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A randomized, double-blind, placebo-controlled and multicentre study aimed to address the role.....

A randomized, double-blind, placebo-controlled and multicentre study aimed to address the role.....

GLOBAL LEADERS is the largest trial (randomized and open-label superiority at 130 sites in 18 .....

GLOBAL LEADERS is the largest trial (randomized and open-label superiority at 130 sites in 18 .....

Partial Oral versus Intravenous Antibiotic Treatment of Endocarditis (POET) Partial Oral versus Intravenous Antibiotic Treatment of Endocarditis (POET), accessed on Sept 10, 2018.

Key Points:

In a randomized trial, switching to oral antibiotics after at least 10 days of intravenous (IV) treatment was not inferior to continued IV antibiotics in patients with endocarditis on the left side of the heart who were in stable condition.

Study Protocol:

This was a randomized, noninferiority, multicenter trial of 400 adults in stable condition who had a good response to at least 10 days of IV antibiotic therapy, and were able to take oral medication. These patients had endocarditis on the left side of the heart caused by Streptococcus, Enterococcus faecalis, Staphylococcus aureus, or coagulase-negative Staphylococci and who were being treated with IV antibiotics. They were assigned to continue IV treatment (199 patients) or to switch to oral antibiotic treatment (201 patients). In all patients, antibiotic treatment was administered intravenously for at least 10 days. If feasible, patients in the orally treated group were discharged to outpatient treatment. Oral antibiotics with good bioavailability (various combinations of moxifloxacin, amoxicillin, clindamycin, rifampicin, dicloxacillin, fusidic acid, and linezolid) were used.

27% had an infected prosthetic valve, and 38% had undergone valve surgery. Median time from diagnosis to randomization was 17 days. After randomization, the intravenously treated group received 19 additional days of inpatient treatment, while the orally treated group was discharged after a median of 3 days and received a total of 17 additional days of treatment.


Fig-1 Kaplan–Meier Plot of the Probability of the Primary Composite Outcome.

The primary outcome was a composite of all-cause mortality, unplanned cardiac surgery, embolic events, or relapse of bacteremia with the primary pathogen, from the time of randomization until 6 months after antibiotic treatment was completed.

Study Results: During 6-month follow-up, a composite endpoint of all-cause mortality, unplanned cardiac surgery, clinically evident embolic events, or relapse of bacteremia with the primary pathogen occurred in 12% of the intravenously treated group and 9% of the orally treated group, indicating noninferiority.

Conclusions: Thus, in patients with endocarditis on the left side of the heart caused by Streptococcus, E. faecalis, S. aureus, or coagulase-negative Staphylococci, who were in clinically stable condition and who had had an adequate response to initial treatment, a shift from initial IV to oral antibiotic treatment was noninferior to continued IV antibiotic treatment.


In contrast to the current guidelines which advocates 4 to 6 weeks of IV antibiotic therapy, this randomized controlled trial from Denmark prompts us to tread a new path on the antibiotic management of endocarditis.

Patients in the orally treated group were shifted from IV to oral treatment at an average of about day 17, that is, during half the treatment period. This may be of great financial and psychological benefit to patients in our country.

It should be noted that although the results seemed consistent across prespecified subgroups, including the subgroups defined according to type of valve affected (native valve or prosthetic valve) and according to type of treatment (surgery during the disease course or conservative treatment) and according to the four different bacterial types, the trial was not powered to assess the primary outcome in any of the prespecified subgroups, in particular the various empirically defined oral antibiotic regimens.

Also, to keep in mind is that in such a lethal infection such as this, selection of the appropriate patients and oral regimens will require profound experience and expertise, as well as the assurance of adherence.

The study shows that for clinically stable, afebrile patients with no evidence of marked inflammation via the inflammatory markers and a negative transesophageal echocardiogram, without antibiotic resistance and who can be seen 2 or 3 times a week in the outpatient a little more than 2 weeks of hospitalization could be replaced by orally treated regimen at home.

Thus, partial duration oral treatment could be an option in carefully selected patients.

Suggested readings:

  1. Habib G, Lancellotti P, Antunes MJ, et al. 2015 ESC guidelines for the management of infective endocarditis: the Task Force for the Management of Infective Endocarditis of the European Society of Cardiology (ESC). Endorsed by: European Association for Cardio-Thoracic Surgery (EACTS), the European Association of Nuclear Medicine (EANM). Eur Heart J 2015;36:3075-3128.
  2. Heldman AW, Hartert TV, Ray SC, et al. Oral antibiotic treatment of right-sided staphylococcal endocarditis in injection drug users: prospective randomized comparison with parenteral therapy. Am J Med 1996;101:68-76
  3. Iversen K, Høst N, Bruun NE, et al. Partial oral treatment of endocarditis. Am Heart J 2013;165:116-122
  4. Al-Omari A, Cameron DW, Lee C, Corrales-Medina VF. Oral antibiotic therapy for the treatment of infective endocarditis: a systematic review. BMC Infect Dis 2014;14:140-140.
  5. Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications: a scientific statement for healthcare professionals from the American Heart Association. Circulation 2015;132:1435-1486.



Cardio Currents

Aspirin for primary prevention: What do AS.....

Cardio Currents

Aspirin for primary prevention: What do AS.....

                                                                                                                                               -Dr Akshay Mehta

A randomized study assessed the cardiovascular events in diabetes (ASCEND) in 15,480 patients (> age 40) with type 2 diabetes (> 90%) but without heart disease. Patients were randomized to aspirin 100 mg or matching placebo and were followed for a mean of 7.4 years.

Majority of the trial participants (80%) were with low or moderate vascular risk score based on age, sex, smoking, systolic blood pressure, body mass index, diabetes duration, HbA1c, assignment to aspirin versus placebo and assignment to omega-3 versus placebo. The baseline 5-year risk of serious vascular events (including transient ischemic attack) without aspirin were thus defined as  <5%, 5-10%, ≥10%. Furthermore, majority of the trial participants (75%) were on statins and 60% were hypertensives.

There was a relative risk reduction in major adverse events (mostly non-fatal) by about 12%, but an increase in major (non-fatal and non-intra cranial) bleeds by 29%.

A Study to Assess the Efficacy and Safety of Enteric-Coated Acetylsalicylic Acid in Patients at Moderate Risk of Cardiovascular Disease (ARRIVE) randomized 12,546 patients (men > 55 years and women > 60 years) to receive aspirin 100 mg or placebo at 501 study sites in 7 countries. The median follow-up was 60 months. The eligible patients had an average cardiovascular risk, deemed to be moderate on the basis of the number of specific risk factors (cholesterol, blood pressure, family history of early CAD). The patients at high risk of gastrointestinal bleeding or other bleeding or diabetes were excluded.

The primary efficacy endpoint was a composite outcome of time to first occurrence of cardiovascular death, myocardial infarction, unstable angina, stroke, or transient ischemic attack. The safety endpoints were hemorrhagic events and incidence of other adverse events.

In the intention-to-treat analysis, acetylsalicylic acid (ASA) did not reduce events. In the per protocol analysis, myocardial infarction rates were significantly reduced, with a 19% relative reduction in the composite primary endpoint. Further, ASA doubled the rate of GI bleeding in relative terms but by only 0.5% in absolute terms.

Summarizing both the trials, from the observed rate of cardiac events (one third of what was expected), one can say that the cohorts were a low to moderate risk group which could be due to a better lifestyle and concomitant statin use.

There was neither a mortality benefit nor fatal bleeding with low dose aspirin, although other events were reduced at the cost of non- fatal bleeds.

A recent patient level analysis of primary prevention ASA trials revealed a relationship between aspirin dose and body weight. Low aspirin doses (75-100 mg) were effective only in patients weighing less than 70 kg  and had no benefit in the 80% men and nearly 50% of all women weighing 70 kg or more (about 154 lbs).  However, this was a post hoc analysis.

Back in the year 2016, recommendation from USPSTF (United States Preventive Services Task Force) was to initiate low-dose aspirin in adults (aged 50-59 years) who have a 10% or greater 10-year CVD risk, are not at increased bleeding risk, have a life expectancy of at least 10 years, and are willing to take low-dose aspirin daily for at least 10 years.

Hence, the decision about low dose (or higher dose in obese people) aspirin use for primary prevention remains an individualized one after a thorough discussion with the patient taking cognizance of the risk of events versus the risk of (mainly GI) bleeding.

Take home message: In patients at low to moderate risk there was a little benefit and little harm hence more importance should be laid on lifestyle changes like diet, exercise, smoking, central obesity and statin therapy if indicated.

Suggested readings :

1. ASCEND Study Collaborative Group. Effects of aspirin for primary prevention in persons with diabetes mellitus. NEJM. Published online August 26, 2018.

2. Gaziano JM, Brotons C, Coppolecchia R, et al. Use of aspirin to reduce risk of initial vascular events in patients at moderate risk of cardiovascular disease (ARRIVE): A randomized, double-blind, placebo-controlled trial. Lancet. Published online August 26, 2018.

3. Rothwell PM, Cook NR, Gaziano JM, et al. Effects of aspirin on risks of vascular events and cancer according to bodyweight and dose: Analysis of individual patient data from randomized trials. Lancet 2018;392:387–99.


Introduction: Patients with Takotsubo syndrome (TTS) have a .....

Introduction: Patients with Takotsubo syndrome (TTS) have a .....

Key Points:

  1. The aim of the study was to analyze the frequ.....

    Key Points:

    1. The aim of the study was to analyze the frequ.....


Recent Randomized CTO T.....


Recent Randomized CTO T.....


Recent Randomized CTO Trials- Clearing the Haze?

                                                                                                                                                          - Dr. Akshay Mehta

Although chronic total occlusion (CTO) of a coronary artery is detected in up to 18% of patients with stable coronary artery disease (CAD) and in 18–50% patients with coronary artery disease during coronary angiography; the question which still continues to be debated, forty years after introduction of percutaneous coronary intervention (PCI), is whether opening of these occlusions are beneficial.

Extensive observational studies suggest benefits (outcomes, exercise capacity, depression etc.)  with CTO recanalization compared to medical therapy; however, they suffer from  selection bias and lack of blinding. This is applicable for those studies which involved opening a well collateralized CTO.

In randomized studies which have compared successful CTO PCI with failed PCI, the complications associated with the latter magnify the benefits with the former.

Hence what was long needed were prospective randomized studies comparing CTO PCI with optimal medical therapy (OMT).

A few recent studies foot the bill.

1. The EXPLORE trial  (Evaluating Xience and Left Ventricular Function in Percutaneous Coronary Intervention on Occlusions After ST-Elevation Myocardial Infarction)  randomized 304 patients who underwent primary PCI for ST-elevation myocardial infarction and had a concomitant non-infarct-related CTO to OMT alone or CTO PCI at 7 days after treating the culprit vessel, along with OMT. Both the primary endpoint of magnetic resonance imaging (MRI)-derived left ventricular ejection fraction and end-diastolic volume, as well as the secondary hard clinical endpoint of cardiac death, MI, or CABG were comparable at 4 months in both groups.

2. In the prospective, randomized Drug-Eluting Stent Versus Optimal Medical Therapy In Patients With Coronary Chronic Total Occlusion (DECISION-CTO) trial, the goal was to assess the safety and efficacy of CTO-PCI + OMT (n = 417) compared with OMT (n = 398) among patients with at least one CTO.

Patients with stable angina (74%), unstable angina (20%) or acute MI (6%) were randomized to the two groups and PCI to non CTO and CTO lesions were done after randomization within 30 days.

The CTO-PCI procedure was a success in 91% of the cases.

At the 3-year follow-up, in the intention-to-treat population, the primary end point [major adverse cardiac events (MACE) at 3 years (all-cause mortality, MI, stroke, repeat revascularization)],occurred in 20.6% patients in the optimal-medical-therapy group vs 19.6% patients in the PCI group (adjusted HR 0.91; p = 0.54).

There were no significant differences between the optimal-medical-therapy group and the PCI group in rates of death (4.4% and 3%, respectively; p = 0.25), MI (10.7% and 8.4%, respectively; p = 0.24), stroke (1.3% and 1.0%, respectively; p = 0.11) or repeat revascularization (10.4% and 8.6%, respectively; p = 0.38).

The Seattle Angina Questionnaire (SAQ) physical limitation, angina stability, treatment satisfaction, angina frequency, and quality-of-life scores were comparable in the two groups, throughout the follow-up.

Thus, in patients with CTO of a coronary artery, medical therapy was not inferior to PCI for the primary outcome of a composite of death, MI, stroke, or any revascularization at 3 years.

Moreover, patients who had optimal medical therapy alone did not report worse angina or quality of life at 3 years than patients who underwent PCI of the completely occluded vessel.

Although it is the first randomized trial comparing the two strategies for CTO, DECISION-CTO suffered from slow enrollment, early termination, high loss to follow-up and reasonably high crossover (about 20%).

Also, since non-CTO lesions were treated after randomization and were not evenly matched for disease severity, that itself could explain the equivalence of the two treatment arms. However, as an initial treatment strategy in clinical practice, OMT for a CTO and PCI for non CTO lesions seems to be as good as PCI for both CTO and non CTO lesions, which is the main message of the trial.

3. Euro CTO was conducted between March 2012 and May 2015 at 26 European centers with expert operators. Although originally planned to enroll 1200 patients for its safety outcome at 3 years, due to slow recruitment only 396 patients with stable coronary disease were randomly assigned to receive PCI with a biolimus-eluting stent plus OMT or OMT. Patients with multi-vessel disease had non-CTO lesions treated before randomization. The primary end point was SAQ five subscales at 12 months.

The procedural success rate was 86.3% and PCI complication rate 2.9%. Ten OMT patients (7.3%) crossed over to PCI because of ongoing angina. At 12 months, MACE rates were comparable in the PCI and OMT groups (5.2% vs 6.7%; p = 0.52).

ACS patients and very symptomatic patients were excluded.

At a median follow up of 19 months, angina frequency score (p = 0.003) and the quality-of-life score (p = 0.007) had improved for PCI compared with optimal medical therapy (intention to treat). There was no improvement in the other parameters of SAQ (physical limitation, angina stability, and treatment satisfaction) for PCI compared with optimal medical therapy.

This is a path breaking trial, the difference from DECISION-CTO being that non-CTO lesions in this trial (Euro CTO) were treated before randomization and baseline assessment, so only the difference in CTO treatment would affect SAQ changes.

Thus, the following can be summarized from these recent RCT’s of CTO PCI:

1. Success rates of CTO PCI which in earlier years were at 50% to 60% have changed in the last 5 to 10 years to 85 to 90%, mainly due to improved wires and wire techniques, specific crossing devices, dissection and re-entry methods, dual injection of contralateral coronary arteries, and retrograde techniques.

2. Against that, the complication rates have reduced to approximately 3% in expert hands (including a minority of deaths) which depends on patient age, lesion complexity, and crossing techniques used and can be pre-assessed with scoring systems.

3. The RCT’s till now have not shown or have not been powered to show reduction in MACE with CTO PCI.

4. They have mainly shown improved symptomatic status and quality of life in trials which have recruited mildly symptomatic or stable patients.

5. Therein too, to remove the placebo effect of CTO PCI on quality of life (QoL),  there is a need for a well-designed and adequately powered sham-controlled, randomized clinical trial to definitively answer the question of the impact of CTO PCI on patient symptoms. The Sham-controlled Intervention to Improve QoL in CTOs trial (SHINE-CTO), currently enrolling patients at some of its 15 sites, may provide the answer by end of this year 2018.

Till then, in view of length of the procedures, risks of contrast-induced nephropathy, bleeding, radiation injury and costs, CTO attempts should probably be reserved for highly symptomatic patients on maximally tolerated medical therapy with evidence of significant residual ischemia. This procedure should be performed by experienced operators at dedicated centers to achieve optimal results, keeping patient preferences also in mind.

Suggested readings :

1. Werner GS, Martin-Yuste V, Hildick-Smith D, Boudou N, Sianos G, Gelev V, et al. A randomized multicentre trial to compare revascularization with optimal medical therapy for the treatment of chronic total coronary occlusions. Eur Heart J. 2018 Jul 7;39(26):2484–93.

2. Fefer P, Knudtson ML, Cheema AN, Galbraith PD, Osherov AB, Yalonetsky S, et al. Current perspectives on coronary chronic total occlusions: The Canadian Multicenter Chronic Total Occlusions Registry. J Am Coll Cardiol.2012;59:991–7.

3. Tajti P, Brilakis ES. Chronic total occlusion percutaneous coronary intervention: Evidence and controversies. J Am Heart Assoc.2018;doi:10.1161/JAHA.117.006732.

4. Henriques JP, Hoebers LP, Råmunddal T, Laanmets P, Eriksen E, Bax M, et al; EXPLORE Trial Investigators. Percutaneous intervention for concurrent chronic total occlusions in patients with STEMI: The EXPLORE trial. J Am Coll Cardiol.2016;68:1622–32.

5. Park S. Drug-eluting stent implantation versus optimal medical treatment in patients with chronic total occlusion (DECISION-CTO). American College of Cardiology’s 66th Annual Scientific Session & Expo; Washington, DC; 2017.


Statins for VTE prevention: Extending pleiotropic effects to the venous side<.....

Statins for VTE prevention: Extending pleiotropic effects to the venous side<.....

Take Home Messages

1. Statins may have an added benefit for primary prevention of VTE in people at high CV risk due to multiple risk factors, though not primarily given for the same.

2. They may be particularly useful for secondary prevention, especially in people with unprovoked VTE who cannot continue long term anticoagulants as recommended, due to adverse effects. 


There often is a rebound phenomenon after the anticoagulant treatment is withheld, in which several markers of coagulation, including D-dimer levels, increase. Statins may serve a useful purpose in such patients by safely preventing coagulation and increase in D-dimer.

Of course, both the above observations now need to be proven in large randomized trials aimed at VTE as the primary end point.

Suggested readings:

1. Biedermann JS,   Kruip M,  van der Meer FJ,   Rosendaal FR, Leebeek FWG,   Cannegieter SC,   et al. Rosuvastatin use improves measures of coagulation in patients with venous thrombosis. European Heart Journal, 2018 May 14;39(19):1740–1747

2. Glynn RJ, Danielson E, Fonseca FA, Genest J, Gotto AMJr, Kastelein JJ, et al. A randomized trial of rosuvastatin in the prevention of venous thromboembolism. N Engl J Med  2009;360:1851–1861.

3. Kunutsor SK, Seidu S, Khunti K. Statins and secondary prevention of venous thromboembolism: pooled analysis of published observational cohort studies. Eur Heart J 2017;38:1608–1612.

4. Migliacci R, Becattini C, Pesavento R, Davi G, Vedovati MC, Guglielmini G, et al. Endothelial dysfunction in patients with spontaneous venous thromboembolism. Haematologica 2007;92:812–818.


Risk Prediction of Atrial Fibrillation Based on Electrocardiographic Interatrial Block.....

Risk Prediction of Atrial Fibrillation Based on Electrocardiographic Interatrial Block.....

                                                                                                                                  -Dr Akshay Mehta


Skov MW, Ghouse J, Kühl JT, Platonov PG, Graff C, Fuchs A, et al. Risk prediction of atrial fibrillation based on electrocardiographic interatrial block. Journal of the American Heart Association. 2018 May 30;7(11). pii: e008247.

Key Points :

1. The aim of the study was to test whether Interatrial Block (IAB) can improve risk prediction of AF in 152 759 primary care patients aged 50 to 90 years from 2001 to 2011.

2. For the study, individuals with P‐wave ≥ 120 ms and the presence of none, 1, 2, or 3 biphasic P‐waves in inferior leads were identified.

3. A dose‐response relationship between the number of biphasic P‐waves in inferior leads and the hazard of AF during follow‐up was observed.

4. Although the highest effect of IAB on the absolute risk of AF was observed in individuals aged 60 to 70 years with CVD, individuals with advanced IAB and no CVD had a higher risk of AF than patients with CVD and no IAB