The New Definition of Hypertension: Are You Closer to Having One?

On the New American guideline on HPT issued by the American College of Cardiology/American Heart Association

Many may be taken by surprise by the new Amerian Guideline on Blood Pressure Management. This new guideline was issued by a joint taskforce of American College of Cardiology (ACC) and American Heart Association (AHA) which coincided with the AHA Annual Scientific Meeting at Anaheim California. For yet another time, the American shocked the world with their all low, new definition of high blood pressure, bringing the definition of hypertension to 130/80mmHg compared to the existing level of 140/90mmHg. Now they have made this bold statement that blood pressure should be classified to one of four: normal (below 120/80mmHg), elevated (120-129/<80mmHg), Stage 1 hypertension (>130/80mmHg), Stage 2 hypertension (>140/90mmHg).

For those who have been reading Cardiology literature and guidelines, may recall how the Americans stirred the world in 2013 when they ‘removed’ the target level for treating hyperlipidaemia (LDL cholesterol) in their new guideline – which later was ‘repositioned’ and added a new target as well as new non-statin agent which initially was not mentioned.

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Then the Joint National Committee (JNC 8) released the new blood pressure guideline, to yet again stirred controversies on the opposite way when they suggested in older people above 60, the ‘normal’ blood pressure cut of was 150/90mmHg. As for younger people and target BP, it was all the same 140/90 mmHg. Of course, they are different and separate taskforce – but coming from the same continent, why there is so much difference of a 30mmHg in hypertension threshold, within a mere period of 3 years? Let’s not debate that since there had been numerous criticism on this JNC 8 (as much as the American new 2013 lipid guideline!) and a later publication suggesting an all new low BP target (refer to SPRINT – A Randomized Trial of Intensive versus Standard Blood-Pressure Control, NEJM Nov 2015).

So, was this new guideline on blood pressure driven by the surprise finding of SPRINT? Let’s examine briefly what this study was about. Prior to SPRINT, there had been a number of clinical trials such as HOT, ACCORD looking at lower BP target which did suggest lowering to a level of 130/80 may be beneficial. However the result of SPRINT seemed to be more impactful since it did also affect mortality, and the trial was stopped early due to the much lower event in the group assigned to lower BP target. The study recruited more than 9000 patients at high risk of cardiovascular events (note, they were not any ordinary person on the street with a slightly high blood pressure!) and randomised to two target BP groups: Standard – target BP <140/90 or Intensive arm – target BP <120/80 mmHg. Primary endpoint was myocardial infarction or other cardiac events and cardiovascular mortality.

What was the findings? In summary, the intensive BP group reached a level of systolic BP of 121.4mmHg while the standard group 136.2mmHg. The Intensive arm had a 25% lower primary endpoint (less overall incident of MI, other cardiac events and CV mortality 1.65 vs 2.19%) – individually it translated into reduction of CV death (by 43% – 0.25 vs 0.43%) as well as all cause death, and reduced Heart Failure by 38% (0.41 vs 0.67%). (All figures were annual incident by %) with median follow up of 3.2 years. Of note, incident of MI was reduced but not statistically significant. Therefore, what we can learn, in those patients with high risk of cardiovascular disease (or already having one), reducing their blood pressure to a target below 120mmHg will improve their overall outcome of death and heart failure, and overall cardiac events. This was a fairly short duration of study (median follow up 3.2 years), imagine the magnitude of benefit you are affording patients by treating their blood pressure to this low target over 10 or 20 years?

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What’s the catch, you may ask. What would happen if you lower blood pressure to that low level? As anyone might guess, there were more incident of hypotension (low blood pressure), syncope (fainting) and decreased glomerular filtration rate (GFR) which is a index of deterioration of your kidney. There is another thing which the main article in the journal did not cover. How was the blood pressure measured? In contrast to all other trials of BP lowering, which used standard “office”blood pressure measurement (BP measured by doctor or trained staff according to standard measurement protocol), SPRINT was the only trial that used ‘unattended’ blood pressure measurement. Patients in the trial were left in a quite room, BP measurement started after 5 minutes of rest and repeated automatically 3 times, an average reading was taken. So this is not a normal way of BP measurement, may be closer to a home BP (patients measure their own BP at home which usually gives lower reading than clinic BP).

 

OK, you are right, those clever Americans did not just rely on one isolated study to support their work, of course. It is to now one surprise that even earlier study like Framingham cohort and MRFIT population data suggested that a linear increase in future cardiovascular event started when your BP climbs to more than 120mmHg (systolic). Lewington et al in 2002 (Lancet) plotted a graph depicting a ‘normal’ BP level whereby there would be no increase in future CV event, was 115/75mmHg! This was the basis, and now further enhanced by a number of studies and meta analysis of observational data suggesting that BP level of 120-129mmHg systolic was associated with increased CVD event by 1.1 to 1.5 times, while BP above 130mmHg (130-130mmHg systolic) by 1.5-2.0 times.

Indeed, if we have a closer look at the ‘older’ guidelines, and consistently be it Americans, Europeans, Canadians or Australians, they have asserted that there is this so-called ‘pre-hypertension’ level of BP between 130-139mmHg, in fact some of them have made recommendation to treat this BP level in high risk populations. Therefore, re-classifying the hypertension BP cut off does make sense, perhaps to put more emphasis to the treating physicians to go all the way in optimising their patient’s care.

It is no secret  that any clinical trial that observed an increase in BP even as low as 2mmHg will be associated with a rise in CV events, in contrast those that showed BP reduction as little as 2 mmHg will be accompanied by lowering in CV events. To quote an example, there was an excellent HDL (high density lipoprotein) raising agent torcetrapib (CETP inhibitor) that showed impressive rise in HDL by 76%, however resulted in increase CV events, one of the reason which, was a rise in BP in the treatment arm (by 5mmHg)! (NEJM Nov 22, 2007). In the LIFE study comparing losartan (ARB) vs atenolol which proved an ARB to be superior in reducing CV outcomes among hypertensive, there was still a slight difference in BP of 1mmHg. Its miniscule, but remember what Lewington (Lancet 2002) et al had concluded in their meta analysis, of BP reduction as little as 2mmHg in clinical trials reduced CV events by up to 10%! Thefore any BP reduction does make a difference, implying the importance of lowering BP in patients at high risk or already having CV events.

So back to the new American guidelines, are you ready to accept being diagnosed as hypertensive by your doctor, if your BP is 130/80mmHg or more? Or even being told that your BP is on the high side, by having a measurement reading of 125/75mmHg? What is more important, perhaps is how do you treat the ‘new’ hypertension that matters. In this regard what being recommended is not a very new thing, since they are still dividing the hypertensive people to 2 categories (see the table). Which means, if you are a ‘normal’ person, not having diabetis or any cardiovascular risk factors, do not smoke, never being diagnosed with heart problem, having a blood pressure reading of 130/80mmHg, does make you a hypertensive person – though, you do not yet need any medication. However, if you already have a heart disease (angina/heart attack (MI)/stroke), or deemed at high risk by having one or more of those risk factors (and calculated ASCVD – atherosclerotic CV disease of 10% or more) then you should take blood pressure medication. This is no surprise, in fact, even before this guideline published, many doctors (cardiologists) would have recommended additional medications for similar situtation, despite you not being diagnosed hypertensive as yet. Basically, the guideline is recommending treating you as a whole person, rather than a blood pressure alone.

So what can you do if your blood pressure is 130/80 mmHg and you are now a new person with hypertension? Provided you have no other risk factors or heart disease, the recommendation is non-pharmacological intervention and regular check up of 6 monthly at least.

Non pharmacological intervention to prevent/delay HPT or reduce BP namely reduce weight, take the DASH (dietary approaches to stop hypertension) diet (high in fruit/vegetables), cut down sodium (salt), Potassium supplement – KCl, or fruit/veg & low fat dairy, regular exercise and cut down alcohol.

However, before you get diagnosed or confirmed hypertensive, ensure that at least two separate measurements (different times), first one preferrably on both arms have been carried out. There is a special condition called White Coat Hypertension – when your office blood pressure is high and home measurement is normal (below 120/80). If you are being diagnosed and medication being contemplated, it is worth to get a set of blood pressure machine (well validated one) to do your own measurement. Just make sure you do the measurement while at rest, not following a vigorous exercise or intake of any stimulant – preferably while seated after 5 minutes. If repeated measurement of home blood pressure is normal, while clinic reading always high, it is likely that you are having a WCH which do not require to be treated with medicines, though it’s still worth instituting all those healthy lifestyle measures.

Another important aspect is to have a thorough assessment of all cardiovascular risk factors which should include BMI, blood glucose and lipid, renal function, full blood count and ECG. A scoring system that predicts future risk of CVD such as the one recommended by the Americans (ASCVD calculator though may be at variance among Asians, may be helpful to gauge how intensive the treatment of blood pressure and other associated risk factors should be). One often forgotten risk factors but seen fairly common is family history of  heart disease at young age (below 55 for men, <65 for women), or family member who died sudden death – which the likely cause is more often cardiac. So now you understand it is not just about the number, it is one’s overall cardiovascular profile that matters. Existence of high blood pressure (the higher, the more risk) along with other risks such as diabetes, kidney disease, obesity, high cholesterol and family history will increase the risk of a person having future CVD.

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BATTLE OF NOACS – Real World Evidence and beyond…what’s left

There has never been any medical products which such a wealth of clinical evidence from randomised studies, supplemented by abundance of real world data, other than the New Oral Anticoagulants (NOAC).

As shown from registry data GARFIELD, usage of NOACs for stroke prevention in patients with Non-Valvular Atrial Fibrillation (NVAF) in 2015 came close to 40%, which is fast overtaking warfarin as the standard of care.

Is this an appropriate rise considering the high cost of these new medicine? Warfarin tablets (generic) cost a mere few cents while a month of NOAC treatment costs an average between RM240-300 depending on institution and subsidies. Is it worth the cost? Of course, in medicine there are things beyond cost, for example pharmacoeconomic etc which may not be a very straightforward thing in practice.

Comparing to warfarin, the landmark randomised clinical trials proved that NOACs are at least as effective as warfarin, with proven safety profile, while reduction of intracranial haemorrhage was consistently seen across all trials.

Aside from this, for clinicians treating patients with atrial fibrillation, they may be caught in the dilemma of which NOAC to prescribe, once they have decided warfarin is no longer the standard of care for these patients.

The researcher group led by Christian Ruff et al had conducted a meta analysis of all the four trials involving NOACs vs warfarin (RELY – dabigatran, ROCKET AF – rivaroxaban, ARISTOTLE – apixaban and ENGAGE AF – Edoxaban) published in Lancet Vol 383 March 15, 2014 which concluded that the NOAC as a group were superior to warfarin for stroke prevention (risk reduction by 19%) accompanied by a stastitically significant reduction in mortality (hazard ratio HR 0.9), as well as reduction in intracranial haemorrhage (HR 0.48). However there was a slight increase in gastro-intestinal bleed (HR 1.25). Low dose NOAC were found to have similar efficacy with warfarin. Therefore what the landmark clinical trials have done was established the efficacy and safety of NOAC, they were at least as good or even better than warfarin.

As to the question of which NOAC is best, one may never find the answer, or he/she would, depending on which set of data he or she believes in. Take it for fact, even in the issue of whether NOAC is better than warfarin, taking the randomised clinical data and real world evidence together, one would not reach a definite conclusion, if a fair and balance analysis were to be conducted. The simple reason because:

The randomised clinical trials of NOACs – all were conducted on a heteregenous group of patients. RELY was an open label trials conducted on patients with a lower CHA2DS2 score, while ROCKET AF recruited older patients, had higher risk patients (higher % of previous stroke for example) and CHA2DS2 score the highest. ENGAGE AF have somewhat closer profile patients with ROCKET AF, while Aristotle (and RELY) recruited more than 30% patients with CHA2DS2 score of 0-1! Therefore no direct comparison is possible.

How about real world data, all comers population? There are many publications on real world evidence of patients treated with NOACs, some sponsored while others independent. Some of the largest so-called real world evidence came from claims database of insurance like Medicare in US like that by Graham et al paper on comparison of dabigatran vs warfarin which showed warfarin to be superior to warfarin in mortality and stroke efficacy as well as safety (bleeding) except gastrointestinal bleed (increased). The same author also head another publication of real world data from Medicare, using propensity matched scoring, comparing dabigatran vs rivaroxaban (no warfarin comparator) – a much debated study which showed the superiority of dabigatran over rivaroxaban on bleeding and mortality but not stroke (indeed rivaroxaban came out superior to dabigatran for stroke reduction, though statistically not significant).

Graham’s controversial findings were apparently not the odd one, a number of other papers including that of European Danish registry had also highlighted the excessive bleeding risk in patients treated with rivaroxaban (compared to dabigatran or apixaban).

In short a number of these real world evidence publications have suggested the increased (or neutral effect) in mortality and bleeding with rivaroxaban when compared to dabigatran or apixaban. However when a warfarin comparator was available rivaroxaban seems to be comparable to warfarin in term of bleeding.

Let me be clear that I am not in the capacity of presenting a systematic analytical data of these real world evidence. What I am highlighting here is based on the individual publications as well as metaanalysis one of those by Lip et al since he is one of the well known authority in this field.

In short, looking at these real world data:

All the NOACs individually and as a group have similar or better efficacy than warfarin in stroke prevention. There are a number of publication showing rivaroxaban having a trend towards superiority in reducing stroke compared to the other NOACs, one study showing apixaban superiority, none showed dabigatran superiority (despite the randomised study RELY which suggested dabigatran 150mg the only NOAC superior to warfarin in reducing stroke).

All NOACs (individually and as a group) showed consistent reduction in intracranial bleeding comparing to warfarin.

Rivaroxaban appeared to have increased bleeding and (in some paper) mortality when compared to apixaban and dabigatran.

Rivaroxaban, and dabigatran (at least in a number of publications) have a risk of increased gastrointestinal bleeding.

Apixaban consistently showed low bleeding risk, including gastrointestinal bleed compated to the other two NOACs.

There are not many real world data accumulated on edoxaban to this date, in order to include for this cursory comparison.

With the above data, is it enough to make any meaningful conclusion regarding ‘superiority’ of one NOAC over another?

Perhaps the most conclusive statements that can be made are as follows:

NOACs as a group have consistently shown good efficacy and safety profile over warfarin, both in randomised landmark clinical trials and real world evidence.

NOACs have similar or somewhat better efficacy compared to warfarin in stroke prevention.

Reduced ICH with all NOACs comparing to warfarin.

Caution should be exercised in patients at risk of gastrointestinal bleed since NOAC may increase it (except apixaban).

NOACs as a group showing trend of superiority over warfarin in total mortality.

There are a number of studies suggesting increased major bleeding in patients treated with rivaroxaban. While there might be differences in the population of patients prescribed each individual NOAC, this may be a pointer for caution in prescribing rivaroxaban particularly in elderly or those with high bleeding risk. This statement in no way consign the drug to be any less than the other NOACs.

I have alluded all the above points, however there is a very recent publication (by Serebruany et al) on mortality among patients treated with NOACs compared to warfarin. The population was derived from the FDA Adverse Event Reporting System which contained more than 7 million records. After narrowing down to those adverse event reported on each NOAC, they have come up with over 120,000 records on NOACs and similar number on warfarin. This was a large database indeed, in which the number of mortality was somewhat 10 times the figure compared to other real world population. In short this study showed that NOACs as a group showed superiority over warfarin in term of reduced mortality, with the exception of dabigatran (showed increased mortality). Do bear in mind the AERS included all patients treated with NOACs, all indications taken together.

What does this new dataset contribute to our existing understanding on the performance of NOACs in the real world? Taken at face value, the study supports the notion that NOACs have shown consistent data in term of its superiority over warfarin (in reducing mortality), in general. Though, the data on dabigatran has to be treated with caution, and I would keep away from making direct conclusion or comparison as in the above case too. Furthermore we have no details as to how many percent of this mortality occurred among those AF patients or those in sinus rhythm, being treated with NOACs for other indications such as venous thromboembolism. Data from NOACs study among patients with acute coronary syndrome for example, have not shown favourable profile among all NOACs except rivaroxaban (ATLAS TIMI 52 trial), and the study on warfarin alternative among patients with valvular disease (including prosthetic valve) randomised to dabigatran or warfarin showed negative result with excess bleeding and CV events in the dabigatran arm. Could there actually be differences among NOACs when they are used for different indications other than stroke prevention in AF? Another possible conclusion from this mortality data is, that compared to warfarin, anti factor Xa based NOACs are showing favourable trend in mortality reduction (consistent data with patients on rivaroxaban, apixaban and edoxaban), while direct thrombin inhibitor showed the opposite trend. We await further data and key opinion leaders input on this issue.

(References on request)

ESC Congress 2017 – Further advances in cardiology with many positive clinical trials?

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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 (PUREstudy

CASTLE AF – Catheter ablation versus standard conventional treatment in patients with left ventricular dysfunction and atrial fibrillation

Determination of the Role of Oxygen in Suspected Acute Myocardial Infarction (DETO2X-AMI)

 

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 (PUREstudy 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.

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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!).

Playing with statistics in medicine…

Finally the therapeutic dilemma came to an end…
There was this young ex-pat patient came to my clinic with new onset atrial fibrillation (irregular heart), as she has hypertension we recommended blood thinning medication (anticoagulation) called warfarin on her. Soon after, another doctor prescribed a new novel anticoagulant A, which costs >100 times more. When she came to my clinic she told me that she has not started the medication, as she was not sure whether it was good or not..
Apparently there was some lack of communication. So I went through a brief counselling till she asked, which one is better? I told her comparing the two, the new one, drug A is of course far better, as has been proven in clinical trials. However, taking warfarin strictly with good INR (a way to check your blood thinning index) is likely going to give you similar protection, with overall higher risk of bleeding – the cost however is the main obstacle.
Now the patient said: I trust your decision, doctor. And I am willing to spend the money….
Knowing she has a very young daughter diagnosed with SLE, I really pity her, and this put me in serious dilemma having to recommend a treatment costing over RM400 (or higher cost for her as foreigner) – and yet there is no sure way to tell her she will benefit more compare to her current treatment – its all about statistic – if the ‘number needed to treat’ is below 30 – then it is something very compelling – but in this case it is far more (167 for efficacy & 67 for serious bleeding)…of course there are other benefits like less interaction with food, drugs, and no need for blood test (INR clinic).
Sighed….in the end I advised her give it a try and see how she tolerates the new medication…today, she came back telling me that the new medication had caused her to have pain, cough and shortness of breath. She happened to suffer from flu as well. Well, not a direct adverse event from the medication, however, to remove the doubt, and due to her reluctance I advised her to revert to warfarin.
The lesson here, decision making in medicine may not be very straight forward especially when cost effectiveness is concerned. Patient counselling is an important part of management, do make the patient aware and understand the benefits and risk of the treatment, as well as potential cost effectiveness.

More on TIMI score

A lot of people have visited my posting on TIMI score, which had been posted quiet a good while ago. Let me update you a bit. There are TIMI score classification for both STEMI and UA/NSTEMI, they are separate of course.

The STEMI TIMI score takes into account many parameters that include ECG changes, presentation time and Killip’s score.

Killip score is a simple but useful risk stratification score of patient’s with MI based on their heart failure status (1 – no failure, 4 – cardiogenic shock).

Both scores are reproduced here (pic linked from cardiachealth.org). From Morrow et al, Antman et al Circ, JAMA 2000

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Is there an ‘easy’ way out to reduce blood pressure?

Anecdote of my personal experience managing my hypertensive patients this week.

At last I was relieved. What I have nearly lost last week, now is back under control!

Last week, I was quite frustated by two cases of severe hypertension patients that came to my clinic. One swas a very elderly lady whom I saw first time, previously treated at another centre. According to her daughter, home BP had been quite labile however lately better controlled around 140mmHg systolic. She was otherwise well with cocominant dyslipidaemia only, no diabetes. Her clinic BP at first measurement was 190/90mmHg. When I rechecked it was still at 180/90. Due to her age and the fact that she was due to undergo cataract surgery, I suggested a few days admission. The daughter declined. She was already on Losartan 100mg daily, so I added 5mg amlodipin to start with, urging the daughter to monitor the BP closely.

Early this week she turned up at the ward for preop admission. Her BP in the ward was still very high at 170-180mmHg. I increased her amlodipin to 5mg BD (sometimes I started this way just to allow patients to cope with the sudden increase in antihypertensive, usual dose of amlodipine is once daily). The next day, her BP was still around 170-190mmHg systolic! I allowed her anyway to undergo the surgery under LA. It went uneventful however the ophthalmologist now handed her case to me for postop BP control.

She is already on amlodipine max dose for at least 48 hours, BP still unchanged. Changing the meds to single pill ARB and CCB combination won’t do much I think, since she was already on both separately, therefore I decided to target a different system. Aldosterone, yes, some of these resistant hypertension may have secondary aldosteronism. I therefore started her on spironolactone 12.5mg once daily. After three doses of this drug, here is the BP monitoring chart…

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Even a minute dose has worked so well in dropping the BP by 20mmHg or more, awesome. This is an indirect evidence of her high sodium retention state (salt retention…secondary to secondary hyperaldosteronism). Well, we have also advised her to curtail salt intake.

Second case was another elderly lady whom I saw before, with severe hypertension. In the past the BP had been under control on atenolol and perindopril. This time she presented again because, according to her, BP check by clinic doctor has been persistently high. At my clinic her BP was 185/100mmHg. Heart rate 88, means not fully betablocked. There was no specific reason, she could be nervous, nothing showed on the ECG. Repeated check found no reduction in her systolic BP, looked dubious, however she also refused admission. I sent her TFT and renal function, and started her on diltiazem slow release (Herbesser R100mg). Last Friday she returned to my clinic, this time her BP had dropped to 140mmHg at home, around 156mmHg at clinic. Not yet at target, but she had moved away from danger zone. Now I changed her perindopril to Coversyl plus adding the diuretic component, to obtain an optimal BP reduction.

In both of these cases we have seen big drop in BP with addition of a single agent. I have maintained my practice of using the first three line of drugs A+C+D in most occasions (A=ACEI/ARB, C=CCB, D=Diuretics), however, there are times when I skip this rule especially in dealing with resistant cases. Whatever it is, the first aim in treating hypertension is to reduce BP to target. Next you have to think of the most appropriate agent, ie one that is likely to confer optimum benefit in term of prognosis. Then I will address comorbidity and risk factors, low threshold in initiating statin especially when there are two or more CVD risks present.

Help, how do I entertain this request to talk about a product I do not really favour…?

I am a doctor, I do not do marketing, I only present evidences…

If someone ask you to give talk to an audience about a product that you do not support, for the purpose of promoting it…what will you do? Hold on, there is some attractive honorarium for it, will you do it?

I was not in that kind of situation, but nearly. Now they had asked me to talk about this product H, that I do use, indeed, but not as my first choice. I have kindly obliged since they approached me in a very persuasive way and I know there is nothing wrong with this product anyway, just that I do not use it enough. Did I do it for money, no way, coz, I gave my agreement even before the rep told me that there is going to be honorarium – true, some company do not really give you anything substantial for speaking for them, I still do accept the invitation. For one, I treat this request as an academic exercise aka my own CME, furthermore it gives me opportunity to meet new people and broaden the horizon of my national appearance.

Here is what I did. First, yes, the product is genuine, endorsed by guidelines. I looked through the literature, some of which were old ie pre-2000, however, on browsing our own clinical practice guidelines, no doubt this product was mentioned as one of the approved treatments, listed at par with other, more established product that I frequently used. Therefore there is no conflict, it’s just that, I did not favour the product, due to my own exposure and previous experience.

fatih dilemma

Second, as usual the company gave me the presentation materials. As a practice, I do not adopt the presentation material completely, instead, I will go through each slides and ensure that the content genuine and does not contradict with my own understanding and the established evidence. Then I only picked materials that are fairly neutral in contents, ie not too patronizing of the product, I keep on the generic rather than brand name in almost all the labelling if possible. Any of the material that is doubtful or overbearing of the product will be put aside.

Then I drew my own concept and perspective for the lecture. I outlined what I wanted to present, rather than what the ‘company want me to talk’. Obviously I have to supplement more than half of the content with additional materials obtained from my own research. This is where I like being given the task of giving a lecture, since it gives me the opportunity to explore and hence broaden my understanding of the subject, in a fair and unprejudiced way. Fortunately, this day it is  not very difficult to search relevant references through internet.

On the day when I arrived, the company rep had already set up a computer, and projected the slides of the presentation! I quietly went to the stage, and asked to use my own laptop, telling them that I had prepared my own material, combining with the material they have supplied. They had absolutely no problem with this, so I showed them the entire content of my presentation, to assure them that the presentation ‘does justice to their product’. They appeared to be pleased, in fact at the end of the presentation the company manager praised me for the wealth of contents that I have presented.

Therefore, by carrying out this exercise, I had given a lecture, which was fair, unbiased and highly academic. This was proven, when during the discussion, audience had thrown various questions that were quite general rather than too focused on the product. At the same time, the company were happy since enough justice was given to introduce their product to the intended audience.

You may be interested to know, if there had been occasions when I refused to talk about products? Yes, as far as I can recall twice. One about a product that now is being withdrawn from the market – I was sent for a special training workshop for it, but later declined to take further steps to promoting it. Another was a product, which is good and genuine, but I do not use it so much (very much like this case), but I declined coz the company rep was so pushy, then it was passed on to my junior colleague. There was another invitation for a special expert group of another product, which I had some doubt about its strength of evidence, however, I sat there merely as adviser or to give expert opinion, if it come to the stage of endorsement or promotion, I will have to take a stand depending on the nature of the proposal.

In principle, I found most if not all companies (at least their senior management personnel) will not allow promotion of their products beyond its approved label. Therefore, some of them will insist on going through the presentation material in advanced, not because they want to see how much you are promoting their products, its rather to rule out any off label marketing being presented.