Recently a 33 year old man who had undergone primary PCI for acute anterior ST segment elevation myocardial infarction (STEMI) with a bare metal stent inserted in the proximal left anterior descending coronary artery a little more than 8 years ago presented with rest angina of increasing severity in the previous 2 days. The twelve lead ECG showed ST segment coving in precordial leads and his troponin was considerably raised. Coronary angiography revealed in stent restenosis (ISR) accompanied by very late stent thrombosis (VLST). The patient was successfully treated with intracoronary tirofiban bolus followed by intravenous infusion of irofiban alongside balloon angioplasty (BA) with successive larger diameter balloons at high pressure. The patient was discharged the next day in stable condition on dual antiplatelets (that included ticagrelor),a statin, and an ace inhibitor.
Very late stent thrombosis occurs in BMS, albeit at a lower rate than with DES. In stent neoatherosclerosis with ruptured plaque and thin cap fibroatheromas has been observed in BMS. Atheroscrelotic plaques harvested from patients with very late stent thrombosis and those with acute coronary syndrome unrelated to stent thrombosis are histologically indistinguishable from each other. Disruption of neoatherosclerosis inside BMS may be an important underlying mechanism of very late stent thrombosis after 3 years of BMS implantation. The mechanism for VLST in DES on the other hand is largely inflammation at strut site.
Balloon angioplasty was chosen in the patient because of its simplicity and reasonable cost. Balloon angioplasty was one off the earliest strategies used to treat ISR. Lumen enlargement results from stent expansion and tissue extrusion. During the procedure balloon to artery ratio of 1.1 : 1 is selected. Crucially the stenosed part is tackled rather than entire stented segment to prevent dissection or trauma. Some operators use only non compliant balloons.
Against the background that transcathere aortic valve replacement (TAVR) carries similar risk of mortality as compared to surgical valve replacement (SAVR) in patients of severe aortic stenosis with a high risk score, the PARTNER 2 trial randomized a little more than 2000 patients of severe symptomatic aortic stenosis with intermediate risk to TAVR and SAVR. Intermediate risk was an STS score between 4% and 8%. About 75% of patients in the TAVR group underwent the procedure by the femoral access route while 25% had TAVR done by thoracic access.
At 2 years the primary endpoint of death and disabling stroke was similar in both groups. Surgical aortic valve replacement was associated with less major vascular complications and paravalvular aortic regurgitation. TAVR on the other hand was associated with fewer episodes of atrial fibrillation, lesser need for blood transfusion and kidney replacement therapy. At 2 years the Kaplan Meier curve for death and stroke was about 20% in both groups. There were fewer deaths and strokes with femoral access TAVR as compared to SAVR, while death and stroke were the same when thoracic access TAVR was done as compared to SAVR. TAVR resulted in larger aortic valve areas. Half of the patients in PARTNER 2 trial were females, the average age was 81 years, and the mean STS score was 5.8.
The researchers pointed out certain limitations. First there was a higher rate of withdrawal of patients from the surgical cohort. The valve used in Partner 2 was the Sapien XT which has now been replaced by the Sapien 3 balloon catheter device. Durability of the bio prosthetic valve is still to be ascertained over 10 years but at 5 years the TAVR valve has been found to be sturdy without signs of degeneration. Also multislice computed tomography imaging was not used consistently to assess aortic annulus dimension.
The other large randomised trial comparing TAVR with SAVR was SURTAVI that included more than 1700 patients of severe symptomatic aortic stenosis with intermediate surgical risk. The mean STS score was 4.5. Severe aortic valvular stenosis was defined as valve area of 1 cm2 or less or valve area index of 0.6 cm2/ m2 and mean gradient greater than 40 mm Hg or velocity across aortic valve more than 4 m/ second. At 2 years the primary end point of death and stroke was similar in TAVR and SAVR , about 14% in both groups. The TAVR valve employers was the Core-Valve bioprosthesis. Surgery was associated with higher incidence of acute kidney injury,blood transfusion, and atrial fibrillation. Permanent pacemaker implantation and paravalvular regurgitation were greater in the TAVR group.
Dabigatran a direct thrombin inhibitor came into reckoning with the RELY trial published in the New England Journal of Medicine in 2009. More than 18000 patients of atrial fibrillation with increased risk for stroke were randomized to receive 110 mg or 150 mg of dabigatran twice a day in blinded fashion compared with warfarin adjusted to therapeutic INR in the remaining cohort. Warfarin, a vitamin K antagonist, has been used as an effective anticoagulant for decades. Warfarin reduces the risks of stroke by two thirds in patients with atrial fibrillation. Atrial fibrillation is the commonest sustained arrhythmia in the world, leading to stroke, systemic embolism, heart failure, ventricular arrhythmia and death. Warfarin however has been a hard task master, it has a bad efficacy/ risk ratio, tricky interactions with drugs and food, wide ranging blood level necessitating frequent blood monitoring. Apart from dabigatran the other non vitamin K antagonist oral anticoagulants (NOAC’s) available in the market are the direct factor Xa inhibitors, apixabn, rivaroxaban and edoxaban.
Dabigatran was launched with the promise that it did not have the awkward baggage that accompanied warfarin. It had a small half life of 12-18 hours, reacted little with food or other drugs, and above all did not need any monitoring. The primary outcome of stroke and systemic embolism was, at the end of 2 years, 1.7% with warfarin, 1.5% with 110 mg dabigatran and 1% with 150 mg of dabigatran. Major bleeds were 3.7% with warfarin, 3.1% with 150 mg dabigatran and 2.7% with 110 mg dabigatran. Haemorrhagic stroke were 0.4% with warfarin, and about 0.1% with both doses of dabigatran( significantly less). Mortality was 4.3% with warfarin, and around 3.7% with both dabigatran groups. In patients with atrial fibrillation, dabigatran at 110 mg twice a day had similar rates of stroke and systemic embolism but lower risk of major haemorrhage. On the other hand the 150 mg twice a dose of dabigatran had significantly fewer stroke and systemic embolism but at equivalent rate of major haemorrhage.
The occasion was the Annual meeting of the Cardiological Society of India ( CSI ; Delhi , and I had been entrusted with the job of debating that “Aggressive treatment in hypertension had Abundant Evidence.” I had to speak against the motion and was quite convinced that the work cut out for me would not be too much of a bother. I however had not anticipated the turn of events that were to unfold in the hall. To begin with strangely nowadays the Annual CSI does not seem to attract the cardiologists or physicians of Delhi. They would come in droves in the eighties and ninetees One would expect with 3 leading institutions of the country offering a doctor in medicine (DM) degree in cardiology there would be senior residents in cardiology attending the Meeting. Maybe cardiologist in training in Delhi do not consider the annual CSI meeting worthy of providing any additional knowledge to what they already possess. In out times the teaching faculty of G B Pant Hospital, New Delhi insisted that we attend these meetings to fill up on our rather scanty knowledge of cardiology. Similarly residents of the All India Institute of Medical Sciences to were nudged to make sure they got around to attend bits and pieces of the conference, duties permitting. Currently apart from the 3 large teaching hospitals , other institutions in Delhi provide DNB cardiology courses, but I doubt if there was single one of the fellows in attendance.
There were far more empty seats in the auditorium of a swanky 5 star hotel in the heart of Delhi than those that were occupied. Your shoulders do slump a bit with you face an empty hall. The effort put in making a talk can be considerable and especially so when gathering relevant data for a fiery debate. I was quite conscious of the emptiness in the hall as I got up to speak but worse was to come. I have always prepared my slide presentation on “Keynote”, which is an Apple Mac product. I carry it on my iPad, while earlier many years ago I would attend these meetings with my MacBook. The iPad is connected by a VGA adaptor to an HDMI cable that goes on to the projector. I possess a VGA adaptor and all these years the HDMI cable that costs from Rupees four hundred to five hundred only is provided by the projection team hired by the organisers of the meeting.
To my horror I realised when I was standing right there at the podium that the chaps did not have the required cable to connect my iPad with my much laboured presentation. I was at a complete loss of words, I realised there was no way that I could now show my slides. My presentation had been shattered and I could not do d thing about it. What a waste. This was the Annual Delhi Cardiology Meeting without a Rupees five hundred cable. The projection personal and the young woman in charge appeared to have never heard of Apple, or of an iPad.
A recent review and meta analysis of 522 randomized trials that included almost 117,000 participants suffering depression, has concluded that all antidepressants are better than a dummy tablet. For decades doctors have been debating about the effectiveness of anti depressant pills in the treatment of depression.Twenty one types of antidepressants were studied as compared with placebo or head to head. In total a little more than 87,000 participants were assigned to an antidepressant, while 29,425 were assigned to a placebo. The mean age of participants was 44 years, 62% were women, and the median duration of acute treatment was only 8 weeks. The bulk of patients included in the meta analysis was from North America (48%), 27% were from Europe, while only 7% of patients were from Asia. Amitryptaline was the most effective anti depressant as compared to placebo, while newer anti depressants such as fluoxetine and sertraline were least effective .
Almost 20% of the world population suffers from psychiatric problems and the majority of these have major depression. The extent of the problem can be gauged by the fact that the US is compelled to spend more than 200 billion $ for the management of depression. This meta analysis has been performed by researchers in Oxford university and has predictably taken the western print media by a storm, every major British daily has prominently displayed the study. The Guardian has gone to the extent of stating the that it’s now official that antidepressants work, its no longer some conspiracy by Big Pharma. The London Times has gone completely over the top by suggesting a million more people need antidepressants based on data provided by this meta analysis.What is however missed is that the authors of the paper concede almost in the beginning of their discussion that effects of the antidepressants were mostly modest, albeit more effective that placebo. Crucially it is also conceded by the authors that non industry funded trials were few in their meta analysis and also that many trials included did not divulge details of funding. The authors acknowledge that despite attempts at obtaining unpublished data, they are “aware a substantial amount of data is still not available to the public.”
We have all grown up being drilled that a dog is man’s best friend. My favourite quotes are from Marlyn Monroe “Dogs never bite. Just humans” and Charles de Gaulle , “The better I get to know men, the more I find myself loving dogs.” The latter never had to deal with the chaps running Allengers, a company that deals among other things with producing and installing cathetrisation laboratories. A catheterisation laboratory provides requisite imaging to safely perform percutaneous coronary interventions such as percutaneous coronary angioplasty and coronary stenting. You could also implant temporary and permanent pacemakers, ICD’s and biventricular pacemakers. These are all life saving procedures. The best catheterisation laboratories are supposed to be manufactured by Seimens and Philips, but I regretfully had opted for Allengers, an Indian company, much before the prime minister came up with the’ Make in India ‘ slogan, I had somehow been lured into believing indian personnel could be more considerate than a Dutch or German corporate manager. Let me assure you Allengers has proved to be merciless beyond the pale; the merchant of Venice would come out as a 4 weeks baby compared to the mandarins in Allengers. Shylock had infamously uttered “ I’ll have my bond. Speak not against my bond. I have sworn an oath that I will have my bond.” Shylock wanted his pound of flesh above everything else, even after the magistrate had offered him thrice the amount of money he was owed. But enough about Allengers, the story is for another day.
As the flu epidemic tightens its grip both in the U.K. and the US it is abundantly clear to scientists that the predominant culprit is the H3N2 subtype influenza A virus. The H3N2 virus subtype is disliked by physicians because it is far more potent than the other A and B influenza virus. H3N2 is capable of rapid transformation to elude the immune system of the human body. It is also associated with more severe symptoms, hospitalisation and death. The other troublesome fact is that vaccination against the H3N2 subtype is feeble, in fact influenza vaccination has been found to be effective for prevention in only 10% of people over 60 years. Vaccines against measles provide 97% protection and over 90% protection against small pox and polio. In short the flu vaccine is far from perfect. Currently more than 6% of people visiting outpatient departments of hospitals in the US are suffering from flu like symptoms, significantly greater numbers than previous years.
People with mild symptoms are best managed at home with lots of oral fluids and rest. In case symptoms are severe, or the elderly, or people with chronic disease such as diabetes, asthma, chronic heart disease, treatment may be initiated with Tamiflu within 2 days of symptom onset. Tamiflu does not reduce mortality but may reduce duration and severity of symptoms. Pregnant women with flu are considered high risk for complications. People down with flu are advised to wash hands frequently with soap, isolate tooth brushes and wash their bed sheets/pillow covers every third day. Recovery from flu usually takes 5-7 days. Antibacterial wipes should be used to wipe remotes, switches and door knobs. The British Medical Journal had warned that oseltamivir or tamiflu was no better than paracetamol in patients with flu, but research by the London school of hygiene and tropical medicine reported that tamiflu significantly cuts incidence of serious complications such as pneumonia. This report a meta analysis for whatever it was worth got published in the Lancet. Crucially tamiflu can cause nausea and vomiting, worse it has been reported that 8 Japanese children committed suicide after taking tamiflu.
The United States is currently in the grip of a flu epidemic with a100 people already reported dead. The flu vaccine seems largely ineffective and there is the grim probability of more mortality. The strain is the same as the “Aussie Flu” H3N2 that acts within hours. You could me normal in the morning and down by evening, have pneumonia the next day. Experts believe this is the same virus that killed more than 50 million people in the Spanish Flu epidemic of 1918. Mortality will definitely be much less this time around because of significantly improved medical care. Tamiflu however is running out of stock in the US. The same virus has decscended in the United Kingdom. England will be hit by an epidemic in a couple of weeks. Around 120 people have already died in the U.K, where predominantly the culprit strain is influenza B ( B Yamagata or the Japanese Flu). The trivalent flu vaccine is ineffective against Japanese flu.The developing furore over lack of efficacy of the vaccine is likely to submerge findings of 2 recent trials that suggest clopidogrel may be as effective as ticagrelor despite guidelines recommending that ticagrelor or prasugrel combined with aspirin be preferred to clopidogrel plus aspirin for at least a year subsequent to a percutaneous coronary intervention (PCI) in patients of acute coronary syndrome ( ACS). Both ticagrelor and prasugrel are more powerful anti platelet agents albeit associated with significantly greater bleeding.
The TOPIC trial randomised 646 ACS patients to ticagrelor or prasugrel plus aspirin ( 323 patients)and after one month to clopidogrel plus aspirin (323 patients) post PCI. More than 90 % received a drug eluding stent and almost all patients were treated by the radial route. After one year the patients who were switched to clopidogrel plus aspirin had more than 50% reduction in the combined clinical end point of death, urgent revascularisation, stroke or bleed ( from 26% to 13%). There was no difference in ischemic events (11.5% versus 9.3%), while bleeding was substantially more in patients assigned to ticagrelor or prasugrel plus aspirin as compared to clopidogrel plus aspirin (15% versus 4%). The researchers explained their findings by the clinical observation that stent thrombosis is commoner in the first few weeks and months and that as time passes bleeding becomes a greater concern with ticagrelor or prasugrel. Switching to clopidogrel with aspirin after the first 4 weeks seems a reasonable clinical option as ischemic events are equivalent with the bonus of reduced bleeds.
A substantial number of patients presenting with ST elevation myocardial infarction (STEMI) have multivessel disease. The jury is still out whether multivessel intervention ( MVI) during index procedure is superior to culprit vessel intervention only ( CVI-O) during primary percutaneous intervention ( PPCI) in the setting of acute STEMI. A Canadian registry examining more than 6000 patients of STEMI concluded that CVI followed by culprit vessel intervention staged ( CVI-S) had better clinical outcomes than CVI or MVI during index procedure. Coronary artery disease was defined by them as stenosis greater than 70% and multivessel disease as CAD in 2 or more epicardial coronary arteries. CVI-S was found to have lesser mortality than MVI or CVI-O, and lower rates of revascularisation than CVI-O. CVI was associated with better survival in patients more than 60 years, diabetes, renal dysfunction, liver disease and when intra-aortic balloon pump was not required. The authors however conceded that because of the observational nature of their data they could not make specific clinical recommendations. An accompanying editorial praised the details provided as anatomical definitions have been vague in most MVI in patients with STEMI, leading to confusion in accurately recommending a PPCI protocol.
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.
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.
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).
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.
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.
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.
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.
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.
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.