically become a knee-jerk reflex reaction. In context with acute MI (AMI), wherein patients have compromised myocardial perfusion due to myocardial hypoxia there could be a role for providing high concentration oxygen to improve oxygenation of ischaemic myocardial muscle, reducing ischaemia, infarct size and perhaps other complications associated with it. However, in reality, there is very little evidence backing it, the practice entirely based on tradition, expert opinion or at best anecdotal evidence. On the other hand, increasing arterial oxygenation may paradoxically increase coronary vascular resistance and thus further decrease the blood flow through an already occluded artery, decrease stroke volume and cardiac output and release oxygen free radicals contributing to reperfusion injury.

Recently DETO2X–SWEDEHEART revealed that routine use of supplemental oxygen in patients with suspected AMI who do not have hypoxemia is not warranted. But what about use of oxygen in patients with hypoxemia or pre-existing lung diseases? Current ESC guidelines recommend that oxygen be given when oxygen saturation levels are below 90%, but not above. Interestingly, a survey conducted among physicians managing AMI revealed that 96% of pts. with ACS receive this therapy and nearly ½ of the treating physicians felt that it reduced mortality, while 1/4th felt that it reduced pain, only 1/4th believing it was useless. A recent, the New Zealand Oxygen Therapy in Acute Coronary Syndromes (NZOTACS) trial which was presented this week at ESC Congress 2019 provided new evidence on this.

The aim of NZOTACS trial was to compare 30-day mortality associated with two different oxygen protocols (high and low usage) as part of routine care in patients with suspected ACS in New Zealand. The high-oxygen protocol consisted of oxygen delivered by face mask at 6 - 8 L / minute, irrespective of oxygen saturation levels. The low-oxygen protocol recommended that oxygen be given only when saturation fell below 90%. Oxygen was then given to a level of 90% to 94% and was stopped when it was not needed to maintain levels above 90%. A total of 40,872 patients were included in a randomised cluster design from two New Zealand registries of ACS patients. Primary outcome showed very similar 30-day mortality rates between the two groups (3.02% in the high-oxygen group vs. 3.12% in the low-oxygen group, NS). However some subgroups did show some possible benefit:

• In patients with STEMI (n = 4000), there was a 19% benefit in the high-oxygen group (8.8% vs. 10.6%, NS)
• In the patients with < 95% oxygen saturation (12% of patients), 30-day mortality was showed a trend towards benefit in high oxygen group (10.1% vs. 11.1%, NS)

Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.

The writer, Dr. Sundeep Mishra is a Professor of Cardiology.