The European Society of Cardiology (ESC) Congress this year took place in Barcelona, Spain from 26th to 30th August. The start of the event was just about a week before the alleged terrorist van attack at the street of Barcelona – La Rambla. No, it did not deter the hardcore cardiologists and scientists from attending, out of more than 32,000 attendees, there were only 40 who cancelled in the last minute. So, they were with the Spanish people, showing their sympathy and solidarity of the recent tragedy, chanting the magic words ‘No Tinc Por’ means I am not afraid. Aggrieved but not at all shaken by the threat, they move forward.
By far this could be the one ESC Congress that have presented with a significant number of groundbreaking clinical trials. Among the most notable ones are:
COMPASS – Cardiovascular OutcoMes for People using Anticoagulation StrategieS (COMPASS) trial
CANTOS – The Canakinumab Anti-Inflammatory Thrombosis Outcomes Study
PURE – Prospective Urban-Rural Epidemiology (PURE) study
CASTLE AF – Catheter ablation versus standard conventional treatment in patients with left ventricular dysfunction and atrial fibrillation
New perspective in diet and CVD? Highlight from PURE study
This is a study which is set to challenge existing dietary guideline for CVD presented by the researches from Hamilton Canada. Prospective Urban-Rural Epidemiology (PURE) study is a long term study involving more than 18 countries worldwide looking at the relationship between dietary behaviours and total and CVD mortality.
This was conducted in the form of Food frequency questionnaire in which the cohort is being followed up over time.
A total of 135,335 subjects were available for analysis.
It found that consumption of Fuit, vegetables and legumes was associated with moderately lower risk of mortality but not CVD mortality. The benefit was seen at 3-4 servings per day. Further they looked into dietary fat & carboydrate and found that, contrary to existing guidelines, dietary fats was protective against total mortality (but not CVD mortality) while increasing quartile intake of carbohydrate was harmful!
People might wonder, do all fats render the same benefit or some types of fats? How about saturated fat which the guidelines advise strict control? Surprisingly there was decreasing overall mortality with increasing concumption of saturated fat (SFA) and again, no effect on CVD mortality with the exception of a decrease in stroke risk.
Carbohydrate also did not increase CVD outcome, only overall mortality, so there were questions as to what mode of death associated with this increased total mortality, which the study did not address fully.
The results challenge current guideline recommendations on intake of saturated fat and carbohydrates.
So what can we learn form the result of this study? The cholesterol and statin skeptics may quickly jump to conclusion and claims the findings support their long term skepticism on the role of cholesterol in CVD…things may not be as simple, maybe we can adopt the advise from the principle investigator, Salim Yusuf – it is all about moderation. In dealing with food intake, we should strike a balance. In this case, clearly fruits and vegetable, including legume should be part of healthy diet, while controlling carbohydrate intake including sugar is important. Fats, you may ease off from the strict diet (provided your lipid profile is within ‘normal’), while decreasing your sugar and carbo, avoid trans fat (not covered in this study), do watch the total calorie intake though, since high calorie would be associated with the prevalence of obesity and metabolic syndrome which are still culprits in CVD.
Beyond LDL and conventional risk factors, time to focus on Inflammation –CANTOS trial
There had been debates on the role of inflammation in atherothrombosis. The earlier finding on role of hsCRP in development of CV events among people with low LDL had been highlighted by no one else but Paul Ridker, in 1999. Among patients diagnosed with ACS, despite advances in treatment, there are still residual risk remaining, it has been thought that this ‘residual risk’ areas could fall into either of Residual Cholesterol risk (highlighted by recent finding of further lowering of LDL resulting in better CV outcomes – FOURIER, IMPROVE-IT), Residual thrombotic risk (role of long term dual antiplatelets? Eg DAPT/PEGASUS study) or Residual inflammation risk – this was earlier demonstrated by Ridker when people, despite having low LDL still having excesse events, and JUPITER study that recruited people with ‘normal’ LDL level but high hsCRP treated with statin demonstrating reduction in risk of CV events in this primary prevention study).
In this study presented by Paul Ridker as the lead researcher, they recruited over 10,000 stable coronary artery disease patients post MI with high hsCRP (>2mg/dl) on statin and optimal medical therapy including statin (OMT). Patients were randomised to receive 50mg, 150mg or 300mg Canakinumab SC injection (3 monthly) vs placebo (4 equal arms).
Canakinumab is an interleukin 1B inhibitor which reduced IL6 and in turn causing reduction in the hsCRP. At a median follow up of 48 months, the groups treated with Canakinumab showed reduction in hsCRP between 26 to 41 % compared to placebo. It showed 15% reduction in endpoints of CV mortality, stroke and MI combined (150mg dose met the prespecified endpoints). There was no effect on cvd mortality or all cause mortality
The effect was observed to be consistent over large number of subgroups, with greater reduction of risk among those with greater hsCRP reduction (>median) 27% reduction in primary outcome.
There was additional non CV benefit including reduction in cancer mortality, 51% reduction in lung cancer. Groups treated with Canakinumab suffered less from arthritis incuding gouts and osteoarthritis
This was definitely a proof of concept that target inflamm (ILIB) resulting in further reduction of cardiovascular endpoints, independent of LDL. As to how it could be implemented in clinical practice still awaits further analysis and expert deliberation, bearing in mind the steep cost of the drug (price about USD 14000 per injection of 150mg dose!). There is also a concern on the increased incidence of fatal infection in Canakinumab recipients.
Afib Ablation early in Heart Failure to save life and improve symptoms
Castle AF is a study that helps to answer the question whether or not patients in heart failure who developed atrial fibrillation should benefit from conversion to sinus rhythm.
Out of 3000 patients screened (US sites), 397 (after further screening 165 vs 153 patients entered randomisation) patients with paroxysmal or persistent Afib and ejectioin fraction <35% were randomised to conventional treatment or AF ablation. They were special group of patients with optimal treatment, proven by the fact that all included patients have AICD or CRTD (resynchronization device with ICD) implanted – though it may not have any confounding issue in this trial. Pulmonary vein ablation was the standard procedure performed plus additional lesions/repeat ablation after blanking period, in the ablation arm.
Primary composite endpoint of 38% reduction favouring ablation. All cause mortality was also reduced, HR 0.53 p = 0.01. In addition, improved CV mortality and CV hospitalisation also seen among the active arm. The ablation group also saw increase in ejection fraction of 8%. High number of patients in the ablation arm remained in sinus rhythm at th end of study (AF burden of 28% vs 65%).
The caveat? The procedure was associated with increased incidence of acute pericardial effusion and severe bleeding (combined figure of 6%). Less Stroke, other notable adverse events were pneumonia, pulmonary vein stenosis, groin infection and acute heart failure.
COMPASS – addressing the residual thrombotic risk in high risk CVD patients
Another groundbreaking study in high risk patients with coronary artery disease and/or peripheral arterial disease is called COMPASS – Cardiovascular OutcoMes for People using Anticoagulation StrategieS (COMPASS) trial
This landmark trial recruited over 20000 patients (602 sites, 33 countries)
with coronary or peripheral artery disease with additional risk factors to receive either rivaroxaban (2.5mg BD) plus aspirin, rivaroxaban 5mg BD or aspirin alone with median follow up of 23 months. There were 2200 primary outcome events with the event rate 4.1, 4.9, 5.4% in R+A, R and A groups respectively (primary components – cv death, stroke, MI). Individual components of All cause mortality, CV death and stroke also were significantly reduced in the R + A group. This came at a cost of increased major bleed 3.1, 2.8, 1.9% respectively, excess 1.7 HR (R + A), 1.51 (R alone) HR but not fatal bleeding or ICH
Further analysis combining the outcomes/efficacy and adverse events (fatal/critical organ bleed) showed net clinical benefit favouring Riva plus aspirin (2.5mg) for this high risk group with HR 0.80, (p=0.0005)
Further evidence in support of no Oxygen in acute MI? – DETO2X study
The subject of harmful effect of oxygen therapy in acute MI has been going around for a while. Earlier there was AVOID study which suggested that supplement of oxygen in patients with acute MI without hypoxia could be harmful, resulting in increase in early myocardial injury and infarct size at 6 months.
DETO2X AMI is a registry-based randomised clinical study conducted by the Swedeheart group involving all major cardiac centres in Sweden. In contrast to the usual prospective randomised study, a registry based randomised study recruits all subsequent patients in a non-restricted criteria, via randomisation process. All patients with suspected of AMI (O2 sats >90%) that were recruited, were randomised to receive 6L/min oxygen for 6-12 hours or room air. Primary endpoint was death from any cause at 365 days.
Over 6600 patients were recruited, making it the largest ever study on oxygen therapy in AMI so far.
Mean spO2 was 97% in both groups (Oxygen vs Ambient), More than 65% of subjects underwent PCI.
There was no difference in mortality at the end of the study. There was a trend towards increased cardiac arrest and death in the Oxygen group (non significant). Analysis of all subgroups showed similar pattern, except in compaing those with spO2 >95% or <95%, trend favouring oxygen for those with the lower saturation.
As a conclusion, Oxygen therapy was not associated with any benefit in mortality in Acute MI. The ESC have got this early and incorporated it in their guideline, therefore chaning the recommendation to only give oxygen in those with spO2 < 90% .
There are a number of other positive clinical trials that you may hear about in due course. Among notable one – in hypertension – promising result on blood pressure reduction (off medication) among patients treated with renal denervation (SPYRAL HTN OFF-MED study). Is this going to see renal denervation making a comeback in the treatment armamentarium of resistant hypertension? Too early, as Medtronic is yet planning a full scale randomised study with long term result.
The battle of New Oral Anticoagulation is till going – with the result of RE-DUAL PCI (Dabigatran in Afib patients undergoing percutaneous intervention), showing dual therapy regime of dabigatran and P2Y12 antiplatelet to be safer, causing less bleeding compared to warfarin.
I would also like to share our abstract which we presented in poster form at the ESC Congress, entitled: Open-labeled randomised controlled study of double dose clopidogrel versus ticagrelor in stable coronary artery disease (CAD) patients with clopidogrel resistance – we found 29% of stable CAD patients resistant to clopidogrel (measured by multi-electrode aggregrometer, Multiplate). They were subsequently randomised to receive double dose clopidogrel for one month OR standard dose ticagrelor (90mg BD). The result showed both groups reached a mean value of AUC (this is how the platelet suppression measured) within therapeutic range. However, only the ticagrelor group showed uniform and consistent platelet suppression, with all of the patients treated reached target platelet suppression, compared to double dose clopidogrel (33% failure rate). This result is fairly convincing of the efficacy of the new P2Y12 antiplatelet ticagrelor, which we are using more often now particularly in patients with acute coronary syndrome or those with complex coronary disease undergoing PCI.
Besides the above late breaking clinical trials, there were also presentations on the new guidelines of practice, as well as number of sessions that focused on certain key issues in cardiology practice such as:
Acute coronary syndrome STEMI – new recommendations including multivessel PCI (but still a debate as to when to be done, perhaps as in patient rather than during the primary PCI), removal of the door to balloon or door to needle time, now changed to First ECG diagnosis, giving interventional cardiologist more control of their performance. A ‘comeback’ of fibrinolysis where it is still recommended when there is a possible delay of over 120 minutes from first diagnosis to primary PCI. This should be followed by ‘pharmacoinvasive’ strategy, means patients should undergo coronary angiogram within 3-24 hours post fibrinolysis.
There was also guidelines on dual antiplatelet therapy – this time focusing on patients rather than procedures, so the whole issue of duration of therapy has undergone extensive revision, which may make things more elaborate for treating physicians. Standard duration of therapy post PCI has been adjusted to 6 months DAPT for all, regardless of bare metal stents, any drug eluting stents (DES) or even drug eluting balloons (DEB)! However, there is some flexibility in which a patient who is deemed to need shorter duration of DAPT maybe given as little as one month therapy. On the other hand, there was also a concomitant recommendation for a more prolonged DAPT, extending up to 30 months (result of analysis of two studies – DAPT and PEGASUS), in those with high risk of events and low risk of bleeding, subject to physician’s discretion.
As regard blood pressure, a number of sessions on the new target blood pressure were highlighted. Basically as result of the much hyped SPRINT trial which advocated lower blood pressure target in those at risk population, now to below 130/80. But to avoid <120/80 and in elderly, the target maybe <140/90. However, this must not be confused as to the absolute threshold for treatment, in those without other associated risk factors or organ damage, in which the benefit is not seen till the level of >145mmHg SBP (as shown in HOPE 3 trial).
In the field of intervention, the congress coincides with the 40 year celebration of Angioplasty. 40 years of rapid advances in intervention now expanding to coronaries, peripherals, valves, structural and beyond. It only means more patients are able to be treated (nature of percutaneous intervention which may simply be carried out even at relatively higher risk patients, compared to surgery), the next phase may see intervention such as transcatheter aortic valve implantation (TAVI/TAVR) coming soon to be at equal footing to surgery (barring the high cost!).