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    Across intensive care units in the country it is not uncommon to see injection furosemide being administered as an infusion in treating patients of acute decompensated heart failure. Acute decompensated heart failure carries considerable morbidity and mortality. Rates of death or rehospitalisation are uncomfortably high in the following 2 months. Millions of patients get admitted for acute heart failure but there is remarkably scanty evidence based upon randomised trials regarding treatment. For more than 6 decades the mainstay of treatment has been a loop diuretic such as furosemide. No new drug has so far emerged that can effectively replace loop diuretics for treatment of pulmonary oedema or acute heart failure. Adverse effects such neurohormonal activation, systemic vasoconstriction, electrolyte derangement or kidney failure are well known, as also the chance of death. But clinicians even today have access to little else but a loop diuretic. Other possible new medicines such as adenosine antagonist, endothelin antagonists, vasopressin antagonist or nesiritide have not lived up to their promise. It therefore becomes imperative that we turn to a modest albeit randomised trial comparing continued infusion with bonus injections of furosemide and high dose with low dose in the DOSE trial published in 2011. No important study has followed the DOSE trial. Maybe the industry does not feel the need to research a worthy new drug that can replace loop diuretics due to lack of fiscal returns.

     

     

    The DOSE trial randomised a little more than 300 patients of acute decompensated heart failure to report that there was no difference in clinical outcomes whether one used continuous infusion of furosemide or gave 2 bolus injections of the same. Patients did not find any difference in their symptoms improvement nor was there any difference in renal function checked after 72 hours. The creating levels recorded after 72 hours was the same in both groups. However almost 43% patients died, needed rehospitalisation, or suffered an emergency visit in the following 60 days, suggesting clearly the seriousness of the problem. During the acute phase furosemide reduced congestion, lowered filling pressures of heart chambers, while improving symptoms.

     

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    Provisional stenting (PS) is the most common technique employed in unprotected distal left main disease bifurcation lesion when patients undergo percutaneous coronary intervention (PCI). The double kissing (DK) 2 stent technique has been found to effective for non left main bifurcation lesions. Recently JACC published a paper that reports the DK technique for kept main lesions. Thus study randomised patients with distal left main bifurcation lesions to the DK technique and PS. The researchers randomised mire than 480 left main bifurcation patients to DS and PS technique. The primary outcome of death, target vessel myocardial infarction and target vessel revascularisation occurred in significantly less in DK technique as compared to PS; 5% versus 11%; p=0.02. DK technique also resulted in lesser myocardial infarction alone with fewer stent thrombosis. Clinically driven target lesion failure and restenosis were also significantly less with the DK technique. There was however no significant difference in cardiac death in the two cohorts. Crucially in complex left main lesions ( more than 10 mm in length and greater than 79% stenosis, the DK technique reduced target vessel failure significantly from 18% to only 7%. In simple lesions target lesion failure was reduced from 8% to 2%. The researchers concluded that in true distal left main bifurcation lesions DK 2 stent technique resulted in significantly less target lesion failure at the end of one year than the provisional stenting strategy. This is the first randomised trial comparing DK crush with provisional stenting in left main bifurcation lesions. The number needed to prevent target lesion failure was 20 overall, and only 9 in complex lesions.

     

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    ADVERSE EVENTS IN SPRINT TRIAL

    ADVERSE EVENTS IN SPRINT TRIAL

     

    The SPRINT trial was terminated prematurely due to substantial reduction in clinical outcomes as also death in participants subjected to rigorous anti hypertension therapy as opposed to standard treatment. More than 9000 participants with hypertension accompanied by cardiovascular risk or kidney disease were enrolled for the trial. The mean baseline systolic blood pressure was les than 140 mm of mercury. The lay press exploded with the information provided by American Heath agencies and the New York Times emphasised that there was a 25% reduction in clinical outcomes with sustained therapy without bothering to mention absolute changes brought about in cardiovascular outcomes by bringing down the blood pressure to 120 mm Hg. The standard treatment grips were permitted to have their blood pressure at 140 mm mercury.
    The complete data was eventually presented in the American Heart Aasociation Meeting in 2015 and simulatenously published in the New England Journal of Medicine. The paper was accompanied by two editorials and a Perspective piece. One of the editorials revealed that the manuscript was checked out by multiple reviewers, a statistician, and the editors themselves. Moreover the editors wrote that they were “proud” to have vetted the paper in a few weeks after receiving the manuscript. The rapidity of the process of vetting the research was fascinating. Normally it takes a month for the NEJM to just acknowledge a manuscript, leave aside receiving the stuff,reviewing and accepting it within a span of four weeks. The tone of the editorial was that despite adverse effects it would be worthwhile getting the blood pressure down to below 120 mm Hg. It was almost as if they were advocating going as low as below 120 mm mercury in all hypertensives.

     

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    At the outset it cannot be emphasized enough that the SENIOR study was funded by the industry. This was presented at this years TCT Meeting and simultaneously published in the Lancet. The aim of the study was to compare clinical outcomes in patients over 75 years assigned to drug eluting stent (DES) and a bare metal stent (BMS) with a short duration of dual antiplatelet therapy (DAPT). In this randomized single blind trial 1200 patients with stable angina (half of them) and acute coronary syndrome were studied (15% had NSTEMI, 10% had STEMI, and 9% had unstable angina). Duration of DAPT was only one month in stable angina patients and 6 months in those with acute coronary syndrome. The primary outcome (death, myocardial infarction, stroke or ischemia driven target lesion revascularization) was significantly less by an absolute 4% in the DES group as compared to the BMS group (12% versus 16%). Bleeding complications were similar (5% vs.5%). Stent thrombosis too was similar in both groups (1% vs. 1%). The mean patient age was 81 years in each arm, 62% in each arm were males, 25% had diabetes and 52% had hypercholesterolemia. The researchers concluded that DES with short duration of DAPT was better than BMS with short duration of therapy in PCI done in elderly patients. The DES advantage was driven largely by ischemia driven target lesion revascularization (2% vs. 6%; p=0.0002).

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    A significant number of patients undergoing PCI with stenting are also suffering from atrial fibrillation (AF). These patients need triple antithrombotic therapy in the form aspirin plus clopidogrel (or another P2Y12 inhibitor) and an oral anticoagulant such as warfarin. Triple therapy is aimed at reduction of emboli (systemic or cerebral), ischemic events (myocardial infarction, death, stroke) and stent thrombosis. Triple antithrombotic therapy is however used with the caveat that there is a substantial increase in fatal and not fatal major bleeding. An alternative strategy is emerging that employs dual antithrombotic therapy of dabigatran (direct thrombin inhibitor) and a P2Y12 inhibitor (clopidogrel or ticagrelor) to prevent thrombotic events without increasing the risk of major bleeding. Aspirin is not included in this prescription. In the multicenter RE-DUAL PCI trial more than 2700 patients with non valvular AF were randomly divided to receive dabigatran 110 mg or 150 mg twice a day with a P2Y12 inhibitor (clopidogrel or ticagrelor) or triple therapy (warfarin plus aspirin plus a P2Y12 inhibitor). These patients had undergone PCI and stenting in the previous 120 hours. The primary endpoint of time to major or clinically relevant non-major bleeds was significantly less in the dual antithrombotic group (hazard ratio 0.52; p<0.01 for non inferiority). At 14 months major bleeds were 15% in the dabigatran 110 mg (twice day) plus P2Y12 inhibitor group versus 27% in the triple antithrombotic group), an absolute difference of 12%. Major bleeds were also significantly lower in the 150 mg dabigatran dual therapy group compared with triple warfarin therapy group. There was no difference in thromboembolic events and deaths in dual versus triple antithrombotic groups, indicating similar efficacy regarding ischemic events. The researchers conclude that in patients with AF undergoing PCI with stenting, a regimen of dabigatran with a P2Y12 inhibitor dual therapy significantly slashes the risk of major bleeds as compared to warfarin triple therapy, with no increase in thrombotic complications.

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    It is known that almost 1 in 4 patients (>65 years in age) of AF undergoing PCI are discharged on triple therapy. Those getting triple therapy have higher rates of major bleeds versus those on dual antiplatelet therapy (DAPT) alone, without any measurable difference in composite of myocardial infarction, death, or stroke. There is also the clear danger of increased intracranial bleeding.

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    Hodgkin’s disease (HD) accounts for 1% of all cancers but remarkably 85 to 95% of early stage disease are curable. Thomas Hodgkin described 6 patients with symptoms that differed from those experienced in tuberculosis, syphilis or inflammation as long ago as 1832. There was no treatment for more than a century and most patients with Hodgkin’s disease perished. Considerable progress has been made in the last 50 years. Hodgkin’s disease was confirmed to be cancerous in 1994, by the use of single cell micro dissection technique that showed Reed Sternberg cells originated from monoclonal B-lymphocytes. Positron emission tomography (PET) with F-fluorodeoxyglucose (FDG) as a tracer makes it easy to assess early treatment responses, thus avoiding excess chemotherapy burden. Chemotherapy for Hodgkin’s disease began in 1943 with use of nitrogen mustard. An explosion in Italy exposing mustard gas to sailors, who subsequently developed lymphopenia and myeloid aplasia, was the triggering factor for use nitrogen mustard in Hodgkin’s lymphoma.

     

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    The median survival was only 2 years with single agent chemotherapy till the 1960’s, but the scenario improved with introduction of the multiple drug regimen consisting of adriamycin, bleomycin, vinblastine and dacarbazine (ABVD) in 1975. The German Hodgkin’s Study Group have achieved overall 5 year survival rates of 96% with 2-4 courses of ABVD plus 30 Gy of involved field radiotherapy. The question seeking answers now is whether chemotherapy alone is good enough to cure early Hodgkin’s disease without the use of radiotherapy. Cure for Hodgkin’s disease comes at a price with increased risk of subsequent malignant cancers. In fact the relative risk of solid cancer is significantly higher among survivors of Hodgkin’s lymphoma than in the general population, and the higher risk lingers up to 25 years post treatment.

     

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    Aspirin has persisted as the bedrock of secondary prevention for coronary artery disease. Vitamin K antagonists when added to aspirin provide superior efficacy in patients with acute myocardial infarction (AMI) albeit at the cost of excess bleeding. One is therefore wary of adding warfarin to aspirin post AMI despite reduction in reinfarction. Aspirin alone at a low dose is associated with a fairly low incidence of serious bleeding. The addition of a second anti-platelet agent again enhances efficacy but at the price of increased bleeding. The addition of an anticoagulant to dual antiplatelet therapy also substantially increases serious bleeding.

     

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    A manufacturer sponsored double blind trial has studied more than 27,000 patients of stable cardiovascular disease. The COMPASS trial randomized patients to rivaroxaban (a direct factor X inhibitor) alone at a dose of 5 mg twice day, aspirin alone at 100 mg a day and a combination of rivaroxaban and aspirin at a dose of 2.5 mg twice a day. The primary outcome was cardiovascular death, stroke or myocardial infarction. The study was stopped after 23 months follow up because there was significant advantage with the combination regimen of rivaroxaban and aspirin versus aspirin or rivaroxaban alone.

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    For decades treatment of type 2 diabetes (T2D) has relied solely on treating high  blood sugar level reflected by the  percentage of glycated hemoglobin (HbA1C). But in the last decade it has been realized that cardiovascular outcomes remain largely unchanged despite pulling down blood sugar and HbA1C. Many clinical trials have reported that merely lowering plasma glucose level with anti-diabetes drugs does not modify cardiovascular risk factors. Cardiovascular disease accounts for 80% deaths in T2D. Lowering high blood pressure and correcting dyslipidemia therefore are very important approaches for treating T2D. Increased plasma level or hyperglycemia however has come out as a weak risk factor for cardiovascular complications.

     

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    The only study to show improved cardiovascular outcomes in T2D was the UKPDS trial in which the drug metformin caused a reduction in clinical events. But the UKPDS included only 342 obese patients of T2D to come to the conclusion of better cardiovascular efficacy with metformin. The ADOPT study on the other hand which included 818 patients of T2D reported that metformin resulted in cardiovascular events than patients getting glyburide, although the difference was not significant.

     

    The main action of metformin is to cut down production of glucose by the liver. It’s ability to sensitize muscle or adipocyte to insulin is feeble in the absence of weight loss. Metformin has no effect on beta cell function in the pancreas, which is the main pathophysiological disturbance resulting in progressive hyperglycemia in T2D. No wonder both UKPDS and ADOPT failed to reduce HbA1C in the long term because of progressive beta cell destruction.

     

    It is time to concentrate on the pathophysiological disturbances in the body that result in T2D. Increased blood sugar is ultimately caused by 8 pathophysiological abnormalities, also called the ‘Ominous Octet.’ It has been well known that beta cell failure and insulin resistance in muscle and liver are the core pathophysiological defects in T2D. In fact people with impaired glucose tolerance have already lost more than 80% of beta cell function and are maximally insulin resistant. The other pathophysiological defects include the fat cell (accelerated lipolysis), gastrointestinal tract (incretin deficiency), alpha cell (hyperglucagonemia), kidney (increased glucose reabsorption) and the brain (insulin resistance). It is obvious that a drug that acts against all or most of these mechanisms will be effective or a combination of drugs.

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    Heart failure is a debilitating and life threatening disease in which the heart is unable to adequately pump blood around the body leading to symptoms of breathlessness, fatigue and fluid retention. About half of heart failure patients have reduced ejection fraction when assessed by 2D echocardiography.

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    Systolic heart Failure continues to torment millions of patients across the world despite enormous progress in drug treatment over the last 30 years. There was no drug capable of cutting down death rate available in the 1980’s when my Mum was suffering from breathlessness, swollen feet and tiredness due to ischemic cardiomyopathy. The CONSENSUS study reporting mortality benefit with enalapril got published just then and I desperately acquired the medicine for my Mum but she sadly found it too toxic. The smallest dose would nauseate her. I was crushed, for there was no alternative then. George Orwell died of TB in the 1940’s; streptomycin had been discovered but Orwell simply could not tolerate the antibiotic despite getting hold of it in the United States. It seems incredible now but there was no treatment for heart failure till the mid 1980’s.

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    My heart sank as I rose to speak in the mid-term Delhi cardiology mid year meting because there was just a handful of delegates left to hear me out. I had wanted very much to stress the redundancy of studies done in the recent past because hardware used then differed from drug eluting stents (DES) currently implanted. Clinical outcomes with second generation DES have improved substantially. Looking at the almost bare hall I for a moment thought that Hurricane Irma had changed course and was barreling to New Delhi. I had never imagined a Delhi cardiology meeting unable to draw less than a dozen physicians at 7 o’clock in the evening. And I had all these years always imagined Delhi to be a city having a fair share of intellectual worth.

     

    I wanted to tell them about the PLATO trial (published in 2009) that randomized more than 18,000 patients of acute coronary syndrome to clopidogrel or ticagrelor. The researchers had reported that Ticagrelor combined with aspirin reduced the composite clinical outcome of death, myocardial infarction, and stroke from 11.7% to 9.8% as compared to clopidorel and aspirin. An absolute reduction of 1.9%. . The absolute decrease in mortality at the end of one year was just 1.4% (5.9% to 4.5%); a relative 22% reduction. Hence 71 patients have to be treated with ticagrelor for one year to prevent one death.Ticagrelor was however associated with more non CABG related major bleeding than clopidogrel (4.5% vs. 3.8%; p=0.03), including more fatal intracranial bleeding. It should also be noted that a loading dose of 300 mg clopidogrel was administered in only 60% of patients in the clopidogrel group.

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    RENE FAVALORO JULY 12, 1923 to JULY 29, 2000.

    RENE FAVALORO JULY 12, 1923 to JULY 29, 2000.

     

    Rene Favaloro had written in 1993 to Dr. Denton Cooley: “ Besides being an outstanding surgeon, you are a good human being, and ……to be good is enough.”

     

     

    More than a half century ago Rene Favaloro, a Sicilian born in Argentina, performed his first coronary artery bypass graft (CABG) operation on 9th May 1967. He and his colleagues had performed 100 CABG operations in 3 years and Favaloro has since been considered the “father” of CABG, even though the first actual procedure was performed by a German immigrant, Robert Goetz, in May 1960. Goetz anastomosed the right internal thoracic artery to the right coronary artery. But Goetz’s colleagues considered the operation “not only highly experimental, but also unwarranted” and prevented him from performing a second CABG procedure. The first CABG was done on a 38-year-old patient who lived for more than a year. There was however no autopsy and details of the surgery were not documented and so Goetz’s achievement went unrecognized until the Society of Thoracic Surgeons, in its Annals of June 2000, acknowledged that Goetz did “the first successful clinical operation on May 2, 1960.”

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    Goetz also is also credited with developing the intra-aortic balloon pump in the 1960’s, which is still used to give mechanical support in patients with poorly contracting harts.

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    Antibiotics have been the bedrock of treating bacterial infections and thereby saving millions of lives, beginning with the discovery of penicillin by Sir Alexander Fleming in the 1940’s. The first randomized trial done in medicine used streptomycin in patients with tuberculosis, again in the 1940’s. Fleming had stated that if one were to use an antibiotic, it should then enough of it should be used. Fleming shared the Nobel Prize for medicine and physiology in 1945 with Howard Florey and Ernst Chain In September 1928, Fleming returned after a month to find that a mold had destroyed a culture of Staphylococcus aureus. The mold was Penicillium notatum. Penicillin, the antibiotic was later purified and isolated, and used extensively in World War II. Fleming died of a heart attack in 1955.

     

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    In his acceptance speech Fleming narrated a fictional scenario in which a man suffering from a streptococcal sore throat takes inadequate penicillin; and subsequently is responsible for the death of his wife by resistant bacteria. The reality as we have learnt is that Streptococcus pyogenes never developed resistance to penicillin.

     

    Current World Health Organization guidelines insist that it is essential to “finish a course” of antibiotics to avoid triggering more virulent forms of disease. In fact physicians all over the world follow the mantra of completing the prescribed “antibiotic course.”

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    Till the COURAGE trial was published , it had remained unclear whether initial treatment with percutaneous coronary intervention (PCI) plus optimal medical therapy (OMT) was superior to OMT alone. Patients with retrosternal pain on effort that disappeared by stopping or taking nitrates were considered to have stable angina (SA). The patients had to have at least 70% stenosis in one proximal coronary artery and objective evidence of myocardial ischemia (substantial ST segment depression or T wave inversion on the resting ECG or inducible ischemia with either exercise or pharmacologic vasodilator stress). Or the patients needed to have at least 80% block and classic angina without provocative testing. All patients were provided aspirin 81 to 325 mg per day or 75 mg of clopidogrel per day if there was aspirin intolerance. Medical ant ischemic treatment in both groups included long acting metoprolol, amlodipine, and isosorbide dinitrate along with lisinopril or losartan for secondary prevention. Simvastatin was given to lower low-density lipoproteins to 60 -85 mg%. Successful PCI was defined as normal coronary artery flow and less than 50% stenosis after balloon angioplasty and less than 20% stenosis post stent implantation. However very few patients received drug-eluting stents (DES).

     

    The researchers concluded that as an initial management strategy PCI added to OMR did not reduce the primary composite end point of death and myocardial infarction (MI) as compared with OMT during follow up of 2.5 to 7 years. The degree of angina relief was significantly greater with PCI. Limitations of the study include the preponderance of male patients (85%), 86% of patients were white, and almost all patients got DES. The COURAGE trial was a randomized study involving 2287 patients  of stable angina.

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    Survivors of acute myocardial infarction (AMI) with impaired left ventricle systolic dysfunction face the prospect of sudden cardiac death (SCD) largely due to the presence of premature ventricular complexes (PVC’s) and ventricular tachyarrhythmia. The incidence of mortality increases 4 folds if there are more than 10 PVC’s in an hour. However anti-arrhythmic medicines proved to be hazardous in these patients. More than 2 decades ago, a major randomized trial confirmed that the anti arrhythmic drugs flecainide and encainide actually increased mortality as compared to placebo in patients who had had an AMI in the past. The CAST trial ensured that anti arrhythmic were no longer used to treat PVC’s and non-sustained ventricular tachycardia.

     

    SINIFICAN REDUCTION IN MORTALITY WITH PROPHYLACTIC ICD IN RANDOMISED TRIALS.

    SIGNIFICANT REDUCTION IN MORTALITY WITH PROPHYLACTIC ICD IN RANDOMISED TRIALS.

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    The 2017 Tour de France (TdF) has begun, and Geraint Thomas has won the first stage. Thomas is the first Welshman to wear the famed yellow jersey. The TdF is a grueling long distance cycling race that covers 3,500 kilometres over 23 days (consisting of 21-long day segments or stages) , in France and bordering countries. The competition is more than a century old and has been held every year except during the 2 World Wars. It is the most physically demanding sporting event of the world.

     

    The most infamous cyclist is of course Lance Armstrong, who won the Tour 7 times, and that too back to back, from 1999 to 2005. The incredible wins gave him legendary status apart from earning millions of dollars and the chance to cycle along the President of the United States. Armstrong would defiantly rebuke any concern of doping directed at him. “I have been tested 500 times, and have never been found positive”. Rumors continued to swirl around him, the American government initiated an inquiry and finally the US Anti Doping Agency stripped him off all titles including every 7 Tour win. He has also been banned from participation in any sporting event whatsoever.

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