THE FIRST EVER HISTORIC SUB 2 HOUR MARATHON AND THE LATEST TREATMENT FOR THE FEARED LEFT MAIN CORONARY ARTERY DISEASE

 

SIR ROGER BANNISTER SHATTERS 4 MIN MILE BARRIER IN OXFORD ON 6th MAY 1954

 

Sir Roger Bannister etched his name in history by breaking the 4 minute barrier for the mile in Oxford on 6th May 1954, after coming fourth in the Helsinki 1952 Olympics in the 1500 m finals. Sir Roger was a junior doctor then and went on to become a consultant neurologist. His training sessions were light compared to todays standards, but was most probably practicing what is now called high intensity interval training. But when asked what was his proudest achievment he is supposed to have replied his academic contribution as a clinical neurologist. He almost gave up running when he missed a medal in Helsinki. It should be borne in mind that competitive middle distance and long distance running in those years was largely done by Europeans; the Africans must have been definitely running but were not noticed as their participation in track events was extremely thin. But all said and done Sir Roger’s feat will stay in human sporting history for eternity. He ran on primitive earthy sort of a track albeit with pacers, but the last 300 m were tough bet cause of a cross wind. After the race young Roger still gasping for breath said he was “glad” the 4 minute barrier was shattered in Oxford and not in the USA. The current 1500 m record for men stands in the name of Hichem el Guerrrouj of Morocco at 3 min 26 secs set in Rome more than 20 years ago in 1998. The fastest Indian at 1500 m is Jinsen Johnson who has clocked 3:35.24 last month in Berlin. The 1500m record is bound to be broken but Bannisters run will always be a reference point for every middle distance runner on the planet.

 

ELIUD KIPCHOGE FIRST MAN TO SMASH THE 2 HOUR MARATHON IN VIENNA ON 12TH OCTOBER 2019

 

 

This brings us to another historic moment in distance running, the day Eliud Kipchoge became the first human to run 26.2 miles also called the “marathon” below 2 hours. This is a phenomenal sporting feat that shall be talked about for hundreds of years by everyone attached to sports in general and running in particular. Vienna was the lucky city to witness the extraordinary marathon by Kipchoge. Guess who have been born in Vienna? My favourite is Lisa Meitner, the woman who figured out that when a heavy nuclear particle divides there is always some loss in mass that actually always converts to energy. No wonder Lisa Meitner famously quoted that “You must not blame us scientists for the use which war technicians have put our discoveries.” She was referring to the atom bomb and the Manhattan Project; Lisa Meitner never got a Nobel for physics despite being manifestly deserving. Einstein called her the “German Marie Curie.” Yes the Nobel committee has goofed up many a times. The Nobel prize for literature this year is considered by many close to a disgrace. We however must stick to Kipchoge’s run. The run had numerous adjuncts that a trained athlete will keep in consideration, The route was almost flat and 90% straight. Kipchoge had world class pace setters along with him, who also protected him from any breeze or wind. Vienna was selected for its languid conditions and mild weather. A fancy green laser was constantly directed on the road in front of Kipchoge to enhance running efficiency and importantly he wore the most advanced running Nike shoes ever that have a trampoline effect. The shoes or “Vaporflys’ are reckoned to give almost a 90 seconds advantage to an elite marathon runner.But all these assisting devices cannot mitigate or in any way shadow the accomplishment. Even this record will eventually be broken but Kipchoge made history as he dazzled the world with the first ever sub 2 hour marathon. His time 1:59.40.2 ! This is mythical. I wonder how many Indians fed on 24 X 7 cricket have any idea about the Kenyan’s run.

 

THE LANCET 2019;394:1325-34
ALL CAUSE MORTALITY IN SYNTAX 10 YEAR FOLLOW UP OF LEFT MAIN DISEASE PATIENTS.

 

We need to shift to something quite different but life saving. For decades it was anathema to consider any treatment other than CABG surgery for patients with what is termed “left main” disease. The left main coronary artery divides usually into the left anterior descending and left circumflex arteries, and thus supplies most of the heart muscle. Life is under great threat if the left main coronary artery gets blocked more than 50 %. Coronary bypass surgery had been the only option, earlier randomised trials had clearly shown that surgery was far superior to medical therapy in patients with left main disease. Also percutaneous coronary intervention (PCI) was never considered as an alternative. A paradigm shift has taken place in the last week or so. Two mammoth randomised trials have shown that left main patients do equally well with PCI (ptca and stenting) when compared to CABG surgery. The trials are big by any standards and there follow up as long as 10 years, which is pretty long. The SYNTAX trial (Lancet 394;1325-34 ) has reported that all cause mortality was more or less similar whether patients with left main disease underwent stenting with first generation paclitaxel eluting stents or CABG surgery. In fact after 10 years mortality in the PCI group was 26% versus 28% in the CABG cohort, so actually there were fewer deaths with PCI albeit this was not significant. Also it did not matter if patients suffered diabetes.More than half of the patients in the left main group had distal disease and 50% block was taken as the cut-off. Hence PCI is a suitable alternative to CABG with similar 10 year death rates. Information was available in almost 95% of the 1800 original patients randomised in the SYNTAX trial. There were 705 patients with left mason disease studied in SYNTAX.

 

28 th SEPTEMBER 2019, NEW ENGLAND JOURNAL OF MEDICINE

 

The other big trial (N Engl J Med ; published September 28,2019) named EXCEL reported 5 year follow up of 1905 left main disease patients. There was no difference in cardiovascular mortality whether patients were subjected to PCI or CABG ( 5% vs. 4.5%) or in myocardial infarction (10.6% vs. 9.1%). Patients had to have left main block of 70% or if the block was between 50% and 70% they needed to have physiological schema confirmed by stress test to FFR. More than 80% had distal left main disease while stents used were the newer durable polymer everolimus stents. The researchers failed to detect a significant difference in the composite rate of death, stroke, or myocardial infarction at 5 years in patients with low or intermediate complexity (SYNTAX score of 32 or less). As in SYNTAX results were no different if diabetes was present. The message is lucid, PCI is a viable alternative to CABG surgery in patients with left main coronary artery disease. Both PCI and CABG unlike a quadruple ton in a cricket test match or a sub 2 hour marathon save human lives.

FROM THIRD GENERATION INDIAN CORONARY STENTS TO PRIMITIVE INDIAN SEWERS.

 

 

 

 

 

Now that Gandhi Jayanti is over here are some charming facts regarding the tribe called “manual scavengers”. Apparently they have existed a,ingest us for generations, in fact have been considered a vital and essential component of the Indian social fabric. The manual scavengers responsibility is to engage directly with human excreta. He ensures sewers are kept operational in the towns of our land. He also is entrusted to tackle septic tanks, manholes and of course sort out dry latrines across the length and breadth of the country. There are thousands of them, more than 50,000 as per official records. A New York Times report placed the figure at 300,00 if not 900,000! More than 800 have died in the last 2 decades. These are conservative figures. Some responsible agencies go to the extent of stating that a manual scavenger dies every fifth day. This may or may not be an exaggeration, but pictures speak for themselves. There will be a young able bodied male entering or exiting a sewer/ man hole with absolutely no protective gear. Deaths are because of poisonous gases produced in sewers. The main stream media including TV channels provide scanty information, they barely scratch the surface. Little wonder there is little or no outrage over the delightful job of engaging with human excreta in the twenty first century. India has the unique distinction of nurturing this band of men. There numbers have actually increased in some North Eastern states including West Bengal. Maximum deaths have occurred in Tamil Nadu, and now hold your breath , the silver medal winning state is Gujarat. Almost 18,000 crore rupees are spent per year in the Swachh Bharat Abhiyaan project, but less than 63 crores were provided by the government for the rehabilitation of our sewer gladiators in the last 4 years. Ironically publicity money for the Swachh Bharat Abhiyaan project ( electronic and print media) during this time exceeded 500 crore rupees. There was recently an uproar in the BBC when a breakfast TV host of Indian origin expressed her anger and frustration on being a target of racism in the UK. The BBC management in its infinite wisdom reprimanded her for disclosing personal views, but was promptly attacked by numerous British journalists for its bigotry. It struck me whether these manifestly decent journalists had any clue about our sewer gladiators who handled excreta possibly with bare hands on a daily basis, without the slightest whisper from the community at large. There is stunning insensitivity where manual scavengers are concerned, one could go further to say there is tacit approval by society. This stunning acquiescence is embedded in culture, for the volunteers to tackle dry latrines and blocked sewers come from a particular section of Indian people. A recent report describes 3 gladiators dying one after the other while tackling a sewer, there was no one prepared to give them water as they were dying(scroll.in). What can be more horrific than this? That Justin Trudeau may lose the next Canadian election because of the crime of polishing his face black is laughable. Canadian, or for that matter the Brits have absolutely no idea of the systemic debasement inflicted on fellow humans in this part of the planet. Mr. Bill Gates are you listening? Indian scientists have an orbiter encircling our moon right now, it shall do so for some years. Very soon they will surely drop a rover on its surface too. They almost did it last month. “Vikram” the rover named after the famed scientist Mr. Vikram Sarabhai travelled nearly almost 380,400 km or more from earth; thats quite a brilliant feat. Less than a handful of nations have achieved that. It is odd to say the least that we are incapable of producing robotic devices that can replace the manual scavenger. Why on earth is there no directive issued to our engineers to construct a robotic system that can clear sewers and man holes of this country ? The Supreme Court has definitely prohibited employment of manual scavengers, this came about as recently as 2013, but this is a toothless law, which is conveniently gone around by Indian culture. Is a sustained media campaign needed to sensitise the general public on this subject? There is little money to be gained from it and also possibly meagre fame. We don’t even have canaries to check out toxic sewers; maybe the first manual scavenger to enter a pit serves as the canary in the mine. There are no middles in national newspapers on this scented subject. Unremarkably no Bollywood icon or corporate honcho has uttered a word.

 

 

 

 

We therefore have the unique situation where there are thousands of manual scavengers operating and at the same time we produce world standard heart valves and latest generation coronary stents. The Lancet has published just yesterday a paper on the superiority of an ultra thin biodegradable polymer sirolimus eluting ultrathin strut stent over a durable polymer everolimus eluting stent in the setting of ST elevation myocardial infarction (STEMI). More than 1300 patients with a STEMI or acute heart attack were randomised; after a follow ups of one year the biodegradable polymer sirolimus eluting stent performed better, it significantly reduced the clinical endpoint of target lesion failure from 6% to 4%. Cardiac death and target vessel myocardial infarction remained the dame in both groups, but target vessel revascularisation or re-intervention was 1% in the biodegradable polymer sirolimus eluting stent group versus 3% in the durable polymer everolimus eluting stent group. Importantly this is the first randomised trial comparing a second generation with a third generation drug eluting stent in patients of acute heart attack or STEMI. I am reporting this study called the BIOSTEMI trial, which is the first ever trial comparing a biodegradable polymer coronary stent with a durable polymer coronary stent for a particular reason. The reason is that we produce world class biodegradable polymer coronary stents in India. We even produce them in a small town called Faridabad, I have in fact visited the factory in Faridabad manufacturing these third generation stents. These stents have struts only 60 microns in thickness. One micron is a millionth of a meter. A human hair is 75 microns while a human red cell is 5-6 microns across. The largest bacteria is 3 microns in size. You can appreciate the precision demanded in producing an ultra thin stent. Not only are Indians manufacturing these stents but a randomised trial published in The Lancet in February this year showed that the Indian biodegradable polymer sirolimus eluting stent was equivalent in clinical performance with the ‘gold standard’ Xience stent ( or a durable polymer everolimus eluting stent). At one year followup there was no difference in death, myocardial infarction or target vessel reintervention.

 

 

 

 


So we now have a charmingly odd situation. We can launch satellites, attempt a robotic landing on the moon’s surface, and also develop an intercontinental ballistic missile that can cover more than 5000 kms. We call it the “Agni V”. The intent is to keep Beijing in sight. We are the only country apart from the US, Russia, China and North Korea with such advanced ICBM’s. Moreover more than $130 billion is to be spent in modernising our armed forces in the coming 4 to 5 years. This is above and beyond the I.6% of the GDP allocated to defence this year; about 3.2 lakh crore Rupees. But, astonishingly we don’t seem to have a roadmap to eliminate the job of the manual scavenger in this country. The sweeping absence of flush toilets and sewer lines in this country ensures that a particular community is compelled to clean up other people’s excreta with their bare hands. No law however stringent shall eradicate this dehumanisation… till we develop a mechanised way to do this work.

 

 

AGNI V

A NEW ERA ? A DIABETES DRUG TO TREAT HEART FAILURE

 

 

New England Journal of Medicine ;19 th September 2019.

 

 

Sodium glucose co-transporter 2 inhibitors (SGLT2i) are weak agents where sugar lowering is concerned in patients with type 2 diabetes. They have at best a modest lowering effect on HbA1C levels; they lower blood glucose by preventing reabsorption in the kidney, at the same time they also ensure that sodium too is not absorbed but excreted by the kidney. Empagliflozin has shown significant reduction in cardiovascular mortality and also hospitalisation for heart failure in patients with type 2 diabetes on background anti diabetes medication. In fact considerable data is now emerging that SGLT2i prevent heart failure in patients with and without atherosclerotic disease, with and without heart failure, across a range of impaired kidney function, and even in patients without diabetes. The mechanism for correcting heart failure is still mystery, it is independent of glucose lowering mechanisms. It is conjectured that improved kidney haemodynamics is associated with a salutatory effect on heart muscle; or maybe there may be a direct positive effect on cardiac muscle metabolism. They also of course act as an expensive diuretic, but the mechanism is quite unique.

 

Conventional diuretics reduce preload and congestion by reducing intra-intra-vascular volume, while SGLT2i deplete interstitial fluid rather than fluid in the vasculature. Afterload is lowered by SGLT2i by reducing blood pressure and vascular stiffness. In heart failure heart cells rely on non -esterified fatty acids for metabolism. SGLT2i increase ketones levels that are considered to be ‘super fuels’ superior to glucose and fats acids for energy production by the mitochondria. The third hypothesis is that SGLT2I interfere with the hydrogen ion exchange pump system and thereby cut down both sodium and calcium in heart cells, resulting in better mechanics. Both fibrosis and collagen synthesis is prevented by SGLT2I, improving cardiac function.

 

 

Now a new large randomised trial has demonstrated that the diabetes drug dapagliflozin (an SGLT2i) substantially improves clinical outcomes in patients with established reduced ejection fraction heart failure, remarkably improvement was also seen in non diabetic patients of heart failure N Engl J Med September 19, 2019). There was a 26% lowering in a composite of time to cardiovascular death, heart failure hospitalisation or urgent heart failure visit requiring intravenous treatment, when dapagliflozin was added to standard therapy, over a median if 18.2 months. Primary outcome was reduced with dapagliflozin from 21% to 16%, p < 0.001.The authors concluded that among patients with heart failure and reduced ejection fraction, the risk of worsening heart failure or death from cardiovascular causes was lower with dapagliflozin as compared to placebo, regardless of the presence of or absence of diabetes. Fifty five percent of patients in this trial did not have diabetes.Standard therapy consisted of an ACE inhibitor/ ARB and a beta blocker in almost 95% of patients, a mineralocorticoid inhibitor in more than 60% , and a sacubitril/valsartan inhibitor in one third patients. Dapagliflozin reduced all cause mortality by 17%. The DAPA HF is being noticed by heart failure specialists around the world. SGLT2i are known to prevent heart failure in type 2 diabetes, but the DAPA HF trial has shown that an SGLT2i can also be used to treat congestive heart failure, as an add on medicine. Earlier both empaglifozin and canagliflozin have significantly prevented heart failure hospitalisation in patients with diabetes.Emagliflozin substantial cut down mortality and hospitalisation for heart failure without reducing the risk of myocardial infarction and stroke.

 

 

Another small double blind randomised trial (DEFINE -HF Trial ) including 263 patients with reduced ejection fraction heart failure has shown significant improvement in symptoms and quality of life as early as 3 months, with addition of dapagliflozin ( Circulation. 2019;140:00–00. DOI: 10.1161/CIRCULATIONAHA.119.042929 ). Crucially there was no difference in NT-proBNP levels over 12 weeks of treatment. The researchers concluded that dapagliflozin produced meaningful clinical improvement in heart failure patients without affecting mean NT-proBNP levels. Benefits of 10 mg dapagliflozin per day were seen both in diabetics and patients without type 2 diabetes. It should be borne in mind that dapagliflozin was used over and above standard heart failure medication. Patients in the trial had to have an NT-proBNP more than 400 pg/ml and eGFR >30/ml/min/1.73m2. The median NT-proBNP level was 1400 pg/ml. Number needed to treat over the course of 2 years was 21 only to reduce the primary composite end points. Diuretics were provided to 94% patients, ACE inhibitor or ARB to almost 90%, Sacubitril-valsartan to 11%, beta blocker to 96%, aldosterone blocker to 72% and digoxin to 19% patients. More than 50% patients were on metformin and 28% were on insulin.

 

There were few adverse effects, no significant increase in hypotension or hypoglycaemia.Serious renal adverse effects were uncommon and significantly less common in the dapagliflozin group. But this was small sized trial. We have to wait for more randomised trials with SGLT2i to make their prescription mandatory. The prevalence of heart failure is humungous; and the accompanying morbidity and mortality well known. The DEFINE HF has too few patients, follow up too short, and it was not powered to detect mortality or hospitalisation for heart failure. The number to treat for improvement in clinical symptoms and quality of life was only 10. The fact that there was little or no change in NT-proBNP level strongly suggest that dapagliflozin did not merely operate as a diuretic. Another icing with SGLT2i is their reno-protective capabilities. Nearly all patients in the DEFINE-HF trial were on ACEi’s, ARB and a beta blocker, 60% were on aldosterone blockers,, while 30% were on a sacubitril/valsartan. Importantly about 35% were on a biventricluar pacemaker. There was no significant increase in 6 minute walking distance nor was there any significant change in weigh.

 

 

DAPA HF TRIAL

 

Unlike the DEDFINE-HF trial, DAPA HF included 4744 patients of heart failure with reduced ejection fraction. Mean left ventricle ejection fraction was approximately 31%, 45% patients had diabetes, and 41% had chronic kidney disease. Dapagliflozin reduced death by 18%, heart failure hospitalisation by 30% and risk of worsening heart failure by 30%. It will however not be easy to optimally mix dapagliflozin with a prescription containing a beta blocker, an aldosterone antagonist, and Sacubitril/valsartan. There will be the problem of drug interaction and also issues with adherence. The researchers of the DAPA Hf trial have not provided details of dosage of the standard treatment given, the optimal prescription will always therefore be a painstaking guess.

 

We are looking at a world where in a patient with reduced ejection heart failure will be teated by a combination of beta blocker, sacubitril/valsratin ( ARNI) , spironolactone and an SGLT2i. A diuretic may not be needed, patients however will need to be carefully chosen. A new era in treatment of heart failure has certainly begun. Time will tell us how safe an SGLT2i is in the long run. The FDA has granted FAST Track designation for the development of dapagliflozin to reduce cardiovascular death or hospitalisation for heart failure. The long term adverse effects are unknown where SGLT2i is concerned. Initially there is a drop in eGFR that improves within a year, but long term effect on eGFR is yet to be ascertained. Fractures have been associated with SGLT2i’s because of mineral changes and the problem of lower limb amputation persists, albeit associated only with canagliflozin but no confirmation of causality. Genital fungal infection can be a problem but this is early treatable.

 

“COMPLETE” REVSACULARISATION IS THE KEY DURING A HEART ATTACK

 

 

 

Percutaneous coronary intervention (PCI) consisting of PTCA with stenting remains the cornerstone for effective treatment in patients with acute myocardial infarction. There is rapid restoration of blood flow in the completely occluded culprit coronary artery, that is not only life saving but also improves left ventricle function, and which goes a long way in improving quality of life. More than 17.7 million people die annually because of cardiovascular disease. Heart disease and stroke kill more people than any other disease. In India alone more than 7 lakh people die of a heart attack each year, and the list is growing.

 

It is often found that 50% of patients with an acute ST segment elevation myocardial infarction (STEMI) that coronary arteries apart from the culprit are also significantly blocked. They have what is termed multi vessel disease. There are additional narrowed arteries apart from the coronary artery causing the heart attack.It was unclear whether tackling all concerned coronary arteries was the way to go or whether treating the culprit vessel and managing the remaining blocked vessel by pills ( and intervening only if symptoms developed) was a better option. Observational trials suggested treating all blocked vessels was the better alternative, but no large randomised trial has shown significant reduction in mortality.

 


A Danish trial randomised more than 600 patients to culprit vessel only PCI or directional flow reserve (FFR) dependent intervention of other coronary arteries to conclude that there was significant reduction in reintervention of non culprit vessels on more than 2 years of follow up, but no reduction in death ( lancet 2015;386:665-71). Another slightly larger randomised trial also came up with a similar recommendation, that intervention of all involved vessels in acute heart attack patients cut revascularisation but not the hard end points of death or myocardial infarction (N Engl J Med 2017;376:1234-44). More than 800 patients of STEMI with multi vessel disease were involved in this trial, both groups had FFR evaluation but the group with culprit alone PCI was unaware of the results ( both patients and the cardiologists).

 

 

 

 

A smaller British trial had shown that clinical outcomes were better with complete revasularisation than with culprit only intervention during pCI in STEMI patients. The CvLPRIT trial enrolled 296 patients in 7 UK centres and followed them for one year only. There was no significant reduction in death or myocardial infarction, but total MACE consisting of death, recurrent myocardial infarction, heart failure or repeat revascularisation was significantly less ( J Am Coll Cardiol 2015;65:963-72). The authors suggested that larger trials were warranted to confirm their findings.

 

 

 

 

But now we have a large adequately powered trial that assigned more than 4000patients with STEMI  having multi vessel disease to culprit vessel only PCI or multi vessel PCI ( N Engl J Medicine 2019; September 1st). In the multi vessel group ,non culprit coronary arteries with either 70% or greater block or stenoses between 50 and 69% with an FFR value less than 0.80 were subjected to PCI. Percutaneous intervention of non culprit vessels in the multi-vessel group was done as long as 45 days after index procedure with a median of 3 weeks. The primary end point of cardiovascular death or myocardial infarction at the end of 3 years was significantly less in the complete revascularisation cohort than in the culprit vessel intervention group; (7.8% vs 10.5%, p=0.004). The difference albeit significant was driven largely by a cut in myocardial infarction, mortality remained unchanged. The secondary end point of a composite of death, myocardial infarction or re-intervention was lowered significantly in the complete revasularisation group by an almost 50%. The researchers concluded that in STEMI patients undergoing PCI clinical outcomes were substantially superior in those who had complete revascularisation as compered to the culprit lesion only group. Only 13 patients were needed to be treated by complete revascularisation to prevent re intervention in a follow up for 3 years, also only 37 patients required complete revascularisation to prevent death or myocardial infarction.

 

 

I saw a female patient just yesterday who had undergone successful primary PCI for a nasty acute inferior wall ST segment elevation accompanied by shock and heart failure a few months ago. During the index procedure she had multi vessel disease with greater than 70% blocks of the left anterior descending and left circumflex coronary arteries. The patient was advised intervention for the non culprit vessels at discharge but she was lost on follow up. She decided to consult me again because of symptoms of giddiness that did not seem to be related to her heart or the vasculature system. But armed with data from the COMPLETE trial I suggested to her to get the remaining coronary vessels tackled. The COMPLETE trial strongly suggests that despite no significant cut in mortality, there is substantial lowering of myocardial infarction and future re intervention if all involved coronary vessels are tackled during or soon after the index procedure. Importantly there were no major differences noted regarding acute kidney injury, stroke, bleeds or stent thrombosis.

 

 

Every patient of STEMI with multi vessel disease may not benefit by complete revasularisation, because some may have complex lesions ( long calcified block, chronic total occlusion or bifurcation stenoses) that may be difficult to treat percutaneously. Suitable non culprit vessels however should surely be treated. There is no urgent need to rush in because the non culprit vessels can be tackled subsequently after a couple of weeks and even later. One does not have to treat every vessel in the middle of the night, the entire cardiac team of the doctor, the nurse and technicians can get drained soon after opening up the culprit vessel at 2 am in the night. Crucially, COMPLETE studied more than 4000 patients of STEMI, while the SYNTAX score was around 16; hence extrapolating to more complex lesions may not be easy. But the COMPLETE trial will definitely have some impact on contemporary management of acute heart attack accompanied with multi vessel disease. Thousands of recurrent heart attacks could be prevented across the planet

SHAHEED BHAGAT SINGH OR VEER SAVARKAR ? TICAGLEROR OR PRASUGREL DURING PCI ?

 

 

 

NEW ENGLAND JOURNAL OF MEDICINE SEPTEMBER 1st 2019

 

I kept advising this young man; all of 23 years only, not to make public his watertight views on religion and Karl Marx. But he is more than obstinate or why would he insist despite all shades of warnings to jot down such inflammatory phrases that religion is the opium of the masses or that religion has served little service apart form providing untold miseries to people. Worse, he noted, one must be wary from the control of machines or people with machines wishing to control men. He had already thought of the title, “ Jail Notebook and Other Writings.” Worse, he is a firm atheist. Not for him the slightest participation in any ritual of Hindu or Sikh mythology. Ladies and gentlemen I present who else but one of the greatest revolutionary’s the world has ever seen, Shaheed Bhagat Singh, who was hanged by our colonial masters 8 days after the Ides of March in 1931. Remarkably the morning he was hanged Shaheed Bhagat Singh was reading a book on Lenin, the architect of the Russian revolution. He did not want a scripture or a sermon uttered the day he died, he could not be bothered.He went to the gallows without a single prayer in his lips, along with his comrades, Sadguru and Sukhdev. Shaheed Bhagat Singh had been charged primarily for the assassination of the policeman John Saunders ( 17 December 1927), who in turn had led the charge that eventually killed Lala Lajpat Rai. Saunders however had not been the intended victim, the target was James Scott the superintendent of police who had ordered the deadly charge. Ironically , Shaheed Bhagat Singh in todays times may be charged an atheist plus a dangerous an urban Naxal. He would certainly today be a subject of the ire of a great number of people .

 

 

Ironically, Vinayak Damodar Savarkar ji too was an atheist and clearly desired that after he died no rituals were to be performed. He in fact most probably did not attend his wife funeral and ensured she went into an electrical crematorium, as he himself would be. Savarkar ji vehemently objected to orthodox Hindu beliefs. He was completely against the caste system, and had had 2 boys of the tailoring community as his best friends. Crucially Savarkar ji was against cow worship, which he dismissed as superstition. He believed that worship of the cow was a consequent to her utility in providing milk and numerous edibles from that milk. He would never hesitate to protect the cow but was reluctant to worship her as a goddess. But despite being an atheist he was of the firm opinion that he was a Hindu just as others who were monists, pantheists, and theists. He attacked the caste system all his life and would have been surely deeply dismayed by the (repeated) contemporary assaults against Dalits; he most certainly would not have kept silent (Savarkar: Echoes From a Forgotten Time by Vikram Sampath). Savarkar ji demanded full and complete independence more than 20 years before the Congress party took up the cause; but curiously met almost all the players who participated in the murder of The Mahatma, a few days before that sad evening of 30th January 1948.

 

 

Remarkably, Madan Lal Pahwa ( of the failed bomb attack on Gandhi ji) had been arrested 10 days before, and interrogated by the police in custody; Pahwa was a member of the gang that eventually participated in the killing of Gandhi ji ; it is difficult to believe that the police of those days was unable to extract information on the imminent mortal attack; also almost the entire top Bombay police brass had been informed of the impending murder ( including the premier of Bombay), and yet no adequate security was provided to Gandhi ji. Some serious investigative journalism is required for this humongous intelligence lapse. Despite having Pahwa, a close associate of Nathu Ram Godse, in the cooler for 10 days , the police had no clue what was about to happen at Birla House on 30 January 1948. Utter incompetence or something murkier than that. But more to the point; Savarkar ji would have felt awkward in today’s season of Hindutva, that he had almost single-handedly conceived. Careful rigorous reading on Shaheed Bhagat Singh and Veer Savarkar ji will reveal that it is near impossible to compare the two or even club them together, the only common factor would be their immense unease amid contemporary political currents.

 

 

 

 

German investigators, however, had the easier task of comparing head to head two powerful anti platelet agents, enjoying a class 1 recommendation during percutaneous coronary intervention (PCI) in patients with acute coronary syndrome (ACS); that is patients admitted for unstable angina, ST segment elevation Myocardial infarction (STEMI) or non ST segment elevation myocardial infarction (NSTEMI). The ISAR React 5 trial included more than 4000 ACS patients and assigned them in a randomised manner to either ticagrelor or prasugrel. Both ticagrelor and prasugrel are P2Y12 inhibitors that are not only more powerful than clopidogrel but also act quicker. When combined with aspirin or what is termed DAPT (dual antiplatelet therapy ) they significantly prevent ischemic events such as heart attacks, death or stroke after PCI. They also prevent stent thrombosis that can be fatal in quite a few cases. The researchers had anticipated that ticagrelor would come out tops because of past data. Ticagrelor was the favourite to be the winner because of its superior record when compared with clopiodogrel. The PLATO study ( N Engl J Med 2009;361:1045-57) had shown superior efficacy with ticagrelor when compared to clopidogrel in ACS patients. Prasugrel on the other hand has been found to be wanting when given before coronary angiography in patients with non ST elevation myocardial infarction in the ACCOAST trial.There was no advantage with before angiography prasugrel administration but in fact there were significantly more bleeds. More than 4000 patients were randomised in this trial ( N Engl J Med 2013;369:999-1010).

 

 

 

Prasugrel was unable to trump clopidogrel in the TRILOGY ACS trial that included more than 7000 ACS patients who not subjected to PCI, but given medical therapy. There were no differences in ischemic clinical endpoints or bleeding complications when Prasugrel was compared to clopidogrel in such patients. The researchers of the ISAR REACT 5 were therefore taken aback when their data revealed that prasugrel was in fact superior to ticagrelor without increasing clinical significant bleeds ( N Engl J Med September 1st, 2019).

 

 

 

Primary end point, a composite of death, myocardial infarction, or stroke at I year was 6.9% with prasugrel versus 9.3% with ticagrelor. Moreover stent thrombosis was almost halved with prasugrel (0.6%) versus ticagrelor 1.1%. The authors were compelled to conclude that in patients of acute coronary syndrome with or without ST segment elevation myocardial infarction, incidence of death, myocardial infarction or stroke was significantly lower among those given prasugrel as compared to ticagrelor. Prasugler was administered as a 60 mg bolus dose followed by 10 mg maintenance daily dose. In people more than 75 years or having weight less than 60 Kg daily Prasugrel was reduced to 5 mg. Ticagrelor was given as 180 mg bolus and 90 mg twice a day maintenance dose. Prasugrel was not given before coronary angiography in NSTEMI patients. The ISAR REACT 5 trial is the first ever head to head comparison of ticagrelor with prasugrel. Forty one percent patients enrolled had ST elevation myocardial infarction, 46% had non ST segment elevation myocardial infarction, and 12% were admitted for unstable angina.

 

 

The results of ISAR React 5 are yet to sink in. It is however well known that prasugrel is once a day regimen while Ticagrelor has to be taken twice day. In India a weeks course of ticagrelor is almost Rupees 700 while a 10 day course of prasugrel is around Rupees 100 only. The reaction of professional societies remains to be seen, but the makers of ticagrelor must be surely scrambling for a suitable response. For now unlike a choice between Shaheed Bhagat Singh and Veer Savarkar ji, the choice between ticagrelor and prasugrel ( in patients with acute coronary syndrome) appears far clearer. Prasugrel is the victor. Remember more than 700,000 people suffer with acute coronary syndrome (heart attack or close to one) for the first time in a year with around 333,000 having a recurring episode the same year, in the United States (Circulatiuon 2019;139(10):e 56-e528). The numbers from India are bound to be substantially greater; a shot in the arm for a diminishing GDP. The importance of an effective anti platelet agent cannot be overestimated. Nor can Veer Savarkar’s diktat that no crow was to be fed after he died ( ‘Savarkar: The True Story of the Father of Hindutva’ by Vaibhav Purandare).

 

 

The majority of Indian cardiologists including myself will now have to rethink on the role of prasugrel during percutaneous intervention in patients with acute coronary syndrome. Between the ages 30-69 years in 2015 there we’re 1.3 million ( 13 lakhs) deaths in India due to cardiovascular disease. About 70%b were because of heart attack while 30% due to stroke.Cardiovascular disease resulted in 2.1 million deaths ( 21 lakhs) in all ages in 2015. The ISAR REACT 5 trial, it should be noted was not sponsored by the industry, but further confirmation of prasugrel’s superiority will be difficult in the near future, because an adequately powered randomised trial is both hard work and expensive. As far as Bhagat Singh and Veer Savarkar are concerned; both were atheists till the end, Shaheed Bhagat Singh a Marxist till his last breath and Veer Savarkar anti caste activist. Would they have felt comfortable today when the cow is worshipped and  while poor school children are served rotis (bread) with salt in their mid day meals. Importantly, however, probably the biggest difference between the 2 was that Savarkar in attempting to get back non-Hindus into what he described the Hindutva peoples, he actually was driving deep wedge between Hindus and non-Hindus. He insisted that oil-Hindus accept India not only as their Father land but also as their holy land. By insisting on Hinduism as a religion he ceased to be as described some to be an agnostic or an atheist. Bhagat Singh on the contrary steered away from religion upto his last breath.

 

 

LANCET GLOBAL HEALTH 2018;6:e 914-23

 

FISH OIL MAKES A COMEBACK

 

 

CIRCULATION AUGUST 19, 2019

 

Triglycerides (Trigs), which are fats in the blood, have not received rigorous attention enjoyed by the ‘bad” cholesterol also called low density lipoproteins (LDL). Trigs when raised in blood ,much like LDL, are also quite capable of triggering a heart attack or stroke. Some trigs are naturally produced by the liver and some by the calories or food we ingest. The more calories you indulge in the greater the Trig level. A level higher than 200 mg% is considered an increased risk for a cardiovascular event such as a heart attack or stroke. Very high levels exceeding 500 mg% can cause acute inflammation of the pancreas. People with high Trigs are usually overweight or have diabetes. Hypothyroidism can also raise Trigs levels. Excercise, reduction of weight, cutting down on alcohol are good ways to cut down Trigs in the blood. One is compelled to resort to medication if life style alterations do not work. Earlier trials with fibrates and niacin did not enjoy much success in reducing Trigs levels and were thus abandoned.

 

 

A lot of work has been done with fish oils containing there omega 3 fatty acids (3FA) eicosapentaenoic acid (EPA) and docosohexaenoic acid (DPA). Numerous previous trials with 3FA’s also have not shown clinical benefits regarding cardiovascular disease. A meta analysis of 10 randomised trials ( JAMA Cardiol 2018;3:225-34) including 78,000 patients did not show any improvement in major adverse cardiovascular events with 3FA when compared to placebo. The ASCEND trial ( N Engl J med 2018; 379:1540-50) that tested 840 mg of 3 FA’s in patients with diabetes also did not report any difference. The VITAL trial that examined 25000 participants with vitamin D and 3FA versus placebo did not show lowering of the incidence of the primary outcome of death, myocardial infarction, or stroke ( N Engl J Med 2019;380:23-32).

 

N Engl J Med 2019;380:11-22

 

A Japanese study (JELIS) done more than a decade ago did show improved clinical outcomes with 1.8 grams of EPA plus a statin; a 19% reduction in cardiovascular events (Lancet 2007;369:1090. The American Heart Association as recently as last week come out with an advisory recommending prescription EPA for safe reduction of Trigs by administering prescription EPA alone or a prescription combination of EPA + DPA ( Circulation ;19 August 2019). The researchers have based their conclusions upon analysis of 17 clinical trials, but the weight of the recommendation is based largely on the REDUCE-IT trial. The FDA has already approved prescription 3FA’s to treat very high Trig levels >500 mg%

 

 

The REDUCE-IT rial randomised more than 8000 patients in a double blind manner to 4 grams of icosapent ethyl ( prescription EPA) plus statin or placebo. Patients that were included had to have established cardiovascular disease or diabetes plus another risk factor. The primary end point was a composite of cardiovascular death, myocardial infarction, stroke, unstable or myocardial re-vascularization. Secondary end point was a composite of cardiovascular death, myocardial infarction or stroke). At the end of 5 years a primary end point event occurred in 17.2 % of patients in the icosapent ethyl group as compared with 22% in the placebo group 9 P<0.001).This is an absolute 20% reduction meaning only 20 patients are needed to be treated for 5 years to prevent a cardiovascular event. Overall 60% patients had diabetes , at base line LDL cholesterol was well controlled ( median value 75 mg%) while Trigs were slightly raised ( median value 216 mg %). These staggering results have raised eyebrows because as mentioned earlier trials have not shown these levels of efficacy. The researchers were themselves at a loss to explain a 25% reduction in clinical outcomes. They also concede that they cannot pin down the exact reasons driving such improved outcomes. There may be an anti thrombotic effect in view of increased bleeding with the icosapent ethyl as compared to placebo. Or there may be an anti inflammatory effect, which stabilises the cap covering the atherosclerotic plaque. It is well to remember that it is not the extent of blockage in a coronary artery but the instability of the cap of the block that is more lethal.

 

 

 

The REDUCE-IT trial however used a mineral oil containing capsule in the placebo group; being a double blind study the mineral oil capsule had to masquerade as the treatment fish oil; 3FA. It is quite possible that the mineral oil interfered with statin absorption as also with other heart medicines in the placebo and therefore results got tilted in favour of the 3 FA treated group. Also LDL cholesterol went up by more than 10% and Trigs were up by 2.2% in the placebo group; once again advantage icosapent ethyl group. By 2 years C reactive protein had gone up a s high as 32.3% in the placebo group. But far more patients in the treated group developed atrial fibrillation requiring hospitalisation (3.1% vs. 2.1%; p=0.004). The authors concluded that among patients with raised Trigs despite intake of statins risk of cardiovascular ascetic events are substantially lower with 4 grams of icosopent ethyl taken daily as compared to placebo. The REDFUCE-IT trial was sponsored by industry that was responsible for collection and management of there data; the lead author of the trial however is a top cardiologist with impeccable academic credentials.

 

More trials are needed to confirm the conclusions of REDUCE-IT that icosapent ethyl significantly prevents cardiovascular events in people with an LDL as low as 75 mg% but slightly raised Triglycerides. Maybe a better option at least for non vegetarians would be to consume a fatty fish like salmon, tuna or a mackerel. Icopent ethyl on the other hand is a synthetic derivative of EPA and thus can be safely taken by vegetarians. The FDA is yet to approve icosopent ethyl for cardiovascular protection; the agency plans to hold an advisory committee meeting in November this year. Currently icospent ethyl is only approved for severe hypertriglyceridemia of > 500 mg%. The REDUCE-IT trial did not use fish oil supplements available overt the counter but a prescription medicine.

The last big meta analysis including 10 randomised trials with more than 75000 patients (mentioned earlier) concluded that  the 2016 European Society of Cardiology and European atherosclerosis Society guidelines for prevention of cardiovascular disease ere unconvinced that omega3 FA’s provide protective effects (JAMA Cardiol 2018;3:225-234). The American Heart association ( Circulation 2017; 135(15) e8670-e884)  on the contrary recommended that omega 3 FA’s are justified for cardiovascular protection in patients with prior heart disease and those with reduced ejection fraction heart failure. But the meta analysis found that use of 1 gram per day of omega 3 FA’s was ineffective in prevention of heart attack, death or any other vascular event, in patients with prior cardiovascular disease. The authors of this meta analysis are prudent enough to suggest that a higher dose of 3-4 grams per day of EPA may be be effective in cutting risk of major vascular events. The REDUCE-It trial has so far filled the gap, but  there shall  be more certitude with  completion of the higher dose EPA/DPA omega 3 FA’s  randomised trials.

 

N Engl J Med 2019;380:11-22

NO TREATMENT YET FOR ACUTE HEART FAILURE

 

PULMONARY CONGESTION

 

Considerable progress has been made in the treatment of chronic heart failure, with multiple randomised trials reporting significant reduction in mortality, improvement in quality of life, reduction in symptoms, bettering of functional capacity and arresting further remodelling of the heart. All guide lines recommend that chronic HF be initiated by an ACE inhibitor or angiotensin receptor blocker (ARB) along with a beta blocker in patients with reduced left ventricular ejection fraction lower than 35%. If the combination dos not prove effective, a mineralocorticoid (spironolactone or eplerenone ) should be added. Further ratcheting of treatment in the event of failure of the above cocktail becomes interesting. Ivabradine may be added in case heart rate persists more than 70 per minute despite full dose of a beta blocker. Ivabradine suppresses the funny cells of the sinus node. A bi-ventricular pace maker (CRT) can be implanted in case there is left bundle branch block with the QRS width more than 120-130 msec. Also if the cocktail does not work there is a new medicine in the market; a combination of valsartan (ARB) and sacubitril (neprilysin inhibitor) or ‘ARNI’ should replace the ACE inhibitor or ARB in the original cocktail of 3 drugs. In fact latest guidelines suggest that ARNI could replace an ACE inhibitor or ARB even if they are effective because of substantial incremental benefit with ARNI as shown in the large PARADIGM trial.

 

Chronic heart failure afflicts almost 1-2% of adult population in developed countries. The prevalence in India also must be in the millions and crores. Morbidity and mortality are sadly quite high. Once hospitalised 10-15% patients have worsening of heart failure and on discharge as many as 10-15% die within 6 months. Congestive heart failure is obviously as “malignant” as any “malignant cancer”. As many as 7% of people above 70 years are affected. But as with hypertension treatment less than 25% patients of heart failure take full dose optimal therapy, largely because treating physicians are unaware or nervous about providing full dose treatment. Treatment of course should be begun at a “low dose”, administered “slow” but “aiming high”. Always look out for hypotension and any alteration in kidney function. The European Society of Cardiology guidelines appreciate high prevalence of chronic kidney disease in patients with heart failure. Usage of loop and thiazide diuretics mandate caution in context of declining renal function; however continuation of an ARB or ACE inhibitor is encouraged unless there is significant decline in kidney function.

 

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TENTATIVE STEPS IN KASHMIR AND IN TREATMENT OF XDR TUBERCULOSIS

 

 

 

We are most certainly living in momentous times, the world has changed as never before, the proof being the scrapping of Articles 370 and 35A from the state of Jammu and Kashmir on a single morning of this month. This naturally created a humongous furore both within Parliament as also the entire nation. The prime minister rightly stated from the ramparts of Red Fort that what could not be done in 70 years he did in 7 weeks. Brutal no doubt but the truth. To his credit the BJP manifesto for decades had underlined abrogation of the above Articles. Modiji had the crucial majority in both Houses to push the Bill through, spectacularly assisted by the home minister. The opposition was left both stunned and speechless. Remarkably Pakistan did not haver a clue ; this includes their infamous ISI that repeatedly has staked claims of being the finest in the business and whose very existence is based on ensuring “freedom” to “Indian Held Kashmir.” On closely examining the photographs published of their military high command one thing is obvious, both the army chief and the ISI head look perplexed, almost confused and tense. Only a few days earlier they had returned from a triumphant visit to the United states, with the promise of a big IMF loan and renewal of spare parts for their F16s. Mr Imran Khan was ecstatic declaring that he felt he had won the Cricket World cup once more. In his mammoth public meeting with Pakistani expatriates he had screamed he would ensure that AC’s and televisions of jailed Mr Nawaz Sharif and Mr Zardari were cut off, to loud cheers from the Pakistani American audience. The newspaper Dawn could not help commenting on the stunning success of Mr Imran Khans successful visit. This collective hubris was however short-lived but in the mean time Mr Khan got Mr Sharif’s daughter Maryam Sharif also incarcerated in a cell. In fact right now the apex of almost the entire Pakistani opposition languishes in jail. So when the “selected prime minister” of Pakistan wails about the 2 former chief ministers of Kashmir being put under house arrest he sounds a bit rich. Also most of the media is directly under the control of Pakistani regulators. The Pakistani media is however putting up a robust fight unlike our chaps who excel in toeing the government line. One of the brightest journalist of the subcontinent has had a defamation suit slapped against him by Mr Khan. Mercifully Seth keeps coming up with his excellent takes on matters in Pakistan. His independent day message to his countrymen is a must watch; its on YouTube. He puts great emphasis on Pakistan resetting its relations with India. He cannot but concede that the economic gap between India and Pakistan has become insurmountable. Pakistan as of now remains on Finacial action Task Force (FATF) grey list of countries recognised as laundering money to support terrorist activities. To get the 6 billion dollars loan agreed by the IMF, Pakistan has to get out of this FATF list or face complete fiscal collapse. Pakistan’s foreign exchange is depleting  fast. No wonder Mr Khan finds himself between a rock and a very hard place. He cannot launch a military operation nor a jihadi movement. His mentor the army chief had accompanied him to the USA and knows every line of the IMF deal.

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TERBUTALINE TURBOCHARGED CRICKET

 

I wonder if you noticed that at least 3 cricketers in the last 2-3 years developed a sore throat, requiring a cough syrup. Sore throats are pretty common , last 5- 7 days, with a virus being usually the cause. It really needs no treatment as the course is self limiting. Drinking warm beverages or warm saline gargling brings considerable relief. A pain killer can be taken in case of excessive discomfort, but never give aspirin to a child ( as this may trigger Reye’s syndrome). But our cricketers were found to have taken terbutaline by the BCCI ( the exalted Indian cricket board), which then slapped bans effective from a back date. So an 8 month ban actually became effective for as little as 4 months. No wonder the Sports Ministry of the government of India has tried its best to make the BCCI realise that it cannot be jury and executioner, not cannot and should not check for banned performance enhancing drugs on its own and then slap strange back dated bans on the culprits. There is obviously a conflict of interest apart from the fact that the testing may neither be robust enough or worse the burden not large enough. Apparently a little ore than 200 samples were sent by the BCCI to a national doping laboratory that detected 5 positive samples; there is no record of how these 5 cricketers were dealt with; or whether they were dealt with at all. The sports ministry is therefore keen to bring the process of checking for doping under the National Anti-Doping Agency or NADA, which operates under the regulatory authority of WADA or the World Anti-Doping Agency. Every Indian sport federation is subject to NADA’s testing; the BCCI insists for some strange reason to be outside NADA’s ambit. It believes that its own system for checking doping is robust enough.

 

A sore throat may be because of streptococcal bacteria , in which case an antibiotic is administered to resolve the infection. This too rarely lasts a more than a week. There is neither science nor logic in administration of terbutaline to an athlete for a sore throat. Remarkably Mr Yusuf Pathan when nabbed with terbutaline in his urine sample , in all wisdom confessed that he had to take terbutaline for a sore throat; the BCCI as customary handed him a back dated ban. Mr Pathan made a statement of how proud he was to play for his state and his Motherland. One can only hope that he does not use terbutaline again while playing for the next edition of the IPL. Or at least does not get caught.

 

 

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SHOULD BLOOD PRESSURE THRESHOLD BE LOWERED FROM 140/90 TO 130/80 ??

 

 

 

 

Recently many cardiovascular  professional bodies pulled down the high blood pressure threshold, needing treatment , from 140 mm Hg systolic and 90m mm Hg diastolic to 130 mm Hg systolic and 80 mm Hg diastolic. The impetus for lowering blood pressure threshold from 140/90 to 130/ 80 was largely based upon a single trial, albeit a large randomised one that showed slight improvement in clinical outcomes but accompanied with the offshoot of serious adverse effects, when blood pressure was lowered below 130 mm Hg systolic. I have never been a great admirer of the “SPRINT” study and have stuck out my neck by expressing my views in the past. I am more comfortable keeping the threshold at 140/90 because I am not convinced that there is incremental advantage in lowering it below 130/80 as many of my colleagues would recommend on the basis of international guidelines. By lowering the threshold millions more people get branded as hypertensives, and hence obviously many millions of tablets get prescribed, with little advantage. Someone somewhere is raking in a lot of moolah. However it is well known that almost 600,000 people die of heart attack or stroke in the US alone in a year.

NEW ENGLKAND JOURNAL OF MEDICINE 2019;381:243-51

 

An interesting study, published last week( N Engl J med 2019;381: 243-51) has received little attention. In fact it has gone completely under the radar. Maybe because it has not shown any difference in the composite of myocardial infarction (heart attack), ischemic or hemorrhagic stroke in more than 1 million middle aged people followed for almost 8 years. The researchers pored through data on more than 36 blood pressure readings of 1.3 million or 13 lakh participants. There were almost 19% participants who could be labeled as hypertensive when the 140/90 threshold was employed, but this jumped to 43.5% with 130/80. The prevalence of people with high blood pressure thus more than doubles with the lower threshold label. Results demonstrated that both systolic and diastolic blood pressure measurements influenced clinical outcomes. There was an increase of 18% in clinical outcomes when the systolic threshold was breached, and an increase of 6% with raised diastolic blood pressure. Crucially, researchers found similar increase in risks with both thresholds of 140/90 or 130/80.I must dilate on this, there was no increase in death or stroke with the 140/90 cohort versus the 130/80 group.

 

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FROM WEAPONISED TICKS TO NUCLEAR WEAPONISED MISSILES.

 

 

 

 

I was always told by our MEA chaps that the best protocol in the business was the American state department. I had first knowledge of their clock work precision, they ensured VIP movement by the second and I mean by the second. The secret service was not to be outdone by any means; I was a part of the delegation of the Indian president in the mid nineties that was travelling to Brazil. We had a stopover in New York city. The entire Indian delegation was put up in the Waldorf with the president, who by any standards was a terrific human being; erudite, sophisticated and spectacularly down to earth. It was therefore a pleasure and privilege to accompany Mr Narayanan in his foreign travels. I have let me confess a poor traveller. But during the Waldorf stay I desperately wanted to trace a child hood mate. Satindar Sood had played for the Indian school boys cricket team, and had been a kind of chaperone when I was a kid. He tried his best to make me take up cricket but my heart form the beginning was always in long distance running, but I did not mind playing for the school cricket team. I do know a little about cricket, but have always tried keep my eyes on the ball, be it a doosra or a googly, that are thrown at you by the dozens each day in current India. That evening in the Waldorf all I remembered was Satindar’s residence, which I provided those big secret service guys. True to form one big guy got back to me in less than 15 minutes with confirmation that my mate was rocking in New Jersey along with his telephone number. I most certainly was impressed by the secret service dude who probably had some inflated impression of my status, Look I was merely Mr Narayan’s cardiologist. I mention this incident because I have witnessed the precision of American protocol, to be a part of the motorcade from the Waldorf to the airport without a single hitch cannot be described, let me underline that unlike the Delhi police there was not a single road block, and yet the motorcade arrived on the tarmac on time without a second’s delay. Why do I remember those times? It’s because of Mr Imran Khan’ visit to the US this week. I am a full blooded Indian without any emotional baggage for Pakistan whatsoever. Yet I am filled with a tinge of sorrow that the prime minister of a sovereign nation travelled to the US as an ordinary passenger in a foreign airline only to be welcomed by not a single US state department official. From the aircraft the honourable prime minister was compelled to take a shuttle till the airport building. Thats taking matters to an unimpressive extreme. Obviously the Donald is more than annoyed with our neighbour, He has already blocked the billion dollar annual military aid, and now this. While Mr Trump in his unrehearsed speech declared he would if he wanted decimate the entire region of Afghanistan in a mere 10 days, an almost shrunken Mr Imran Khan sat in stoic silence. He almost looked both terrified and exceedingly helpless because he basically had come for some badly financial aid. He dis not then in Mr Trump’s presence or any time later till today expressed any discomfort.But then he primarily gone for some badly needed financial assistance. Pakistan is an a dire state of affairs, but yet Mr Khan had to have his “Something Stupid “. Originally a song best known by Frank and Nancy Sinatra. Its a great song that I strongly recommend you listen to. However Mr Khan’s “something stupid “ moment was not that “ I love you” but that incorrigible “K” word in public. Yes the retired cricketer could not refrain from Kashmir. Here he is almost pleading for money from any and every quarter but the bedrock of all his country’s woes is Kashmir. 50% of Pakistani children are stunted, polio stays endemic but all that Mr Khan can focus on is Kashmir and building a champion cricket team for the next world cup. It is obvious that his excellency is missing the wood for the trees, our rather for the fiscal bailout. Whats with these cricketers active or retired?

Continue reading “FROM WEAPONISED TICKS TO NUCLEAR WEAPONISED MISSILES.”

REDUCE DAPT DURATION AFTER STENTING BUT NEVER REDUCE THE STRIKE RATE AT DEATH OVERS.

 

LANCET 2015;385:2371

Coronary stenting has revolutionised the treatment of heart disease. Lakhs of patients destined for CABG surgery are now tackled with a percutaneous technique that does not need general anaesthesia, almost completely does the job of rectifying ischemia, with the patient being discharged next day or even the same day in selected cases. No amount of praise for the pioneer researchers can be enough. We have a device that cuts mortality apart from providing excellent symptomatic relief. Chest pain and breathlessness become complaints of the past as if by magic, by the insertion of a thin catheter from the wrist or the groin. The stent is a metallic mesh tube that is lined by a plastic polymer laced by a medicine that prevents restenosis of the coronary artery.We now have second generation stents that are markedly thin in size. The procedure is reasonably simple for the experienced operator. Experts in the field do not hesitate to treat complex lesions that would surely have been managed by bypass surgery in the past.

 

The job however is not complete with insertion of the stent. Stenting procedure has to be followed by months of anti platelet therapy, which consists of pills. The pills are invariably tablet aspirin accompanied with a P2Y12 inhibitor. The P2Y12 receptors on the surface of platelets are the glue that binds them to form a clot. There are 3 P2Y12 inhibitors in the market; clopidogrel, prasugrel and ticagrelor, all available in the Indian market.

 

In cricketing analogy ,once the base has been set in a one day game, someone has to consolidate the score by launching himself in the death overs. Bairstow and Roy have been laying down superb foundations for the English, while Stokes and Buttler do the demolition job towards the end. Dhoni has been a stunning finisher all these years, in fact he has been regarded as the best in the business. But it is becoming obvious that he no longer possesses that prowess. The ongoing World Cup has exposed his inability to ratchet up the strike rate , a strike rate of 100% or less in a World Cup semifinal would just not good enough. Good work done by Sharma and Kohli at the top has to be bolstered by a strike rate around 140-150% later on, the strike rate of course should fetch some handsome runs too.

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IT’S NOT THE CHOLESTEROL STUPID, IT’S TMAO WHICH IS THE CULPRIT

 

 

 

I distinctly remember Mr Imran Khan stating more than once that the solution to the Kashmir problem should be a cricket match. If India were to win ,Kashmir would be hers, but in case Pakistan were the victors then ‘paradise on earth’ would be rightfully their territory. Those were the days when the Pakistani cricket team more or less had an edge on India. Pakistani batting then was not only rock solid but buttressed by arguably the finest pace attack on the planet. Mr Imran Khan, no minnow with the bat , was a terrific fast bowler. Somewhere down the line he mastered the reverse swing too. It would be interesting to know of his personal opinion in current times, bearing in mind that now its the Indian cricket team that bats deep with one of the most potent pace attack. Mr Imran Khan understandably refrains from attaching any form of cricket to Kashmir. Not test, not one day cricket nor the T20 form. To his credit Mr Imran Khan was right up there as one of the best all rounders in the world. So it comes as some surprise that such a fine cricketing brain is now batting in the murky world of Pakistani politics. I personally preferred him when he made those frank promulgations that smacked of simplicity in a man who played with a straight bat.

 

I am compelled to recollect those artless days; we also believed that saturated fat was a killer. The equation was simple, eat meat particularly red meat and you would kick up your cholesterol level. The spike in cholesterol in turn would clog your arteries, resulting in heart attacks and stroke. There was the famous “seven countries” data that set up the high cholesterol diet equals heart attack hypothesis. It was only much later we all found that that the “seven countries” data was full of holes. I have elaborated on the flaws in the past. Every randomised study on saturated fats has failed to show reduction in heart attacks by having a diet with reduced saturated fats. The Women’s Health Initiative followed 49,000m postmenopausal women for 8 years who had been on a low fat diet, but could not record reduction in the risk of death, heart attack or diabetes. The conclusion was no different when saturated fat was replaced by a vegetable oil (polyunsaturated fat). There were more heart attack and death in the intervention group. There have been 2 such randomised trials, both concluded that replacement with a vegetable oil somehow did not lower clinical events.

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INTRA-AORTIC BALLOON TRUMPS INOTROPES IN DECOMPENSATED HEART FAILURE

 

EUROINTERVENTION MAY 2019
IABP BESTS INOTROPES IN HEART FAILURE; SIGNIFICANT GREATER INCREASE IN MIXED VENOUS OXYGEN SATURATION

 

An interesting article recently published dilates on the fact that a drug backed by solid evidence in the past may be found ineffective some years later. Beta blockers considered indispensable subsequent to an acute myocardial infarction are now not recommended in post MI patients with normal left ventricle function. A beta blocker does not improve clinical outcomes in a post MI patient who does not have an impaired left ventricle. Another drug seems to be fizzling out as a prophylaxis against cardiovascular events. Three randomised trials have shown little or no benefit in clinical outcomes with prophylactic aspirin. In fact prophylactic aspirin is almost always associated with increased bleeds, which can be a serious advert effect. Some years ago however aspirin had consistently demonstrated good efficacy as a prophylactic in middle aged people. Prophylactic aspirin was backed by reasonably good evidence of better clinical outcomes. Why does the same medicine at the same dosage not work any longer? The explanation is simple; over the years population has altered, people are more health conscious now with much better lifestyle application. Also there is much greater emphasis on control of high blood pressure and management of lipids with statins. The net result is that the marginal albeit clinically significant prophylactic advantage has evaporated. Evidence based medicine is not forever, there can be an expiry date.

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IMPELLA IS YET TO OUTSCORE THE INTRA-AORTIC BALLOON PUMP IN SEVERE CARDIOGENIC SHOCK

THE IMPELLA 2.5 DEVICE
IMPELLA UNDER FLUOROSCOPY

 

Treating a patient with shock can be an extremely daunting task for any clinician. Shock is a common reason for admission into an intensive care unit. Shock is accompanied with low blood pressure that is invariably raised by vasopressors and inotropes. Two thirds of patients entering an intensive care unit septic shock, which is a distributive type of shock. Other albeit uncommon causes of distributive shock are drug/toxin induced, anaphylactic shock, endocrine shock (Addison crisis) and neurogenic shock. Every protocol on spec shock mandates administration of norepinephrine at 0.2 mcg/kg/min (recommneded first line) and if need be vasopressin at 0.3 units /min. Norepinephrine can be combined with epinephrine, both having combined vasopressor and inotropic effects. The latest vasopressor to be found effective is angiotensin II. Angiotensin II acts by Gq protein stimulation in vascular smooth muscle. The ATHOS -3 (N Engl J Med 2017;377:419-30) randomised trial comparing angiotensin II with placebo in 344 patients with vasodilatory shock (80% had sepsis), showed that significantly more patients had their mean blood pressure raised more than 75 mm Hg at 3 hours with angiotensin II than placebo against background conventional vasopressor therapy ( 70% versus 23%). It must be noted that all these patients were suffering from vasodilatory shock defined as cardiac index greater than 2.3 litresb per minute per square meter or as central venous oxygen saturation greater than 70% coupled with central venous pressure more than 8 mm Hg, with mean arterial pressure between 55 and 70 mm Hg.

 

THE INTRA-AORTIC BALLOON PUMP
INTRA-AORTIC BALLOON PUMP UNDER FLUOROSCOPY; UPPER END OF BALLOON SHOULD BE 2 cms BELOW SUBCLAVIAN ARTERY OR AT LEVEL OF CARINA

 

Cardiologists on the other hand are confronted with cariogenic shock where low blood pressure is a result not of dilated peripheral arteries but inability of the heart to pump adequately. Poor pumping of the heart is usually due to acute myocardial infarction, and in other instances due to mechanical failure (valvular dysfunction, ventricular septal defect, atrial myxoma), and arrhthmias. Initial treatment includes inotropic support with dobutamine and vasopressor support with norepinephrine. Vasodilatory shock by itself is very difficult to treat, but cariogenic shock is even more so because of the fact that too much vasopressor administration can be detrimental to the already struggling heart. No sweet spot has so far been determined for vasopressor/inotrope dosage, and hence patients of cariogenic shock will need supportive treatment consisting of the intraaortic balloon pump (IABP), Impella, or extracorporeal membrane oxygenation (ECMO).

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SEMAGLUTIDE SWINGS IN FOR PATIENTS WITH DIABETES.

 

It has become impossible to get a happy story on diabetes. Every succeeding story is grimmer than the preceding one. We yet again learn that Asian patients with diabetes are exquisitely vulnerable to the disease. More than 230 million people in Asia suffer from type 2 diabetes, which is more than half of the world population. A recent study on Asian patients with diabetes  has established that in a follow up of 12.6 years 148,868 participants died. The study included more than a million (10 lacs) individuals from China, Japan, India, Bangladesh and South Korea. Individuals with diabetes had twice the number of deaths as compared to those without diabetes. The risk of relative mortality far exceeded that seen in Western populations. The researchers concluded that Asian people with diabetes were at increased risk of dearth due to a variety of causes. You just cannot take diabetes lightly (JAMA Netw 0pen 2019:2(4):e192696). Therefore the recommendation for urgent need for Asia-centric diabetes management strategies. It is against this background of a looming diabetes epidemic that one needs to become aware of newer more effective medicines to tackle diabetes; albeit they will be outside the reach of most Indian patients.

 

Type 2 diabetes is a complex problem with multiple underlying pathophysiological mechanisms. It therefore makes sense to administer combined therapy. Treatment with an SGLT2 inhibitor may increase production of glycogen even as it reduces glucose level via the kidney. Semaglutide a GLP 1 receptor agonist on there other hand not only kick starts insulin production by the pancreatic islet cells but also tone down glycogen delivery. The recently published SUSTAIN 9 trial ( Lancet Diabetes Endocrinol 2019;7:356-67 ) employed addition of once weekly injection of semaglutide in addition to daily ingestion of an SGLT 2 inhibitor in patients of type 2 diabetes. The primary outcome of this trial was change in HbA1C at 30 weeks while the secondary outcome was change in weight.

 

Patients with an HbA1c ranging from 7% – 10% despite 3 months of an SGLT2 inhibitor were randomised to subcutaneous 1 mg of semaglutide or placebo once weekly. Semaglutide dose was gradually increased from O.25 mg to 0.5 mg to eventually 1 mg per week. Apart from randomised medication and SGLT2 inhibitor, 70% patients were on metformin and about 13% were taking a sulfonylurea. SUSTAIN 9 showed that addition of semaglutide to existing therapy with SGLT2 inhibitor resulted in significantly greater reduction in HbA1C and fasting glucose levels. Moreover almost 80% of patients got their HbA1C level down to less than 7%.

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APIXABAN FOR PATIENTS WITH ATRIAL FIBRILLATION UNDERGOING CORONARY STENTING

 

 

The WOEST trial ( Lancet 2013; 381:1107-15) was the first randomised study to show that a combination of a vitamin K antagonist (VKA) and a P2Y12 inhibitor when employed inn a patient of atrial fibrillation undergoing PCI resulted in significantly less bleeds than a triple combination of VKA, aspirin and a P2Y12 inhibitor. The study however randomised less than 600 patients. At the end of a year major bleeds were reduced from 45% in the triple therapy group to 20% in the double therapy group; p<0.0001). The conclusion was that use of clopidogrel minus aspirin was associated with a significant reduction in bleeding complications, without an increase in thrombotic events. The study was not powered to assess changes in ischemic events or mortality.

 

Atrial fibrillation (AF)s the commonest arrhythmia in adults and therefore more than 10% of patients suffering from acute coronary syndrome are found to be in AF. The aim is to prevent ischemic events such as myocardial infarction or stent thrombosis, and also simultaneously prevent thromboembolism because of AF. Ischemic events can be avoided by dual anti platelet therapy (DAPT) while embolism (stroke) is prevented by an oral antocaogulant (OAC). The problem is that combining DAPT with an OAC increases the risk of major bleeding considerably. Choosing antithrombotic treatment for an AF patient suffering also from acute coronary syndrome becomes quite a challenge.

 

Apart from WOEST, 2 more randomised trials comparing a new oral anticoagulant (NOAC) plus a P2Y12 inhibitor with triple therapy consisting of VKA, aspirin and P2Y12 inhibitor showed a lower incidence of bleeding with double regimen therapy without aspirin. These 2 rials were not powered to assess whether lower bleeds were due to avoidance of aspirin or due to use of a NOAC.

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MORE ON THE ULTRA THIN STENT WITH BIODEGRADABLE POLYMER

 

 

LANCET 2019;393:987-97

 

All said and done the promise of ultra thin strut stents with biodegradable polymer to cut down the incidence of stent thrombosis and neoatheroscelrosis remains to be fulfilled. Drug eluting stents (DES) have indeed reduced restenosis but have been hampered by development of late stent thrombosis and neoatherosclerosis. In order to improve clinical results ultra thin stents were developed in which strut size is a mere 60 microns. These stents are made of the allow cobalt chromium and are covered by a polymer that is only 5 microns in thickness. Moreover the polymer is biodegradable, which means that it melts away in a few months to a year, having done its job of preventing smooth muscle proliferation or restenosis. Crucially the stent left behind behaves like a bare metal stent that is incapable of inducing inflammation in the coronary artery wall. The situation that we have currently is that every ultra thin strut stent in the market carries biodegradable polymer (BP). All randomised studies done with the ultrathin strut stent have compared them with the durable polymer (DP) everolimus eluting stent ( or the Xience stent). The Xience stent has a strut thickness of 80 microns, which is also quite thin. The Xience stent and other thin strut stents with a durable polymer have provided excellent clinical outcomes compared to earlier generation drug eluting stents, but results have flattened. Second generation DP-DES have a lower risk of stent thrombosis, restenosis, myocardial infarction and death in comparison with bare metal stents. The latest ultra thin strut BP-DES also provide clinical outcomes comparable to second generation BP-DES but no randomised trial has shown superiority.

 

The latest trial comparing BP-DES with DP-DES ( the TALENT trial) reported similar outcomes by 12 months (Lancet 2019,393:987-97). TALENT studied 1435 patients and the primary endpoint was a composite of death, myocardial infarction or clinically indicated target vessel revascularization. At the end of one year both groups had an incidence of about 5%. Participating centres were from Europe.

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TRANS CATHETER AORTIC VALVE REPLACEMENT FOR THE LOW RISK PATIENT

 

SELF EXPANDING TAVR VALVE(LEFT) AND BALLOON EXPANDABLE TAVR VALVE( RIGHT)

 

Trans catheter aortic valve replacement (TAVR) is an established technique that has been found to be a viable alternative to surgical valve replacement (SAVR) in patients of severe aortic stenosis (AS) at high risk or moderate risk for death following SAVR. Severe AS includes patients of AS who have a valve area equal or less than 1cm2 ( equal or less than 0.6 cm2 per square meter of body surface area) or mean gradient greater than 40 mm Hg or Doppler flow across the aortic valve exceeding 4 meter per second, assessed by 2D echo performed at rest.

 

Aortic stenosis can become as life threatening condition once symptoms develop. The aortic valve becomes narrowed, obstruction blood flow from the heart to the rest of the body. Patients develop breathlessness, chest pain and can even faint. Open heart surgery in which a mechanical valve with solid carbon leaflets is inserted has been the mainstay of treatment for the last half century. The mechanical valve however requires life long anticoagulation or blood thinners. Biological valves made from cow and pig heart tissue are also implanted when anticoagulation is undesirable, such as in patients who are old (more than 65 to 70 years, pregnant women, and in those who are incapable of takin blood thinners for life).

 

It was inevitable that the next target would be patients of severe AS at low risk defined as predicted 3% risk of death by 30 days. We now have 2 large studies that have taken the interventional cardiology world by a storm. In fact the entire audience at the latest American College of Cardiology Meeting was left breathless the presentation of these 2 studies; both studies were published simultaneously by the New England Journal of Medicine.

 

 

The first trial to be discussed used a self expanding valve in more than 1400 severe AS patients (N Engl J Med March 17). The researchers compared outcomes of SAVR ( in which the chest and heart are opened in the operation room) versus the far less invasive procedure of TAVR, in which the aortic valve is inserted via the groin. All patients were considered ow risk ( predicted death less than 3% at 30 days); 65% were male while mean age was 74 years.

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THE TALENTED ULTRATHIN STRUT DRUG ELUTING STENT KICKS IN

 

Lancet 2019;393:987-97

 

The introduction of first generation drugs eluting stents ( 1G- DES) sub substantially reduced rates of in stent restenosis (ISR) as seen with bare metal stents (BMS). Bare metal stents had significantly cut down plain balloon angioplasty complications such as emergency coronary artery bypass grafting surgery and restensis, but were associated with stent thrombosis (ST). ST is a dreaded complication of coronary stenting that apart from killing a patient, invariably results in a large myocardial infarction. Improved anti platelet therapy in the form of dual anti platelet therapy (DAPT) and improved stent technology with better implantation techniques did reduce early ST events (less than 30 days). In stent restenosis with BMS was due to neo intimal hyperplasia, and this pathological phenomenon paved way for the entry of the IG-DES. The IG-DES significantly reduced in stent restenosis but became associated with late ST (30 days to 1 year), and with very late ST (later than 1 year) ST. Late ST necessitated development pf more powerful anti platelet medication, administered for prolonged duration, which in turn brought in the spectre of increased bleeding.

 

Delay in re-endotheliazation is considered the primary substrate for late and very late ST. Optical coherence tomography (OCT) has revealed that stent malapposition and rupture of a neoatherosclerotic plaque are nearly always associated with late and very late stent thrombosis. In a few cases uncovered struts are the cause. Delayed re-endotheliazation is due to the anti proliferative effect of the drugs released by the 1G-DES.

 

Another phenomenon to explain late ST was a chronic inflammatory reaction induced by the polymer attached to the stent struts, and even the stent struts themselves. The stent itself essentially has 3 components, the metallic platform, the polymer (drug carrier) and the pharmacological agent.

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