Cardiology TodayCover May-June 2018 - CIMS · Andrew M Tonkin, Bhagwan Koirala, Carlos A Mestres,...

Cardiology TODAY

VOLUME XXII No. 3MAY-JUNE 2018

PAGES 73-104

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EDITORIALWorkaholic Doctor - A Bane or a Boon? 75OP YADAVA

REVIEW ARTICLELiraglutide and Cardiovascular Outcomes 77JUGAL KISHOR SHARMA, AMIT GUPTA

REVIEW ARTICLEAnticoagulants in Atrial Fibrillation 82GEETHA SUBRAMANIAN, AVIRAJ CHOUDHARY, VIKAS AGRAWAL, KAMALDEEP

REVIEW ARTICLENewer Antidiabetic Agents & Cardio-Renal Benefits 88VINOD MITTAL

Cardiology Today VOL.XXII NO. 3 MAY-JUNE 2018 73

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CLINICAL OPINIONFunctional Assessment of Coronary Artery Disease Beyond Coronary Angiography 93NEERAJ BHALLA, AMIT GOEL

ECG OF THE MONTHProminent (Tall) T waves 98SR MITTAL

PICTORIAL CMEInterrupted Aortic Arch 103MONIKA MAHESHWARI

74 Cardiology Today VOL.XXII NO. 3 MAY-JUNE 2018

EDITORIAL

Cardiology Today VOL.XXII NO. 3 MAY-JUNE 2018 75

Workaholic Doctor - A Bane or a Boon?

EDITORIAL

Right from our training days it has been thrashed and driven into our mind and psyche that, unless one works his butts off till the cows come home, one cannot make a meaningful doctor. This incessant work-order, with no ‘fun and frolic’ or ‘sun-n-sand’ during our entire residency days, as also during the early formative years as a Consultant, has been a major factor in the physician burn-out rates being as high as 60 per cent in some studies.

And the buck doesn’t stop just there. A high proportion of medical morbidity and mortality are iatrogenic - direct off-shoot of acts of commission by medical professionals. What percentage of these medical errors can be attributed to acts of omission, and what percentage of them are legitimately an off-shoot of an over-worked mind, body and soul can be a matter of debate and contest. In other professions requiring critical decision making like pilots, train drivers, bus drivers etc., where the lives of other people are dependent on their decision making, there has been traditionally a cap on the number of working-hours to prevent exhaustion and blurring of decision-making. Alas, not in medicine ! This has been brought into limelight by a recent editorial in the Journal of the International society of Arthroscopy, Knee Surgery and Orthopaedics sports medicine1 by van Dijk, “Why are not we the surgeons monitored and similarly prevented from overworking? Are we assumed to be morally superior because of the Hippocratic oath? Or is it because we can only damage the occasional patient if we are exhausted rather than an entire plane load?”

Not withstanding the need, there are no rules in our country on this front. In fact it is said, often with pride, in a lot of specialities - especially my own Cardio Thoracic Vascular Surgery, that as a resident we had been on duty continuously for 36-48 hours and at times even 72 hours. This suits the corporate world as also the seniors, but the resultant burn-out, the depersonalization and disillusionment with the profession that the poor young brain develops, is never spoken of. When mistakes occur, he is made a scape-goat without factoring his level of fatigue and mental exhaustion into account.

Dr KK Aggarwal, past National President, Indian Medical Association, in an editorial for MediNexus comments,” Sleep deprivation is even more dangerous than working under the influence of alcohol. Being awake for at least 18 hours has been shown to be the same as someone having a blood alcohol content of 0.05%. And, being awake for at least 24 hours is equal to having a blood alcohol content of 0.10%. So, driving while drowsy is equivalent to driving after drinking too much of alcohol.”

DR. OP YADAVACEO and Chief Cardiac Surgeon

National Heart Institute,New Delhi

76 Cardiology Today VOL.XXII NO. 3 MAY-JUNE 2018

At times the long working hours are a demand from the employers, but yet at other times - it is the lust for money or perhaps still more important, the ego and the one-man upmanship with contemporary colleagues, as to who performs more number of cases. Some times it may even be altruism at its best, where we may not want our patient from an outstation to wait and may therefore compromise our own comfort for the patient’s sake.

In a report created by the American College of Surgeons in 2012, it was acknowledged that all this may even lead to risk of substances abuse, especially of alcohol, and “personality traits such as obsessive compulsive disorder may lead to success in medicine, but may also predispose physicians to impairment”. Even intuitively speaking, therefore, an individual surgeon cannot be left to make a rational decision on his fitness to perform a surgery, as a surgeon may be “conflicted and unable to make a rational evaluation” of his level of sleep deprivation.

Certainly this issues calls for some attention and brain - storming. Therefore, no matter what the reason, this tendency of overwork - either by design or default, should be controlled by the Regulatory Authorities, who must lay down very strict guidelines as to the number of hours that an individual doctor can put in.

Not only regulations must be introduced but also implementation ensured and one way is by widely publicizing them in the lay press to arm the patients with this knowledge so that the patients can themselves monitor, to some extent, the implementation of the guidelines.

REFERENCE1. Van Dijk C.N. Are we surgeons finding it all too much? Dealing with the pressures of our profession JISAKOS 2018; http://

dx.doi.org/10.1136/jisakos-2018-000237.

Cardiology Today VOL. XXII NO. 3 MAY-JUNE 2018 77

Liraglutide and Cardiovascular Outcomes

REVIEW ARTICLE

JUGAL KISHOR SHARMA, AMIT GUPTAKeywords z glycemic control z cardiovascular safety z glucagon-like peptide 1 (GLP-1) z glycemic targets z metformin z life style modification

Dr Jugal Kishor Sharma is Medical Director & Senior Consultant, Central Delhi Diabetes Centre, New Delhi; Dr Amit Gupta is Senior Consultant and Diabetologist, Director Promhex Amrapali Hospital, Sector P2, Omega 1 Greater Noida (UP)

AbstractType 2 diabetes is a complex metabolic disorder that is characterized by hyperglycemia and associated with a high-risk of cardiovascular, microvascular, and other complications. Although glycemic control is associated with reductions in the risk of microvascular complications, the macrovascular benefits of glycemic control are less certain. Furthermore, concern has been raised about the cardiovascular safety of antihyperglycemic therapies. Consequently, regulatory authorities have mandated cardiovascular safety assessments of new diabetes treatments. Liraglutide, an analogue of human glucagon-like peptide 1 (GLP-1), has been approved for the treatment of type 2 diabetes. Its efficacy in lowering glucose levels has been established, and it has been associated with slight reductions in weight and blood pressure. Recent clinical trials aimed at studying cardiovascular episodes have been conducted with GLP-1 RAs. Only liraglutide and semaglutide have shown superiority in cardiovascular benefit compared with placebo. Although many of the mechanisms by which liraglutide and semaglutide produce a cardiovascular benefit are still unknown, it would be desirable for these benefits to be incorporated into the therapeutic algorithms routinely used in clinical practice. The purpose of this review is to explore GLP-1 RA actions not only in cardiovascular risk factors (glucose, weight, and hypertension) but also the possible effects on established cardiovascular disease.

INTRODUCTIONDiabetes mellitus is a chronic progressive disease with ever-rising incidence and

is now equally affecting young as well as older individuals.1-3 Type 2 diabetes is seen in more than 90% of the patients with diabetes. Diabetes is a major cause of

78 Cardiology Today VOL. XXII NO. 3 MAY-JUNE 2018

morbidity and mortality. It is also leading to increased expenditure on healthcare and poses a significant global economic burden. Cardiovascular diseases (CVD) remains the number one cause of mortality and morbidity in diabetic patients.4

DIABETES AND CARDIOVASCULAR RISKCVD is responsible for nearly 80% of the mortality in patients with type 2 diabetes. It is equally true that hyperglycemia alone is not a very strong risk factor for cardiovascular disease as it is for microvascular complications and we all have learned from ACCORD5

(Action to Control Cardiovascular Risk in Diabetes), ADVANCE6 (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation), VADT7 (Veterans Affairs Diabetes Trial) and UKPDS8 (United Kingdom Prospective Diabetes Study) trials that intensive glycemic control have modest impact in reducing CVD risk and mortality. This is evident from the fact that in UKPDS and VADT trials it took more than ten years before any cardiovascular benefit could be seen in these studies. For many decades, drugs like metformin, sulfonylureas and insulin remained the principal pharmacological means of management of diabetes along with lifestyle management. However, over the last one decade, as we have learned that diabetes is not just a disease of insulin deficiency or insulin resistance, there are many other pathophysiological mechanisms as suggested by Defronzo as the classical ominous octet.9

The better insight and knowledge as the pathophysiology of diabetes paved the way for the development of many new classes of drugs, and there has been a revolution in the development of drugs for diabetes in last one decade. These drugs include the therapies like DPP4 inhibitors, GLP1 agonists and SGLT2 inhibitors. With the advent of newer drugs and some of the bad experiences with the older ones like rosiglitazone in the year 2008,10 the FDA verdict shifted the focus to cardiovascular safety of all the anti-diabetic drugs. FDA mandated

that all drugs henceforth use for the management of diabetes must be tested for cardiovascular safety and laid down certain criteria before a drug could be approved for used for the treatment of diabetes. Some curious investigators than not only assessed CV safety but also powered various studies to look for any real or additional CV benefits. In this review article drug in focus is Liraglutide, a GLP-1 receptor agonist. This article will look into the CV safety of Liraglutide and review the results of various CVOT trials.

GLP-1 AGONIST –LIRAGLUTIDELiraglutide is a GLP1 analogue and is 97% similar to human GLP-1.11 It is an acylated molecule. Endogenous GLP-1 has a very short half-life because of it’s degradation by DPP-4 enzymes and neutral endopeptidases. In Liraglutide molecule there is single amino acid substitution of lysine with arginine at position 34 and c16 fatty acid chain is attached to lysine at position 26.12 These changes allow Liraglutide to self-associate and exist in heptameric structure. These structural changes protects Liraglutide against degradation and prolongs its half-life by 13 hours in comparison to very short half-life of endogenous GLP-1 proteins (only1.5 to 2 minutes).

The GLP-1 receptor is a membrane-bound cell surface G protein coupled to adenyl cyclase in beta cells of pancreas. Following ingestion of the food GLP-1 is released from L cells in the distal intestine. GLP-1 than binds to the GLP-1 receptor on pancreatic beta cells leading to glucose-dependent release of insulin from pancreatic beta cells. These receptors are the target for endogenous GLP-1. Liraglutide binds to these receptor proteins and stimulates the beta cell via cyclic AMP pathway to release insulin. Liraglutide acts in a glucose-dependent fashion13 mimicking the physiology of GLP-1 agonists and also by decreasing the glucagon secretion from alpha cells which is inappropriately high in patients with diabetes. Liraglutide delays gastric

emptying, decreases body weight and these effects are also responsible for a desirable glycemic response.

Liraglutide’s pharmacokinetics is not altered to a meaningful extent by use of different injection sites, namely upper arm, abdomen, and thigh. After subcutaneous administration Liraglutide is absorbed slowly exhibiting dose proportional absorption across the therapeutic dose and maximum plasma concentration is reached in 8-12 hours.14 Mean apparent volume of distribution of Liraglutide ranges between 11-17 L. Liraglutide is 98% bound to plasma protein and absolute bioavailability is approximately 55%. Liraglutide is metabolized like the large proteins and no specific organ is major route of elimination. Liraglutide has very low potential for drug-drug interaction as shown in in-vitro studies.It is effective and has established efficacy both as monotherapy and as add-on therapy to oral anti-diabetic drugs in adult patients with uncontrolled type 2 diabetes as shown in various LEAD trials.15

GLP1 AGONISTS AND CARDIOVASCULAR EFFECTSGLP1 agonists improved many of the important and established CV risk factors like obesity, hypertension, dyslipidemia, inflammation and visceral fat in patients with type 2 diabetes. GLP-1 receptors are present in the myocardium and vasculature and affect CV functions by their direct as well as indirect effects on heart and blood vessels.16 GLP-1 agonists increase production of nitric oxide from vascular endothelium and cause vasodilation, thus increasing blood flow to the myocardium. GLP-1 agonists can also decrease the CV events by slowing the atherosclerotic process, Liraglutide accelerates endothelial recovery following injury, retards the formation of atheroma, has anti-inflammatory action on vascular endothelium and inhibits platelet aggregation. Studies have shown that GLP-1 agonists like Liraglutide and Semaglutide have cardio protective effect on ischemic myocardium by increasing

REVIEW ARTICLE


coronary blood flow, reducing infarct size, reduced risk of cardiac arrhythmias, decreasing left ventricular filling pressure, improving left ventricular function and consequently improving survival. GLP-1 agonists also stimulate parasympathetic nervous system leading to increasing heart rate. Whether these CV effects are a class effect or specific to Liraglutide or Semaglutide is difficult to say at this time.17-20

CARDIOVASCULAR OUTCOME TRIALS (CVOTs)Ever since it has become mandatory to conduct CVOT trials by FDA before approval of any anti-diabetic drugs, In the last 10 years, since, 2008 more than 190,000 participants have been subjected to CVOT trials, many of these trials have already been published while 13 are still underway. Each of these trials have demonstrated that drugs tested in these trials were non-inferior to placebo in these major adverse cardiovascular endpoints (MACE). What is important is that few of these trials also provided evidence for CV benefit with reductions in CV death as well as all-cause mortality.

Out of eight CVOT trials published till 2017, six has been conducted with incretin based therapies and two with SGLT2 inhibitors. SAVOR-TIMI (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus – Thrombolysis in myocardial infarction) with Saxagliptin,21 EXAMINE (Examination of CV Outcomes with Alogliptin versus Standard of Care) with Alogliptin,22 TECOS (Trial Evaluating CV Outcomes) with Sitagliptin23 are trials with DPP4 inhibitors. Trials with GLP-1 analogues are ELIXA (Evaluation of Lixisenatide in Acute Coronary Syndrome) with Lixisenatide,24 LEADER trial with Liraglutide25 and SUSTAIN-6 (Evaluate CV and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes) with Semaglutide.26 EMPA-REG (Empagliflozin Reducing Excess Glucose) with Empagliflozin,27 The CANVAS Program (Canagliflozin

Cardiovascular Assessment Study) with Canagliflozin.28 A detailed statistical review of all the CVOT trials will be beyond the scope of this article it will be important to understand the results and their clinical implications.

CVOTs AND DPP-4 INHIBITORSIt is important to mention that in SAVOR-TIMI, EXAMINE and TECOS, the three DPP4-inhibitors were able to achieve non-inferiority on major adverse cardiovascular events (MACE). DPP4-inhibitors were not superior on MACE in comparison to placebo, and none of the CVOTs with DPP4-inhibitors showed any benefit in reducing CV mortality.21-23 There was a statistically significant increase in hospitalizations due to heart failure (A pre-specified exploratory end point in all CVOTs) with SaxaglIptin in SAVOR -TIMI - with 27% increase in the relative risk of HHF (HR = 1.27; 95% CI = 1.07–1.51, P = 0.007).

CVOTs AND SGLT-2 INHIBITORSEMPA-REG OUTCOME trial was an event-driven trial. The trial was conducted in patients with high CV risk. The trial population was randomly treated with empagliflozin or placebo. The primary endpoint was significantly reduced and there was significant reduction in CV death. There was statistically robust 38% risk reduction in CV mortality (P<0.001).There was also decrease in non-fatal MI and hospitalization due to heart failure.27 However, there was a slight increase in incidence of stroke (statistically non-significant) in patients treated with empagliflozin. What is interesting is that it’s not the glucose-lowering effect but other pleiotropic effects of SGLT2 inhibitors which are thought as the possible mechanism for CV benefit. The pooled data from CANVAS (Canagliflozin CV Assessment Study) trial and CANVAS-R (Renal) study shows that canagliflozin was superior to placebo for 3 point MACE,28 However, there are challenges in combining data from two different trials.

CVOTs AND GLP1-AGONISTS Four out of eight trials assessing the CV safety of GLP1 agonists have already reported outcome. In ELIXA trial, Lixisenatide is non-inferior to placebo on 4P-MACE24 while in SUSTAIN-6 and LEADER, Semaglutide and Liraglutide respectively are superior to placebo on four-point MACE.25,26 Long-term effects of Liraglutide on cardiovascular system were not known and to assess the cardiovascular effects of Liraglutide, LEADER trial was started in 2010. Results of the LEADER trial were published in 2016.

LEADER was a multi centric, double blinded and placebo-controlled trial.29 It was conducted at 32 countries with 410 sites. A total of 9340 patients were randomized to Liraglutide and placebo group. The primary composite event driven endpoints were first occurrence of death from cardiovascular causes, non-fatal myocardial infarction or non-fatal stroke, occurred in significantly fewer patients in the Liraglutide group25 (608 of 4668 patients [13.0%]) than in the placebo group (694 of4672 [14.9%]) (hazard ratio, 0.87; 95% confidence interval [CI], 0.78 to 0.97; P<0.001 for non-inferiority; P=0.01 for superiority).The death rate from any cause was lower in the Liraglutide group (381 patients [8.2%]) than in the placebo group (447 [9.6%]) (hazard ratio, 0.85; 95% CI, 0.74 to 0.97; P=0.02). The rates of nonfatal myocardial infarction, nonfatal stroke, and hospitalization for heart failure were non-significantly lower in the Liraglutide group than in the placebo group.25 Gastrointestinal side effects were the most common reason for discontinuation of Liraglutide.

An interesting and important observation between LEADER and EMPA-REG OUTCOME is that Kaplan-Meier curves (an indicator of time to benefit) were separated as early as less than 3 months in EMPA-REG OUTCOME while the separation was delayed for more than a year in LEADER trial. This suggests that


Liraglutide may be having an impact on atherosclerosis and consequently, time to benefit was delayed. Following the results of this landmark trial, FDA approved Liraglutide for one more indication i.e. “to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes mellitus and established cardiovascular disease”.30

Semaglutide another GLP-1 agonist has shown promising results by a favorable effect on 3 point MACE. Once weekly exenatide in EXSCEL31 and continuous delivery exenatide in phase 3 FREEDOM-CVO32 trial has shown non-inferiority to placebo but unlike Liraglutide and Semaglutide, CV benefit is not established. It is of importance to highlight that all GLP-1 agonist are not alike. They differ in their molecular structure, pharmacokinetics as well as pharmacodynamics. This might probably explain the different CV results with Different GLP-1 agonists for example null effects with lixisenatide and exenatide while favorable effects with semaglutide and Liraglutide. These differences may also be because of differences in design of various trials, study populations and other factors like treatment persistence.

CVOTs AND OTHER DRUGSThe AleCardio33 trial and ALEPREVENT trial with PPAR agonist aleglitazar was terminated early due to safety concerns. Pioglitazone has shown evidence of CV benefit in both the PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events) and IRIS ((Insulin Resistance Intervention After Stroke Trial) trials34,35 but TOSCA. IT (Thiazolidinediones or Sulfonylureas Cardiovascular Accidents Intervention Trial) failed to replicate treatment benefit.36 ORIGIN Trial (Outcome Reduction with an Initial Glargine Intervention) has already established the CV neutral effects of Insulin Glargine.37 DEVOTE (A Trial Comparing Cardiovascular Safety of Insulin Degludec Versus Insulin Glargine in Patients With Type 2 Diabetes at High Risk of Cardiovascular

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Events) has confirmed the CV safety of insulin degludec compared with insulin glargine (HR 0.91 [95% CI 0.78–1.06], P = 0.21) primarily because of lesser risk of nocturnal hypoglycemia with insulin degludec however no difference in CV mortality was found between insulin degludec and glargine.38

SUMMARY AND CONCLUSIONSCVOTs trials have opened new areas of research, given valuable information on CV safety of drugs. It’s only because of CVOTs we know that insulin glargine, insulin degludec, Sitagliptin, alogliptin, saxagliptin, lixisenatide and once weekly exenatide have neutral effects on MACE outcomes.39 But at the same time, it will be important to answer a certain question like are these CVOTs looking at correct end points. CV safety is demonstrated well by primary endpoints i.e. MACE but inclusion of secondary endpoints like hospitalization for heart failure or time to first hospitalization to heart failure or new microvascular event may provide more robust evidence for CV safety. CVOTs have given the evidence for CV benefit from empagliflozin, canagliflozin, Liraglutide and semaglutide. These results have been discussed extensively by all major diabetes associations worldwide. ADA now recommends the use of a glucose-lowering agent with proven cardiovascular benefit and or mortality reduction as seen with Liraglutide and Empagliflozin in type 2 diabetes patients with established atherosclerotic cardiovascular disease (ASCVD) who don’t meet glycemic targets with lifestyle modifications and metformin.40

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22. White WB, Bakris GL, Bergenstal RM, Cannon CP, Cushman WC, Fleck P, Heller S, Mehta C, Nissen SE, Perez A, Wilson C. EXamination of cArdiovascular outcoMes with alogliptIN versus standard of carE in patients with type 2 diabetes mellitus and acute coronary syndrome (EXAMINE): a cardiovascular safety study of the dipeptidyl peptidase 4 inhibitor alogliptin in patients with type 2 diabetes with acute coronary syndrome. American heart journal. 2011 Oct 1; 162(4):620-6.

23. Green JB, Bethel MA, Armstrong PW, Buse JB, Engel SS, Garg J, Josse R, Kaufman KD, Koglin J, Korn S, Lachin JM. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. New England Journal of Medicine. 2015 Jul 16;373(3):232-42

24. Pfeffer MA, Claggett B, Diaz R, Dickstein K, Gerstein HC, Køber LV, Lawson FC, Ping L, Wei X, Lewis EF, Maggioni AP. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. New England Journal of Medicine. 2015 Dec 3; 373(23):2247-57.

25. Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, Nissen SE, Pocock S, Poulter NR, Ravn LS, Steinberg WM. Liraglutide and cardiovascular outcomes in type 2 diabetes. New England Journal of Medicine. 2016 Jul 28; 375(4):311-22.

26. Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jódar E, Leiter LA, Lingvay I, Rosenstock J, Seufert J, Warren ML, Woo V. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. New England Journal of

Medicine. 2016 Nov 10;375(19):1834-44.27. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E,

Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. New England Journal of Medicine. 2015 Nov 26;373(22):2117-28.

28. Mahaffey KW, Neal B, Perkovic V, de Zeeuw D, Fulcher G, Erondu N, Shaw W, Fabbrini E, Sun T, Li Q, Desai M. Canagliflozin for primary and secondary prevention of cardiovascular events: results from the CANVAS program (Canagliflozin Cardiovascular Assessment Study). Circulation. 2018 Jan 23;137(4):323-34.

29. Marso SP, Poulter NR, Nissen SE, Nauck MA, Zinman B, Daniels GH, Pocock S, Steinberg WM, Bergenstal RM, Mann JF, Ravn LS. Design of the liraglutide effect and action in diabetes: evaluation of cardiovascular outcome results (LEADER) trial. American heart journal. 2013 Nov 1;166(5):823-30.

30. Marathe PH, GAO HX, Close KL. American Diabetes Association standards of medical care in diabetes 2017. Journal of diabetes. 2017 Apr 1;9(4):320-4.

31. National Institutes of Health. Exenatide study of cardiovascular event lowering trial (EXSCEL): a trial to evaluate cardiovascular outcomes after treatment with exenatide once weekly in patients with type 2 diabetes mellitus. ClinicalTrials. gov [Internet]. Bethesda, MD, National Library of Medicine. 2016.

32. Ryder B, DeFronzo RA. Diabetes medications with cardiovascular protection in the wake of EXSCEL: is there a class effect for long-acting GLP-1 receptor agonists?. British Journal of Diabetes. 2017 Dec 15;17(4):131-3.

33. Staehli BE, Nozza A, Schrieks IC, Malmberg K, Neal B, Nicholls S, Mellbin L, Svensson A, Wedel H, Weichert A, Lincoff AM. ASSOCIATION BETWEEN HOMEOSTASIS MODEL ASSESSMENT OF INSULIN RESISTANCE AND SURVIVAL IN DIABETIC PATIENTS WITH ACUTE

CORONARY SYNDROMES: INSIGHTS FROM THE ALECARDIO TRIAL. Journal of the American College of Cardiology. 2017 Nov 29;69(11 Supplement):184.

34. Kernan WN, Viscoli CM, Furie KL, et al.; IRIS Trial Investigators. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med 2016;374:1321–1331.

35. Kernan WN, Viscoli CM, Furie KL, Young LH, Inzucchi SE, Gorman M, Guarino PD, Lovejoy AM, Peduzzi PN, Conwit R, Brass LM. Pioglitazone after ischemic stroke or transient ischemic attack. New England Journal of Medicine. 2016 Apr 7;374(14):1321-31.

36. Packer M. Are physicians neglecting the risk of heart failure in diabetic patients who are receiving sulfonylureas? Lessons from the TOSCA. IT trial. European journal of heart failure. 2018 Jan;20(1):49-51.

37. ORIGIN Trial Investigators. Basal insulin and cardiovascular and other outcomes in dysglycemia. New England Journal of Medicine. 2012 Jul 26;367(4):319-28.

38. Marso SP, McGuire DK, Zinman B, Poulter NR, Emerson SS, Pieber TR, Pratley RE, Haahr PM, Lange M, Frandsen KB, Rabøl R. Design of DEVOTE (Trial comparing cardiovascular safety of insulin degludec vs insulin glargine in patients with type 2 diabetes at high risk of cardiovascular events)–DEVOTE 1. American heart journal. 2016 Sep 1;179:175-83.

39. Abdul-Ghani M, DeFronzo RA, Del Prato S, Chilton R, Singh R, Ryder RE. Cardiovascular disease and type 2 diabetes: has the dawn of a new era arrived?. Diabetes Care. 2017 Jul 1;40(7):813-20.

40. American Diabetes Association. 8. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes—2018. Diabetes Care. 2018 Jan 1; 41(Supplement 1):S73-85.


Anticoagulants in Atrial Fibrillation

REVIEW ARTICLE

GEETHA SUBRAMANIAN, AVIRAJ CHOUDHARY, VIKAS AGRAWAL, KAMALDEEP

Keywords z atrial fibrillation z thromboembolic stroke z warfarin z anticoagulants

Dr. Geetha Subramanian is Professor and Head, Dr. Aviraj Choudhary is Senior resident, Dr. Vikas Agrawal is Assistant Professor, Dr. Kamaldeep is Senior Resident, Department of Cardiology at IMS, BHU, Varanasi

AbstractAtrial fibrillation increases the risk of stroke, which is a leading cause of death and disability worldwide. The use of oral anticoagulation in patients with atrial fibrillation at moderate or high risk of stroke, estimated by CHA2DS2VASc score improves outcomes. However, to ensure that the benefits exceed the risks of bleeding, appropriate patient selection is important, however, Warfarin has been the mainstay of treatment; newer drugs with novel mechanisms are also available. These novel oral anticoagulants (direct thrombin inhibitors and factor Xa inhibitors) obviate many of warfarin’s shortcomings, and they have demonstrated safety and efficacy in large randomized trials of patients with non-valvular atrial fibrillation.

INTRODUCTION Atrial fibrillation (AF) is a common arrhythmia affecting approximately 1% of the general population. As the frequency of AF increases with age, it is anticipated that the number of people with AF will double in the next 25 years. One of the major goals in treating AF is a reduction in the incidence of thromboembolic stroke, the most feared complication of AF. It is estimated that about 17% of all strokes are caused by AF. Ischemic stroke associated with AF is nearly twice as likely to be fatal as non-AF stroke and the

functional deficits among survivors more severe. In the Framingham Study, the risk of stroke in patients with non-valvular AF was increased fivefold in comparison with the general population. Valvular AF increases this risk to 17-fold.1-5

RISK FACTORS Hypertensive heart disease and coronary heart disease are the most common causes of AF in developed countries. In developing countries, rheumatic heart disease is much commoner than in developed countries. Other risk factors


include heart failure, hypertrophic cardiomyopathy, obesity, diabetes mellitus, congenital heart disease, chronic kidney disease, cardiac and non-cardiac surgery, hyperthyroidism, and alcohol.

ANTICOAGULANTS IN AF The ESC Guideline recommends the use of the CHA2DS2VASc score to assess the risk of stroke in patients with AF (Table 1). Risk factors are cumulative and the total score guides management.6

Anticoagulation should be considered for any patient with a CHA2DS2VASc of ≥1 However, a female, aged less than 65 years with lone AF has a low risk of stroke, so no anticoagulation therapy is recommended.

The bleeding risk should be assessed before initiating anticoagulation therapy. The HAS-BLED7 score may be useful to determine the modifiable risk factors. A score of >3 indicates high risk. Prescribing of anticoagulation must be carefully considered in patients with a recent history of active bleeding or previous spontaneous bleeding.

ANTICOAGULANTSThe coagulation cascade of secondary

hemostasis has two initial pathways which lead to fibrin formation (Figure 1). Vitamin K is an essential factor to a hepatic gamma-glutamyl carboxylase that adds a carboxyl group to glutamic acid residues on factor II,VII,IX and X as well as Protein C and Protein S. The anticoagulants (Figure 2) lowers the risk of thromboembolism significantly compared to aspirin and other combinations of antithrombotic therapy that utilize aspirin. With the availability of the non-vitamin K antagonist oral anticoagulant (NOAC) agents, Aspirin is not recommended as preventive therapy for preventing thromboembolic events in patients with atrial fibrillation (AF).

ASPIRIN AND CLOPIDOGRELThe most commonly used antiplatelet agent worldwide is aspirin. In AF

the protective value of aspirin as monotherapy has come under question. Warfarin is superior to aspirin in patients aged >75 years, offering a 52% reduction in yearly risk of a combined end-point of stroke, intracranial hemorrhage and peripheral embolism. Thus, the use of aspirin for stroke prevention in patients with AF should be limited to those who refuse any form of oral anticoagulation, or, perhaps, to those with a CHA2DS2-VASc score of ≤1.8-10

The combination of aspirin and clopidogrel is preferred when warfarin is contraindicated. This combination offers increased protection compared with aspirin alone, but this increases the risk of major bleeding. However, aspirin and clopidogrel together offer less protection than warfarin alone (RR of 1.44 for stroke, peripheral embolism,

Table 1: CHA2DS2VASc scoring system Stroke clinical risk factor ScoreRisk factor Score

Congestive heart failure/

Left ventricular dysfunction 1

Hypertension 1

Age 75 years and over 2

Diabetes mellitus 1

Stroke, TIA or thromboembolism 2

Vascular disease 1

Age 65-74 years 1

Sex: Female 1

Table 2: HAS-BLED scoreCondition Score

Hypertension 1

Abnormal renal function 1

Abnormal liver function 1

Stroke 1

Bleeding 1

Labile INR 1

Elderly (age >65 years) 1

Medication usage

predisposing to bleeding 1

Figure 1: Blood Coagulation Pathways in-vivo showing the central role by thrombin


MI and vascular death). In patients who sustain an ischemic stroke despite international normalized ratio (INR) of 2.0–3.0, targeting a higher INR should be considered (3.0–3.5) rather than adding an antiplatelet agent, as major bleeding risk starts at INR >3.5.11-12

ORAL ANTICOAGULANTSWarfarinWarfarin is a water-soluble vitamin K antagonist. It is a coumarin derivative. It interferes with the synthesis of the vitamin K–dependent clotting proteins, which include prothrombin and factors VII, IX, and X. Warfarin also impairs synthesis of the vitamin K–dependent anticoagulant proteins C and S. The effective dose of warfarin varies among individuals, as a result of genetic variations in its receptor, metabolism via the cytochrome P450 (CYP) system and interactions with other drugs, vitamins and green vegetables. Recommended INR values for AF are 2–3. Pharmacogenetic testing for guiding doses, by means of genotyping for the variants CYP2C9 and VKORG1, which are associated with reduced clearance and thus a decrease in warfarin requirement, is not clinically useful. Patients initiating warfarin may be at an increased risk of stroke during the first 30 days of treatment, probably owing to rapid deactivation of proteins S and C, two endogenous anticoagulants. In high-risk cases, warfarin should be started with concomitant low molecular weight heparin administration for the initial 3–5 days of treatment. Increased levels of

coronary calcification have been recently reported in patients on long-term therapy with vitamin K antagonists.13-15

Non-vitamin K Oral Anticoagulants (NOACs)Non-vitamin K oral anticoagulants (NOACs) are direct thrombin (dabigatran) or factor Xa (rivaroxaban, apixaban, edoxaban) inhibitors. Thrombin catalyzes the final step in the coagulation cascade by converting fibrinogen to fibrin. Factor Xa, in conjunction with factor Va, mediates activation of prothrombin to thrombin. In patients with nonvalvular AF, they are associated with a relative 50% reduction in the risk of hemorrhagic stroke compared with warfarin that is also maintained in elderly patients. There is no need for frequent laboratory monitoring and dose adjustments. The main problems associated with NOACs are the lack of antidotes and specific assays to measure anticoagulant effect, and the considerably higher cost than warfarin. It should be also noted that all major clinical trials with warfarin have included patients without severe renal impairment (CrCl <25–30ml/min), and renal function should always be considered, especially when treated with dabigatran. They are not indicated in patients on haemodialysis because they may precipitate inadvertent bleeding. NOACs do not interact with food but with inhibitors (or inducers) of P-glycoprotein transporters and CYP3A4. Caution is required when they are coadministered with drugs such as verapamil, amiodarone and dronedarone.

In patients taking warfarin, switching to a new agent is appropriate when the INR is <2.16-20

DIRECT THROMBIN INHIBITORSDabigatranDabigatran etexilate is an oral thrombin inhibitor. It is preferred to warfarin for nonvalvular AF as recommended by the European Society of Cardiology10 and the Canadian Cardiovascular Society.21 In 2010, the US Food and Drug Administration (FDA) approved dabigatran at a dose of 150 mg twice daily (CrCl >30 ml/min), or 75 mg twice daily (CrCl 15–30 ml/min) based on the results of the Randomised Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial.22 The RE-LY trial23 shows the promise of these new agents for long-term indications. This trial compared two different dose regimens of dabigatran etexilate (110 or 150 mg twice daily) with warfarin (dose-adjusted to achieve an INR between 2.0 and 3.0) for stroke prevention in 18,113 patients with nonvalvular atrial fibrillation. The annual rates of the primary efficacy outcome, stroke or systemic embolism, were 1.7% with warfarin, 1.5% with the lower dose dabigatran regimen, and 1.1% with the higher-dose regimen. Thus, the lower-dose dabigatran regimen was noninferior to warfarin, whereas the higher-dose regimen was superior. Annual rates of major bleeding were 3.4% with warfarin, compared with 2.7% and 3.1% with the lower-dose and higher-dose dabigatran regimens, respectively. Thus, the lower-dose dabigatran regimen was associated with less major bleeding than warfarin, whereas the rate of major bleeding with the higher-dose regimen was not significantly different from that with warfarin. Rates of intracerebral bleeding were significantly lower with both doses of dabigatran than with warfarin, as were rates of life-threatening bleeding. There was no evidence of hepatotoxicity with dabigatran. In the RE-COVER trial, unmonitored dabigatran etexilate (150 mg twice daily) was compared with warfarin for treatment of venous thromboembolism. The primary efficacy outcome, recurrent venous thromboembolism and related

REVIEW ARTICLE

Figure 2. Classification of currently available anticoagulants, based on their route of administration.

Anticoagulants

Parenteral Oral

Indirect Direct Indirect Direct

Thrombininhibitors

Factor Xa inhibitors

Thrombininhibitors

Factor Xa inhibitors

UFMLMWH

foundaprinux M118

Irudinbivallirudinargatroban

Otamixaban VKA Dabigatran Ivaroxaban apixaban edoxaban


mechanisms, and is not recommended in patients receiving concomitant treatment with strong inhibitors of both CYP3A4 and P-glycoprotein. The drug is not recommended in patients with a CrCl of <15 ml/min. Anti-factor Xa assays are used to estimate the anticoagulant effect.10 APTT and PT are prolonged by rivaroxaban but they cannot be used to guide dosage as the correlation is not linear.28 However, prolonged PT bleeding can be attributed to rivaroxaban, and PT can be used as a rough estimate in case of emergencies.29

EdoxabanIn the ENGAGE AF-TIMI 48 trial, Edoxaban has been demonstrated as noninferior to warfarin with respect to prevention of stroke or systemic embolism and shown to be associated with significantly lower rates of bleeding and death from cardiovascular causes, and it is approved by the FDA.30 Both the 30 and 60 mg doses were not inferior to warfarin, but in the intention-to-treat analysis with the 60 mg dose there was a trend favoring edoxaban.

PARENTERAL ANTICOAGULANTSHeparin A sulfated polysaccharide, heparin is isolated from mammalian tissues rich in mast cells. Most commercial heparin is derived from porcine intestinal mucosa and is a polymer of alternating d-glucuronic acid and N-acetyl-d-glucosamine residues.

Heparin activate antithrombin and

deaths, occurred in 2.4% of patients randomized to dabigatran and in 2.1% of those given warfarin. Major bleeding episodes occurred in 1.5% of patients randomized to dabigatran and in 1.9% of those assigned to warfarin. Therefore, dabigatran appears equally effective and safe as warfarin for the treatment of venous thromboembolism.24 For dabigatran, the aPTT may provide a qualitative assessment of dabigatran level and anticoagulant activity. The thrombin time (TT) is very sensitive to the presence of dabigatran and a normal TT excludes even very low levels of dabigatran.

RivaroxabanRivaroxaban is an oral factor Xa inhibitor. The ROCKET-AF trial (Efficacy and Safety Study of Rivaroxaban With Warfarin for the Prevention of Stroke and Non-Central Nervous System Systemic Embolism in Patients With Non-Valvular Atrial Fibrillation), has showed that rivaroxaban was not inferior to warfarin (INR 2–3) in patients with nonvalvular AF for the prevention of stroke or systemic embolism, and offered a lower rate of intracranial bleeding, but a higher rate of gastrointestinal bleeding.26 In a substudy of this trial, rivaroxaban demonstrated equal safety and efficacy with warfarin in patients aged >75 years.27 The half-life of rivaroxaban is 7–11 hours, but factor Xa is inhibited for up to 24 hours, allowing once-daily dosage. Its bioavailability increases with food consumption. The drug is metabolized in the liver via P450- dependent and -independent

inhibits clotting enzymes, particularly thrombin and factor Xa. Heparin requires parenteral administration; it usually is administered subcutaneously or by continuous intravenous infusion. The plasma half-life of heparin ranges from 30 to 60 minutes with bolus intravenous doses of 25 and 100 U/kg, respectively. The aPTT or anti–factor Xa level is used to monitor heparin. Anti–factor Xa levels also can be used to monitor heparin therapy.31

Low-molecular-weight heparin LMWH is prepared from unfractionated heparin by controlled enzymatic or chemical depolymerization. The low-molecular-weight heparin has a longer half-life than unfractionated heparin and a predictable antithrombotic effect that is attained with a fixed dosage administered subcutaneously twice a day. It has been a practical alternative to unfractionated heparin for initiation of anticoagulation in patients with AF, because it can be self-injected by patients outside of the hospital. A randomized study compared low-molecular-weight heparin with the combination of a vitamin K antagonist (phenprocoumon) plus unfractionated heparin until the INR was ≥2.0 in patients undergoing cardioversion of AF who were not already anticoagulated. Both study groups were anticoagulated for 4 weeks after cardioversion. The primary endpoint (a composite of all embolic and hemorrhagic events and all-cause mortality) occurred in 2.8% of patients in the group that received low-molecular-weight heparin compared with 4.8% of patients in the group that received unfractionated heparin plus phenprocoumon. This study demonstrated that low-molecular-weight heparin is noninferior to conventional anticoagulation for prevention of ischemic and thromboembolic events after cardioversion of AF.32

Because of its high cost, low-molecular-weight heparin rarely is used in clinical practice as a substitute for long-term conventional anticoagulation. Low-molecular-weight heparin typically is used as a temporary bridge to therapeutic anticoagulation when therapy

Table 2: Oral anticoagulants for AF Warfarin Dabigatran Rivaroxaban Apixaban Endoxaban

Dose Variable 150 or 110 mg bd 20 mg od 2.5-5 mg bd 30-60 mg od

Target Vitamin k Thrombin Factor xa Factor xa Factor xa

dependent

factors

Half life 40 h 12-14 h 9-13 h 8-11 h 8-10 h

Onset of action 3-5 h 2 h 2.5-4 h 3 h 1-5 h

Renal clearance 0 80% 60% 25% 40%

Anticoagulation INR 2-3 Not required Not required Not required Not required

monitoring

Antidote Vitamin k 3and 4 factor 4 factor 4 factor 4 factor

prothrombin prothrombin prothrombin prothrombin

complex complex complex complex


concern in patients with heparin-induced thrombocytopenia. The dose of PCC is 20 to 50 U/kg.35-39

OTHER REVERSAL AGENTS. Idarucizumab, is a specific antibody to dabigatran. In the REVERSE-AD(A study of the Reversal Effects of Idarucizumab on Active Dabigatran) study, idarucizumab was successfully used in patients on dabigatran presenting with major or life-threatening bleeding, or with the necessity of emergency surgery. Idarucizumab completely reversed the anticoagulant activity of dabigatran within minutes in almost all patients. It is hence recommended as first-line therapy in such situations. A total of 5 g idarucizumab is administered intravenously in two bolus doses of 2.5 g no more than 15min apart.25

Andexanet alfa, a modified FXa molecule that binds to FXa inhibitor allowing the patient’s intrinsic FXa to participate in coagulation, has been reported to provide rapid and near-complete reversal of factor X inhibitors in healthy volunteers. Aripazine, a small synthetic molecule with broad activity against heparin products and factor X agents, is undergoing testing in healthy subjects. Recombinant factor VIIa has been effective for reversal of the anticoagulant effect of VKA.40-44

CONCLUSIONIn conclusion, the new, non-vitamin K dependent oral anticoagulants, i.e., direct thrombin or Xa inhibitors, appear to be safer and more effective than warfarin in preventing thromboembolism in patients with non-valvular AF (in absence of prosthetic valves or rheumatic mitral valve disease).

REFERENCE 1. Go AS, Hylek EM, Phillips KA, Chang Y, Henault LE,Selby

JV, et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA 2001;285:2370e5.

2. Saxena R, Lewis S, Berge E, Sandercock PA, Koudstaal PJ.Risk of early death and recurrent stroke and effect of heparin in 3169 patients with acute ischemic stroke and atrial fibrillation in the International Stroke Trial. Stroke 2001;32:2333e7.

3. Lin HJ, Wolf PA, Kelly-Hayes M, Beiser AS, Kase CS, Benjamin EJ, et al. Stroke severity in atrial fibrillation. The Framingham Study. Stroke 1996;27:1760e4.

with warfarin is initiated or in high-risk patients for a few days before and after a medical or dental procedure when anticoagulation with warfarin has been suspended.

Transition between NOACs/WarfarinTransitioning from one anticoagulant to another is a period of high-risk for both strokes and bleeding. A reasonable strategy is to reduce the NOAC dose by half, start warfarin and stop the NOAC when the INR is ≥2. When the patient is on warfarin, the NOAC is started after cessation of therapy and three-daily INR measurements to detect a value <2.33

AGENTS TO REVERSE ANTICOAGULATIONAfter introduction of NOACs , reversal of anticoagulation became more complex. Newer agents (such as Idarucizumab, prothrombin complex concentrate [PCC]) are expensive and not always readily available. Consultation with a hematologist is recommended.

VITAMIN K. VKAs reduce the synthesis of functional vitamin K–dependent coagulation factors, providing a rationale for vitamin K therapy as a reversal agent. IV vitamin K does not begin to reduce INR for 6 h, often taking longer than 24 h for complete reversal IV vitamin K may result in allergic reactions (particularly when given as a bolus), and IV infusions should generally be limited to patients with major bleeding. Oral vitamin K is used for minor bleeding with an elevated INR. Subcutaneous and intramuscular administration is not recommended. Although effective at lowering the INR, there are few data demonstrating improvement in outcomes with vitamin K. High doses of vitamin K will prolong the time to achieve a therapeutic INR when warfarin is restarted. Vitamin K does not reverse the anticoagulant effect of NOACs.34

FRESH FROZEN PLASMA. Fresh frozen plasma (FFP) and blood transfusion provide volume, which is a potential advantage in a volume-depleted patient, but a potential disadvantage in patients with heart failure or renal dysfunction.

FFP is readily available, although there are delays associated with thawing frozen plasma. For a patient with a high INR who is actively bleeding, it may be necessary to administer >1,500 ml of FFP to meaningfully increase coagulation factors. Even with a reduction in INR, there are few data showing improvement in outcomes with FFP. FFP in clinically-feasible quantities does not reverse the anticoagulant effect of NOACs.

PROTHROMBIN COMPLEX CONCENTRATE(PPC). The patients who are receiving VKA with an elevated INR, a 10 to 30 min infusion of PCC improves INR values within minutes and lasts for 12 to 24 h. The half-lives of infused factors are similar to endogenous factors. Vitamin K is generally recommended for use with PCC to sustain the reversal effect. The impact of PCC appears to be different with different NOACs. PCC did not normalize the aPTT, and thrombin time in healthy volunteers who had received dabigatran, but immediately reversed a prolonged PT and an abnormal thrombin potential in rivaroxaban-treated healthy volunteers. Studies show that reversal of an anticoagulation effect can occur within 15 min, but may differ between direct thrombin inhibitors and FXa inhibitors. Recent studies show that PCC reverses anticoagulant activity in healthy volunteers given either dabigatran or rivaroxaban within 2 h. The composition of PCC varies with the manufacturer. The 4-factor PCC contains factors II, VII, IX, and X. The 3-factor PCC contains little or no factor VII. In healthy volunteers who received rivaroxaban, 3-factor PCC restored thrombin generation better than 4-factor PCC, but 4-factor PCC produced larger reductions in mean prothrombin time within 30 min.These discrepancies may be related to differences in factor concentration in these agents. Data linking improved clinical outcomes with the use of PCC in DOAC-treated patients are lacking. In addition, there is concern about myocardial infarction (MI) and arterial thromboembolism with the more potent agents,that must be balanced against potential benefits. Some forms of PCC contain heparin, a

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26. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883–91.

27. Halperin JL Hankey GJ, Wojdyla DM, et al. Efficacy and safety of rivaroxaban compared with warfarin among elderly patients with nonvalvular atrial fibrillation in the rivaroxaban once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation (ROCKET AF). Circulation 2014;130:138–46.

28. Cuker AM, Siegal DM, Crowther MA, et al. Laboratory measurement of the anticoagulant activity of the non-vitamin K oral anticoagulants. J Am Coll Cardiol 2014;64:1128–39.

29. Blann AD, Lipp GY. Laboratory monitoring of the non-vitamin K oral anticoagulants. J Am Coll Cardiol 2014;64:1140–2.

30. Giugliano RP, Ruff CT, Braunwald E, for the ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. NEJM 2013;369:2093–104.

31. Hirsh J, Bauer KA, Donati MB, Gould M, et al: Parenteral anticoagulants: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133:141S.

32. Stellbrink C, Nixdorff U, Hofmann T, et al: Safety and efficacy of enoxaparin compared with unfractionated heparin and oral anticoagulants for prevention of

thromboembolic complications in cardioversion of nonvalvular atrial fibrillation: The Anticoagulation in Cardioversion using Enoxaparin (ACE) trial. Circulation 2004; 109:997.

33. Ruff CT, Giugliano RP, Braunwald E, et al. Transition of patients from blinded study drug to open-label anticoagulation: The ENGAGE AF-TIMI 48 trial. J Am Coll Cardiol 2014;64:576–84.

34. Lubetsky A, Yonath H, Olchovsky D, Loebstein R, Halkin H, Ezra D. Comparison of oral vs intravenous phytonadione (vitamin K1) in patients with excessive anticoagulation: a prospective randomized controlled study. Arch Intern Med2003;163:2469–73.

35. Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo controlled, crossover study in healthy subjects. Circulation 2011;124:1573–9.

36. Marlu R, Hodaj E, Paris A, Albaladejo P, Cracowski JL, Pernod G. Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban: a randomised crossover ex vivo study in healthy volunteers. Thromb Haemost 2012;108:217–24.

37. Levi M, Moore KT, Castillejos CF, et al. Comparison of three-factor and four-factor prothrombin complex concentrates regarding reversal of the anticoagulant effects of rivaroxaban in healthy volunteers. J Thromb Haemost 2014;12: 1428–36.

38. Levi M, Levy JH, Andersen HF, Truloff D. Safety of recombinant activated factor VII in randomized clinical trials. N Engl J Med 2010;363: 1791–800.

39. Baudo F, Collins P, Huth-Kuhne A, et al. Management of bleeding in acquired hemophilia A: results from the European Acquired Haemophilia (EACH2) Registry. Blood 2012;120:39–46.

40. Lin J, Hanigan WC, Tarantino M, Wang J. The use of recombinant activated factor VII to reverse warfarin-induced anticoagulation in patients with hemorrhages in the central nervous system: preliminary findings. J Neurosurg 2003; 98:737–40.

41. Deveras RA, Kessler CM. Reversal of warfarininduced excessive anticoagulation with recombinant human factor VIIa concentrate. Ann Intern Med 2002;137:884–8.

42. Nishijima DK, Dager WE, Schrot RJ, Holmes JF. The efficacy of factor VIIa in emergency department patients with warfarin use and traumatic intracranial hemorrhage. Acad Emerg Med 2010; 17:244–51.

43. Skolnick BE, Mathews DR, Khutoryansky NM, Pusateri AE, Carr ME. Exploratory study on the reversal of warfarin with rFVIIa in healthy subjects. Blood 2010;116:693–701.

44. Ansell JE, Bakhru SH, Laulicht BE, et al. Use of PER977 to reverse the anticoagulant effect of edoxaban. N Engl J Med 2014;371:2141–2.


Newer Antidiabetic Agents & Cardio-Renal Benefits

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VINOD MITTAL

Keywords z cardio-renal z end-stage renal disease z DPP-4 inhibitors z SGLT-2 inhibitors z CANVAS study

Dr. Vinod Mittal is Sr. Consultant Diabetologist & Head, Centre for Diabetes & Metabolic Diseases, Delhi Heart & Lung Institute, Director - Delhi Diabetes Care Centre

AbstractCardiovascular disease (CVD) is the most prevalent cause of morbidity and mortality in diabetic patients. Improvement in cardio-renal complications with glycaemic control and managing cardio-renal risk factors is well established. However, the impact of hypoglycaemic medications on CVD is of increasing importance. In 2008, the U.S. Food and Drug Administration issued study regulations for hypoglycaemic agents after rosiglitazone was shown to increase the incidence of myocardial infarction, and the European Medicines Agency provided their own guidance in 2012. As a result, multiple studies have been published evaluating the cardiovascular safety of newer hypoglycaemic medications. Empagliflozin and liraglutide are among the newer agents that have shown cardiovascular benefit and are now recommended for patients with CVD or are at an increased risk of CVD per the 2017 American Diabetes Association Guidelines. Given the influx of new literature and other ongoing studies, it is important to understand the cardiovascular and renal safety of newer hypoglycaemic medications. The purpose of this article is to provide a comprehensive review of clinical trials conducted evaluating cardiovascular and renal outcomes of newer hypoglycaemic medications and their role within diabetic management.

The care of patients with type 2 diabetes mellitus (T2DM) include not only prevention and management of diabetes-specific microvascular complications, but also prevention of macrovascular disease, including coronary artery disease (CAD), myocardial infarction (MI), cerebrovascular disease, peripheral vascular disease (PVD), and heart failure (HF). Indeed, cardiovascular disease is the leading cause of death among patients with T2DM.1

Along with cardio-vascular disease epidemic, diabetic kidney disease has also become the leading cause of end-stage renal disease (ESRD) worldwide and is associated with high cardiovascular morbidity and mortality. As established in landmark randomized trials and recommended in clinical guidelines, prevention and treatment of diabetic kidney disease focuses on control of the two main renal risk factors, hyperglycaemia and systemic


hypertension. Emerging evidence shows that obesity, glomerular hyperfiltration, albuminuria, and dyslipidaemia might also adversely affect the kidney in diabetes. Control of these risk factors could have additional benefits on renal outcomes in patients with type 2 diabetes. However, despite multifactorial treatment approaches, residual risk for the development and progression of diabetic kidney disease in patients with T2DM remains, and novel strategies or therapies to treat the disease are urgently needed (Figure 1).2

NEWER ANTI-DIABETIC AGENTS IN CARDIO-RENAL PROTECTION Appropriate selection of antidiabetic agent (ADA) might impact the risk of atherosclerotic cardiovascular disease (CVD), which include non-fatal MI, non-fatal stroke, and cardiovascular death, with some ADAs possibly superior to others. Plausible mechanisms include differing effects of ADAs on traditional cardiovascular risk factors such as glucose levels, blood pressure, and lipid profile, non-traditional risk factors such as insulin and glucagon levels, and off-target effects such as cardiovascular toxicity mediated through hypoglycemia.3

In 2008, the US FDA issued guidance that all future ADA approvals would be dependent on pooled results from Phase 2 and Phase 3 trials demonstrating no greater than an 80% increase in the risk of atherosclerotic CVD, with a requirement that post-marketing studies be conducted to exclude a 30% increase in the risk of cardiovascular events. This change has led to an increase in the number of large, randomized placebo-controlled studies of new ADAs with primary cardiovascular outcomes.4

Furthermore, although intensive glycemic management has been shown to delay the onset and progression of increased urinary albumin excretion and reduced glomerular filtration rate (GFR) in patients with diabetes, conservative dose selection and adjustment of antihyperglycemic medications are necessary to balance glycemic control with safety. A growing body of literature is providing valuable insight into the renal safety and efficacy of newer antihyperglycemic medications in the dipeptidyl peptidase 4-inhibitor (DPP4-i), glucagon-like peptide-1 receptor agonist (GLP1-a), and sodium-glucose

cotransporter 2 inhibitors (SGLT2-i) classes of medications.

DPP4-INHIBITORSData are available on the cardiovascular effects of DPP-4 inhibitors in both preclinical and clinical settings.

The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR) – Thrombolysis in Myocardial Infarction (TIMI) 53 trial (SAVOR-TIMI 53)5 compared the DPP-4i Saxagliptin with placebo in 16,492 patients with type 2 diabetes who had a history of CV disease (~80% of the study population) or who were older and had elevated risk factors (~20%).

In this trial, DPP-4 inhibition with saxagliptin did not increase or decrease the rate of ischemic events, though the rate of hospitalization for heart failure was increased, although statistically non-significant. The authors concluded that although saxagliptin improves glycemic control, other approaches are necessary to reduce cardiovascular risk in patients with diabetes.

The EXAMINE study (Examination of Cardiovascular Outcomes: Alogliptin versus Standard of Care in Patients with T2DM)6 compared the DPP4-i Alogliptin with placebo in patients with T2DM who had had an acute coronary syndrome 15–90 days before randomization into the trial. This study was in favour of alogliptin, as the study indicated that among patients with T2DM who had had a recent acute coronary syndrome, the rates of major adverse cardiovascular events were not increased with the DPP-4i alogliptin as compared with placebo.

The Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) assessed long-term CV safety of the DPP-4 i sitagliptin versus placebo in addition to usual care in patients with type 2 diabetes and established CV disease (defined as a history of major coronary artery disease, ischemic cerebrovascular disease, or atherosclerotic peripheral arterial disease). Among these patients with type 2 diabetes and established cardiovascular disease, adding sitagliptin to usual care did not appear to increase

HypertensionInflammation

Na+ load

Aldosterone

Cardiac and Renal fibrosis

Endothelial dysfunction

Diabetes

GFR, solute excretion

Adverse cardiorenal outcomes

Atherosclerosis, vascular calcification

Myocardial infarction Ischemia Renal failure

Figure 1. Pathophysiology of cardio-renal complications in diabetes


the risk of major adverse cardiovascular events, hospitalization for heart failure, or other adverse events.

However, the finding of increased risk of heart failure hospitalization with saxagliptin in SAVOR-TIMI 53 trial has prompted further evaluation of this risk in newer studies. A recent meta-analysis by Li et al suggests that the jury is still not out for the heart failure safety of DPP4-i based on the duration of the trials and the inconclusive evidence from observational studies. However, the totality of observational data supports the safety of incretin-based therapies in patients with heart failure.8

DPP4-i have however, proven reno-protective effects. Using albuminuria and glomerular filtration rate (GFR) as indicators, a recent study showed that mean Urine Albumin-to-Creatinine Ratio (UACR) in the entire study population decreased to approximately 45mg/g 1 year after DPP4-i treatment, while it was increased approximately 39 mg/g 1 year before DPP4-i treatment (p < 0.05). Patients with macroalbuminuria showed a significant reduction in albumin levels after DPP4-i treatment (p < 0.05); however, patients with microalbuminuria and normoalbuminuria did not show improvements in albuminuria levels after treatment. Although eGFR was not changed 1 year after DPP-4i treatment, reductions in eGFR were slowed in patients with microalbuminuria and reversed in the macroalbuminuria or normoalbuminuria groups, 4 years after treatment. These results suggest that administration of DPP4-i reduces urine albumin excretion and mitigates reduction of eGFR in T2DM patients.9

Overall DPP4-i are cardiovascular safe with a little trend towards an increase in hospitalization due to heart failure with saxagliptine and alogliptine, and not with sitagliptine. With linagliptine the CVOT (Carolina) is ongoing, would be completed by 2019. As far as renoprotection is concerned, DPP4-i result in decrease in albuminuria, although an ongoing dedicated trial CARMELINA with linagliptine might give the final answer.

GLP-1 RECEPTOR AGONISTSThe clinical CV effects of native GLP-1 and GLP-1 receptor agonists have been extensively studied. Patients undergoing coronary angioplasty following an acute myocardial infarction (MI) showed improvements in LV ejection fraction and myocardial wall motion with a 72-hour infusion of GLP-1.10 Additional improvements in LV function, oxygen consumption, and 6-min walk distance times were seen following a five-week infusion of GLP-1 in 12 patients (8 with type 2 diabetes) with New York Heart Association (NYHA) class III/IV heart failure.11

On administration of a 6 hour infusion of exenatide or placebo to 172 patients undergoing percutaneous coronary intervention for an ST-elevation myocardial infarction, the primary endpoint of myocardial salvage index assessed using cardiac magnetic resonance imaging, was significantly increased (p=0.003), and the infarct size relative to the myocardial area at risk was reduced (p=0.003), although this did not translate into improved LV function (p=0.82) or 30-days cardiac death (p=0.91). A greater reduction in infarct size was seen in patients who had shorter door-to-balloon time.12

Reductions in blood pressure of patients with type 2 diabetes or obesity have also been seen with GLP-1 receptor agonist use. A meta-analysis of randomized controlled trials has shown that GLP-1 receptor agonists reduces systolic and diastolic blood pressure by 5.2 mmHg (p<0.00001) and 5.9 mm Hg (p <0.00001), respectively, compared with placebo. These blood-pressure-lowering effects appear to be independent of glycemic or body-weight changes.13

Furthermore, current evidence shows that these drugs exert a protective role in diabetic nephropathy with mechanisms that many times are independent of their glucose-lowering effect. GLP-1 receptor agonists have also been shown to influence water and electrolyte balance. Although most of these effects have been demonstrated in culture or animal models and their mechanism of action need to be better elucidated, they may represent new

ways to improve or even prevent diabetic nephropathy.14

The ongoing and completed cardiovascular outcome trials (CVOT) include ELIXA with lixisenatide, EXSCEL (Exenatide Study of Cardiovascular Event Lowering) with exenatide once weekly), FREEDOM-CVO (exenatide via ITCA 650 miniature osmotic pump), HARMONY Outcomes with albiglutide, LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results) with liraglutide), REWIND (Researching Cardiovascular Events With a Weekly INcretin in Diabetes) an ongoing trial with dulaglutide,and SUSTAIN-6 with semaglutide.15

A meta -analysis of the four trials, ELIXA (lixisenatide), LEADER (liraglutide), SUSTAIN 6 (semaglutide), and EXSCEL (extended-release exenatide) showed that GLP-1 receptor agonist treatment showed a significant 10% relative risk reduction in the three-point major adverse cardiovascular event primary outcome (cardiovascular mortality, non-fatal myocardial infarction, and non-fatal stroke; HR 0·90, 95% CI 0·82-0·99; p=0·033), a 13% RRR in cardiovascular mortality (0·87, 0·79-0·96; p=0·007), and a 12% relative risk reduction in all-cause mortality (0·88, 0·81-0·95; p=0·002), with low-to-moderate between-trial statistical heterogeneity, compared with placebo. No significant effect of GLP-1 receptor agonists was identified as fatal and non-fatal myocardial infarction, fatal and non-fatal stroke, hospital admission for unstable angina, or hospital admission for heart failure. Overall, no significant differences were seen in severe hypoglycaemia, pancreatitis, pancreatic cancer, or medullary thyroid cancer reported between GLP-1 receptor agonist treatment and placebo.

These findings show cardiovascular safety across all GLP-1 receptor agonist cardiovascular outcome trials and suggest that drugs in this class can reduce three-point major adverse cardiovascular events, cardiovascular mortality, and all-cause mortality risk, albeit to varying degrees for individual drugs, without significant

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safety concerns. GLP-1 receptor agonists have a favourable risk-benefit balance overall, which should allow the choice of drug to be individualized to each patient’s needs.16 LEADER trial also showed reduction in albuminuria.

SGLT-2 inhibitorsSodium glucose co-transporter 2 (SGLT2) inhibitors are the newest class of drugs approved for the treatment of T2DM, in use since 2013. Empagliflozin, Canagliflozin, and Dapagliflozin are currently approved for use by the US FDA. By decreasing renal glucose absorption, SGLT2 inhibitors lead to increased urinary glucose excretion resulting in a lower blood glucose level and thereby a reduction of glycated hemoglobin (HbA1c).17

In addition to improving glycemic control, SGLT2 inhibitors improve other potential cardiovascular risk factors, including blood pressure, body weight, visceral adiposity, hyperinsulinemia, albuminuria, serum uric acid, and oxidative stress. Further mechanisms for improving cardiac outcomes include osmotic diuresis and natriuresis, a direct cardiac or vascular effect (such as improved arterial stiffness), shifts in metabolism away from fat and glucose oxidation towards potentially more efficient energy sources such as ketones (super fuel) and modulation of glucagon release.18-20

A meta-analysis of 25 smaller trials comparing canagliflozin and dapagliflozin to placebo or an active comparator (17,181 patients with 283 events) included only 4 cardiovascular events and reported a HR of 0.89 (95% CI 0.70, 1.14) in favor of canagliflozin and dapagliflozin.21

Substantial data on SGLT2 inhibitors and cardiovascular safety, however, came from the Empagliflozin Cardiovascular Outcome Event Trial (EMPA-REG OUTCOME). This study randomized 7020 patients with T2DM and established cardiovascular disease (history of myocardial infarction (MI): 47%, multivessel disease: 47%, coronary artery bypass grafting: 25%) to one of three groups: empagliflozin

10 mg, empaglifozin 25 mg, or placebo. The primary outcome was a composite of death from cardiovascular causes, nonfatal MI, and nonfatal stroke. After a median 3.1 years of follow up, the primary endpoint occurred in 490 of 4687 patients (10.5%) in the empagliflozin groups and in 282 of 2333 patients (12.1%) in the placebo group. The hazard ratio for the pooled empagliflozin groups relative to placebo was 0.86 (95% CI 0.74–0.99, p=0.04). Patients on empagliflozin had a relative risk reduction of 38% for cardiovascular mortality (3.7% in the pooled empagliflozin group vs. 5.9% in the placebo group), and 32% for all-cause mortality (5.7% and 8.3%, respectively). Heart failure hospitalizations were significantly decreased (2.7% and 4.1%, respectively; 35% relative risk reduction).22

Using the Health ABC HF Risk Score, patients were categorized into low-to-average (<10%), high (10-20%), and very high (≥20%) risk for incident HF over 5 years. The incidence of HF per 100 patient-years for empagliflozin vs. placebo: low to average risk (1.2% vs. 1.68%), high (2.07% vs. 4.03%), and very high (3.8% vs. 7.0%).23

Cherney et al published the results of the EMPA-REG OUTCOME concerning the albuminuria levels.24 Of 7020 patients treated, 2250 patients had prevalent kidney disease at baseline, of whom 67% had a diagnosis of type 2 diabetes mellitus for >10 years, 58% were receiving insulin, and 84% were taking angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. In patients with prevalent kidney disease at baseline.25 In this study, at baseline urinary albumin-to-creatinine ratio (UACR) data for 6953 patients was available, 4171 (59% of treated patients; 1382 assigned to placebo and 2789 assigned to empagliflozin) had normoalbuminuria, 2013 (29%; 675 assigned to placebo and 1338 assigned to empagliflozin) had microalbuminuria, and 769 (11%; 260 assigned to placebo and 509 assigned to empagliflozin) had macroalbuminuria. Median treatment duration was 2·6 years (IQR 2·0-3·4; 136 weeks) and median observation time was

3·1 years (2·2-3·6; 164 weeks). After short-term treatment at week

12, the placebo-adjusted geometric mean ratio of UACR change from baseline with empagliflozin was -7% (95% CI -12 to -2; p=0·013) in patients with normoalbuminuria, -25% (-31 to -19; p<0·0001) in patients with microalbuminuria, and -32% (-41 to -23; p<0·0001) in patients with macroalbuminuria. The reductions in UACR were maintained with empagliflozin in all three groups compared with placebo during long-term treatment when measured at 164 weeks. At follow-up, after cessation of treatment for a median of 34 or 35 days, UACR was lower in the empagliflozin versus placebo group in those with baseline microalbuminuria (placebo-corrected adjusted geometric mean ratio of relative change from baseline with empagliflozin: -22%, 95% CI -32 to -11; p=0·0003) or macroalbuminuria (-29%, -44 to -10; p=0·0048), but not for patients with baseline normoalbuminuria (1%, -8 to 10; p=0·8911).

Patients treated with empagliflozin were more likely to experience a sustained improvement from microalbuminuria to normoalbuminuria (hazard ratio [HR] 1·43, 95% CI 1·22 to 1·67; p<0·0001) or from macroalbuminuria to microalbuminuria or normoalbuminuria (HR 1·82, 1·40 to 2·37; p<0·0001), and less likely to experience a sustained deterioration from normoalbuminuria to microalbuminuria or macroalbuminuria (HR 0·84, 0·74 to 0·95; p=0·0077). The proportions of patients with any adverse events, serious adverse events, and adverse events leading to discontinuation increased with worsening UACR status at baseline but were similar between treatment groups.

These results supported short-term and long-term benefits of empagliflozin on urinary albumin excretion, irrespective of patients’ albuminuria status at baseline.

The two other major compounds in the SGLT2 inhibitor class, canagliflozin and dapagliflozin, have also demonstrated this potential. The CANVAS Program (Canagliflozin Cardiovascular Assess-ment Study) enrolled 10,142 participants


with type 2 diabetes mellitus and high cardiovascular risk. Participants were randomly assigned to canagliflozin or placebo and followed for a mean of 188 weeks. The primary endpoint for these analyses was adjudicated cardiovascular death or hospitalized heart failure. Participants with a history of heart failure at baseline (14.4%) were more frequently women, white, and hypertensive and had a history of prior cardiovascular disease (all P<0.001). Greater proportions of these patients were using therapies such as blockers of the renin angiotensin aldosterone system, diuretics, and β-blockers at baseline (all P<0.001). Overall, cardiovascular death or hospitalized heart failure was reduced in those treated with canagliflozin compared with placebo (16.3 versus 20.8 per 1000 patient-years; hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.67-0.91), as was fatal or hospitalized heart failure (HR, 0.70; 95% CI, 0.55-0.89) and hospitalized heart failure alone (HR, 0.67; 95% CI, 0.52-0.87). The benefit on cardiovascular death or hospitalized heart failure may be greater in patients with a prior history of heart failure (HR, 0.61; 95% CI, 0.46-0.80) compared with those without heart failure at baseline (HR, 0.87; 95% CI, 0.72-1.06; P interaction =0.021). The effects of canagliflozin compared with placebo on other cardiovascular outcomes and key safety outcomes were similar in participants with and without heart failure at baseline (all interaction P values >0.130), except for a possibly reduced absolute rate of events attributable to osmotic diuresis among those with a prior history of heart failure (P=0.03).26 Canagliflozin was recently found to lower albuminuria and delay progression of albuminuria (class shift) in the CANVAS program,27 as a secondary outcome. Dapagliflozin has demonstrated similar potential in pooled meta-analyses of trials as well as in a study in patients with type 2 diabetes and renal impairment.

A recent review has concluded that SGLT-2 inhibitors have clinically meaningful benefits in diabetic patients in relevance to chronic kidney disease.28

CONCLUSIONSWorldwide Diabetes is a major cause of morbidity, simultaneously causing cardiovascular and renal dysfunction. Consequently, cardiorenal syndrome (CRS) is a complication that is closely related to diabetes and is associated with increased mortality, growing complications, and increased cost of care. Cardiorenal syndrome can be defined as a bidirectional pathological impairment of either the heart or the kidney due to acute or chronic primary dysfunction in either organ.

Newer antidiabetic agents namely DPP4i, GLP1RA and SGLT2 i have been assessed for their cardio-renal protective effects. As new data emerges, it appears, that these agents will offer protective benefits, beyond that of glycemic control.

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17. Hattersley A, Thorens B. Type 2 Diabetes, SGLT2 Inhibitors, and Glucose Secretion. N Engl J Med. 2015;373:974–97.

18. Brunton S. The potential role of sodium glucose co-transporter 2 inhibitors in the early treatment of type 2 diabetes mellitus. Int J Clin Pract. 2015;69(10):1071–87.

19. Inzucchi S, Zinman B, Wanner C, et al. SGLT-2 Inhibitors and cardiovascular risk: proposed pathways and review of ongoing outcome trials. Diab Vasc Dis Res. 2015;12(2):90–100.

20. Ceriello A, Genovese S, Mannucci E, Gronda E. Understanding EMPA-REG OUTCOME. The Lancet Diabetes & Endocrinology. 2015;3(12):929–30.

21. Vasilakou D, Karagiannis T, Athanasiadou E, et al. Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med. 2013;159(4):262–74.

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Functional Assessment of Coronary Artery Disease Beyond Coronary Angiography

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NEERAJ BHALLA, AMIT GOELKeywords z coronary atherosclerosis z individualized assessment z noninvasive imaging z coronary flow reserve z chemogram

Dr. Neeraj Bhalla, Director & Senior Consultant, & Dr. Amit Goel is Associate Consultant Interventional Cardiologist, Department of Cardiology, BLK Super Speciality Hospital Pusa Road, New Delhi

AbstractCoronary atherosclerosis and the precipitation of acute myocardial infarction are highly complex processes, which make accurate risk prediction challenging. Rapid developments in invasive and non-invasive imaging technologies now provide us the detailed and exquisite images of the coronary vasculature. These modalities include sophisticated assessments of luminal stenoses and myocardial perfusion, complemented by novel measures of the atherosclerotic plaque burden, adverse plaque characteristics and disease activity. Together, they can provide comprehensive, individualized assessment of coronary atherosclerosis as it occurs in patients. Not only can this information provide important pathological insights, but it can also potentially be used to guide treatment decisions. We describe the latest advances in both established and emerging imaging techniques, focussing on the strength and weakness of each approach and how these technological advances will translate into definite improvement in clinical risk prediction and patient outcome.

Cardiovascular risk scores based on traditional risk factors are widely employed to assess the burden of underlying atherosclerotic disease, but they remain imprecise in estimating the risk of myocardial infarction on an individual basis. Established imaging techniques identify patients with angina who might drive symptomatic benefit from revascularization. Invasive coronary imaging relies on gaining access to the arterial system and administering contrast media and specifically designed catheters

into the coronary vessels. Advances in catheter design and technology now allow for an array of additional invasive approaches, beyond the standard assessments of luminal stenosis. For example, coronary physiology can be routinely assessed using fractional flow reserve (FFR), whereas coronary plaque imaging has become possible using intravascular ultrasonography (IVUS), and, more recently, optical coherence tomography (OCT), near-infrared spectroscopy (NIRF). Noninvasive


imaging has undergone similar developments. In assessing physiology, quantification of myocardial blood flow has become possible, and detailed coronary plaque imaging is now feasible through developments in computed tomography (CT), cardiovascular magnetic resonance imaging (MRI) and positron emission tomography (PET). In particular, we can directly evaluate and visualize the functional severity of individual luminal stenoses, the overall plaque burden, high-risk plaque characteristics, and even disease activity as atherosclerosis proceeds in patients. Non-invasive imaging, however, is still dependent on equipment, patient co-operation and operator expertise and expensive and is still not as precise as to allow therapeutic decisions to be routinely made.

PATHOLOGYCoronary atherosclerosis is an almost invariable pathological finding from middle age onward. It is characterized by lipid deposition and modification within the vessel wall and is frequently accompanied by inflammation and vascular matrix remodeling within discrete coronary plaques.1 These lesions can result in progressive obstruction of the coronary vascular lumen, causing symptoms of angina owing to myocardial ischemia. Sudden plaque rupture or erosion can precipitate coronary thrombosis and acute myocardial infarction.2

Ruptured culprit plaques frequently have specific histopathological characteristics, typified by the so-called thin-cap fibroatheroma (TCFA). These features include extensive inflammation, a large necrotic core, a thin fibrous cap, positive remodeling with a large plaque volume and microcalcification. In inflamed lesions, this cap becomes thinned and weakened by the action of matrix metalloproteinases, predisposing it to rupture at sites of increased mechanical stress.3 The consequent exposure of the necrotic core to the circulating blood can lead to extensive and occlusive thrombus formation causing myocardial infarction.

STENOSIS, OBSTRUCTION, AND ISCHAEMIATo date, imaging assessment of coronary artery disease has largely been aimed towards detecting luminal stenosis and downstream myocardial ischaemia. These assessments are widely used to estimate patient risk and to guide revascularisation. Indeed, a large body of outcome data supports this approach, demonstrating that a greater number of obstructive lesions and a larger myocardial ischaemic burden are both associated with a worse prognosis.4,5 This approach is however, not so accurate to predict myocardial infarction.

INVASIVE CORONARY ANGIOGRAPHYInvasive coronary angiography has been the gold standard for many decades to diagnose coronary artery disease (CAD), involves the intracoronary administration of radio-opaque contrast to opacify the lumen and delineate any existing stenoses. The presence of luminal stenoses in one, two or three vessels is associated with a step-wise increase in adverse outcome.6,7 However, the visual assessment of luminal stenosis correlates poorly with haemodynamic significance, particularly for coronary stenosis between 30% and 70%, so-called intermediate lesions, also eccentric stenosis, ostial stenosis and left main lesions.8 Therefore, the haemodynamic significance of lesions can be substantially undersestimated or oversestimated by assessment of coronary stenosis alone, particularly in the setting of multiple or eccentric stenoses. These deficiencies have prompted the increasing use of invasive physiological assessment.

Pressure-wire derived FFR, is defined as a ratio of the distal and proximal coronary pressure (Pd/Pa) during stable hyperemia averaged over 3-5 complete cardiac cycles.8,9,10 Hyperemic agents such as adenosine, papaverine, ATP, or regadenoson are used to reduce resistance and increase coronary flow, thereby magnifying a trans-stenotic pressure gradient that is often present at rest.12 Conceptually, a vessel with FFR of 0.80 has 80% of the blood flow it should have if the stenosis was absent.

FFR value over 0.80 has over 90% sensitivity of excluding ischemia. The FAME and FAME II studies both used a 0.80 threshold to ensure potentially ischemic stenoses were not missed.8,10 FFR is measured using pressure-tipped guidewire (pressure wire), positioned distal to the coronary stenosis under fluoroscopic guidance.9 The use of FFR measurement to guide revascularization decisions seems to improve outcome after intervention compared with standard visual estimations of stenosis and has therefore been widely adopted worldwide.8

Instantaneous wave-free ratio (iFR), is a resting index of stenosis severity that quantifies the impact a stenosis upon the coronary circulation.12 It is measured during the wave-free period in diastole, which is a period where the conflicting forces that control blood flow are quiescent, and microcirculatory resistance is at its lowest compared to whole cardiac cycle and does not need an exogenous vasodilator. iFR is calculated in the same manner as FFR with high fidelity pressure wires that are passed distal to the coronary stenosis13 iFR values below 0.9 is suggestive of flow restriction (normal value is 1.0). iFR has been compared with FFR in a number of studies, notably the ADVISE family of studies14,15 DEFINE-FLAIR and the iFR-Swedeheart studies will compare clinical outcomes when patients undergo revascularization based upon either iFR or FFR.

Coronary flow reserve (CFR) is an alternative haemodynamic assessment, which is defined as the ratio of steady state maximal hyperemic flow to resting flow in a given artery.15 This approach assesses the combined effects of epicardial stenosis and microvascular disease. CFR <0.2 strongly correlates with ischemia in the subtended territory. CFR is calculated using either Doppler flow velocity or thermodilution. In the absence of epicardial stenosis, CFR is a measure of microcirculatory reserve. CFR cannot estimate the relative contribution of microvascular dysfunction and epicardial stenos because it inherently combines both. CFR has undergone less clinical validation and is less commonly performed than FFR.

REVIEW ARTICLE


PLAQUE BURDEN Simple measures of the atherosclerotic plaque burden can be used as screening tools for the presence and extent of atherosclerosis in a particular patient. Moreover, they provide powerful prognostic information, presumably on the basis that the more plaque a patient has, the greater the likelihood that one will rupture or erode and cause an event. Such measures are possible using either invasive or noninvasive technology.

INTRAVASCULAR ULTRASONOGRAPHY (IVUS)Coronary angiography depicts the coronary anatomy as a longitudinal silhouette of the lumen and significantly underestimates the presence, severity and extent of atherosclerosis. Conversely, IVUS with its tomographic perspective directly images the lumen, atheroma and the vessel wall and routinely shows significant atherosclerosis in angiographically ‘normal’ segments in patients undergoing PCI.17 IVUS involves a miniaturized ultrasound transducer to record the reflection of a high-frequency sound waves, generating greyscale cross-sectional images of the arterial wall. This process provides accurate assessment of luminal dimensions and plaque volume that can aid in the evaluation of luminal stenoses, particularly in the left main coronary artery.18 In addition IVUS can provide accurate quantification of plaque burden, acting as a powerful predictor of disease progression and adverse clinical outcomes.19,20 Indeed, this features has been widely used in trials to measures the effect of medical therapies on atherosclerosis.21

ADVERSE PLAQUE CHARACTERISTICSHistopathological postmortem studies have consistently shown that majority of culprit plaques responsible for plaque rupture and myocardial infarction have particular pathological characteristics, such as a thin fibrous cap, inflammation, a large necrotic core, intraplaque haemorrhage and microcalcification. This understanding has prompted extensive clinical research in these so

called vulnerable plaques, using each of these adverse characteristics as a potential imaging target. In patients with acute coronary syndromes, culprit lesions more frequently exhibit positive remodeling and a large plaque area; conversely, patients with a stable clinical presentation more frequently show negative remodeling and a smaller plaque area.22 Echolucent plaques are also more common in unstable than in stable lesions. Typical IVUS features of acute myocardial infarction include plaque rupture, thrombus, positive remodeling, attenuated plaque, spotty calcification and thin-cap fibroatheroma.23 Attenuated plaque is defined as hypoechoic or mixed atheroma with deep ultrasound attenuation without calcification or very dense fibrous plaque. Plaque ruptures and attenuated plaques are considered to be unstable and have been identified in both culprit and non-culprit lesions of patients with STEMI.24 Histopathologically, the vast majority of attenuated plaques correspond to either a fibroatheroma with a necrotic core or pathologic intimal thickening with a lipid pool; almost all segments with superficial echo attenuation indicated the presence of an fibroatheroma with an advanced necrotic core.25

VIRTUAL HISTOLOGY IVUSVirtual histology (VH)-IVUS is an invasive technique that uses spectral analysis of the ultrasound back scatter signal to categorize plaque constituents into fibrous, fibrolipidic, calcific, and necrotic tissue in real-time. Although VH-IVUS lacks the resolution to image the thin fibrous cap, lesions with necrotic core in contact with the lumen have been termed VH-TCFAs.26 In the PROSPECT study,27 596 VH-TCFs, were identified in 313 out of 623 patients. Around half the lesions that went on to cause coronary events were VH-TCFAs, although the majority of these events were hospitalizations with angina. Importantly, only six patients had subsequent myocardial infarction, with a further 25 having a cardiac arrest or dying from a cardiovascular cause. The vast majority of these VH-TCFAs, therefore, did not result in an event and, although

the positive predictive value improved if the presence of a large plaque volume (>70%) and small luminal area (<4.0 mm2) were also considered. Likewise, in the ATHEROREMO-IVUS study,28 242 patients had TCFAs, but only seven went on to have a myocardial infarction. Nevertheless, these studies point towards a more profound and general limitation when trying to identify individual vulnerable plaques, that ultimately these plaques have a fairly low probability to themselves causing a clinical event.

OPTICAL COHERENCE TOMOGRAPHY (OCT)OCT incorporates an intracoronary fiber-optic wire, which emits light in the near-infrared spectrum (wave length 1,250-1,350 nm) and measures the backscatter from tissues during a rotational pullback along the artery.29 Image acquisition requires the generation of a blood-free field, using small flushes of saline or contrast media.30,31 A particular advantage of OCT is its excellent axial resolution (12-18 um versus 150-200 um for IVUS) which allows detail microstructural analysis of the superficial plaque layers.29 In particular, OCT allows imaging of thrombus, plaque rupture, and superficial plaque erosion with improved sensitivity compared with alternatives modalities.32,33 OCT is also increasingly being used clinically to assess stent deployment and for post-intervention complications.34 Detailed measurement of the fibrous-cap thickness is also possible, providing a means not only of assessing plaque vulnerability, but also monitoring disease progression and plaque stabilization in response to therapy.35 Interestingly, OCT (as well as IVUS) can be used in combination with computational fluid dynamics to assess local patterns of endothelial shear stress, which holds promise in improving the prediction of plaque vulnerability and progression.20,36

NEAR-INFRARED SPECTROSCOPY (NIRS)NIRS relies on the phenomenon that organic molecules absorb and reflect light differently at specific wavelengths. When near-infrared light is emitted into a tissue,


the spectrum of absorbance, therefore, reflects its chemical composition.37,38 This technique can be tuned to detect lipid within atherosclerotic plaque creating a ‘chemogram’ that can be used to identify lipid-rich lesions and quantify the lipid core burden index (LCBI).38-

41 Combined NIRS and IVUS imaging catheters have been used to measure both the plaque burden and the LCBI, demonstrating improved accuracy in the detection of fibroatheroma.42 In a small cohort of patients presenting with ST-segment elevation myocardial infarction, NIRS-IVUS imaging showed that LCBI could be used to differentiate between acute culprit and nonculprit plaques.43 Currently, this modality remains a research tool, although the capacity of hybrid NIRS-IVUS imaging to identify lipid-rich plaque and to improve cardiovascular risk prediction is currently under investigation.44

CONCLUSIONAdvances in cardiac imaging now allow coronary atheroma to be visualized directly using both invasive and noninvasive strategies. Imaging modalities can provide detailed and complementary information concerning disease burden,

luminal stenoses, myocardial ischemia, adverse plaque characteristics and disease activity. This information has greatly improved our understanding of the disease but considerable work remains to translate this information into accurate risk prediction tools and improved clinical care and outcomes for patients with coronary artery disease.

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14. Petraco R, Escande J, Sen S et al. Classification performance of instantaneous wave free ratio (iFR) and FFR in a clinical population of intermediate coronary stenoses: results of ADVISE registry. Eurointervention 2013;9, 91-101.

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16. Miller DD, Donohue TJ, Younis LT et al. Correlation of pharmalogical 99mTc-sestamibi myocardial perfusion imaging with poststenotic coronary flow reserve in patients with angiographically intermediate coronary artery stenos is. Circulation 1994;89:2150-2160.

17. Mintz GS, Painter JA, Pichard Ad et al. Atherosclerosis in angiographically normal coronary artery reference segments: an IVUS study with clinical correlations. JACC 1995;25:1479-1485.

Table 1. Current and Emerging Invasive and Noninvasive Imaging Techniques

Invasive / Imaging modality Current or potential value Current limitation or future challenges

Noninvasive

In Clinical Use

Invasive Coronary angiography, Well established assessment of Lumenogram: does not image plaque

FFR luminal stenosis,

FFR improves identification of

haemodynamic obstructions

IVUS, VH-IVUS Provides assessment of plaque Lacks resolution to image fibrous cap

burden and identification of and so might overestimate thin-cap

vulnerable plaque characteristics fibroatheroma, can be used to assess disease

only in the absence of critical stenoses

OCT Excellent axial resolution enables Poor depth penetration limits assessment of

assessment of superficial plaque deep plaque volume, lacks outcome data

features including thrombus, erosion

and stent position

Emerging Technology

Invasive NIRS-IVUS Quantification of plaque liquid burden Prospective outcome data awaited

Investigative Techniques

Invasive NIRF Invasive assessment of coronary disease Require development and clinical

activity, high spatial resolution approval of molecular tracers and catheters

REVIEW ARTICLE


18. Hermiller J B et al. Unrecongnized left main coronary artery disease in patients undergoing interventional procedures. Am J Cardiol. 1993;71:173-176.

19. Nicholls S J et al. Intravascular ultrasound derived measures of coronary atherosclerotic plaque burden and clinical outcome. JACC 2010;55:2399-2407.

20. Stone P H et al. Prediction of progression of coronary artery disease and clinical outcomes using vascular profiling of endothelial shear stress and arterial plaque characteristics: the PREDICTION study. Circulation 2012;126:172-181.

21. Nissen S E et al. Effect of intensive compared with moderate lipid lipid lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA 2004;291:1071-1080.

22. Schoenhagen P, Zaida KM et al. Extent and direction of arterial remodeling in stable versus unstable coronary syndromes: an intravascular ultrasound study. Circulation 2000;101:598-603.

23. Hasegawa T, Ehara S et al. Acute myocardial infarction: clinical characteristics and plaque morphology between expansive remodeling and constrictive remodeling by intravascular ultrasound. Am Heart J 2006;151:332-337.

24. Souza C F, Doi H, Mintz GS et al. Morphological changes and clinical impact of unstable plaques within untreated segments of acute myocardial infarction patients during a 3 year follow up: an analysis from the HORIZONS-AMI trial. Coron Artery Dis 2015;26:469-475.

25. Pu J, Mintz GS, Biro s et al. Insights into echo-attenuated plaques, echolucent plaques and plaques with spotty calcifications: novel findings from comparisons among intravascular ultrasound, near-infrared spectroscopy and pathological histology in 2,294 human coronary artery segments. JACC 2014;63:2220-2233.

26. Obaid D R et al. Atherosclerotic plaque composition and classification identified by coronary computed tomography. Circ. Cardiovasc. Imaging 2013;6:655-664.

27. Stone G W et al. A prospective natural history study of coronary atherosclerosis. NEJM 2011;364:226-235.

28. Cheng J M et al. In vivo detection of high risk coronary plaque by radiofrequency intravascular ultrasound and cardiovascular outcome: results of ATHEROREMO-IVUS study. Eur Heart J 2014;35:639-647.

29. Bezerra HG, Costa MA et al. Intracoronary optical coherence tomography:a comprehensive review of clinical and research applications. JACC Cardiovasc. Interv 2009;2:1035-1046.

30. Suter M J et al. Intravascular optical imaging technology for investigating the coronary artery. JACC Cardiovasc. Imaging 2011;4:1022-1039.

31. Tearney G J et al. Consensus standards for acquisition, measurements and reporting of intravascular optical coherence tomography studies: a report from International Working group for intravascular OCT standardization and validation. JACC 2012;59:1058-1072.

32. Kubo T et al. Assessment of culprit lesion morphology in acute myocardial infarction:ability of OCT compared with intravascular ultrasound and coronary angioscopy. JACC 2007;50:933-939.

33. Prati F et al. OCT based diagnosis and management of STEMI associated with intact fibrous cap. JACC Cardiovasc. Imaging 2013;6:283-287.

34. Kim B K et al. OCT based evaluation of malapposed strut coverage after DES implantation. Int. J. Cardiovasc. Imaging 2012;23:1887-1894.

35. Hattori K et al. Impact of statin therapy on plaque characteristic as assessed by serial OCT, grayscale and

integrated backscatter IVUS. JACC Cardiovasc. Imaging

2012;5:169-177.

36. Vergallo R et al. Endothelial shear stress and coronary

plaque characteristics in humans:combined frequency

domain OCT and computational fluid dynamics study.

Circ. Cardiovasc. Imaging 2014;7:905-911.

37. Caplan JD et al. Near-infrared spectroscopy for

detection of vulnerable coronary artery plaques. JACC

2006;47:C92-96.

38. Waxman S, Caplan JD, Rationale and use of near-infrared

spectroscopy for detection of lipid rich and vulnerable

plaques. J. Nucl> Cardiol 2007;14:719-728.

39. Waxman S et al. In vivo validation of a catheter based

near infrared spectroscopy system for detection of lipid

core coronary plaques:initial results of the SPECTACL

study. JACC Cardiovasc. Imaging 2009;2:858-868.

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based near infrared spectroscopy system. JACC

Cardiovasc. Imaging 2008;1:638-648.

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intravasculat ultrasound assessment of vulnerable

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2423-2431.

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43. US National Library of Science. ClinicalTrials.gov 2016.


Prominent (Tall) T waves

ECG OF THE MONTH

SR MITTAL

AbstractT wave amplitude >0.5mv in limb leads and > 1.0mv in precordial leads is considered as “tall.” Vagotonia and early repolarization alone can also produce prominent T wave in leads V5 and V6. Prominent T waves of acute subendocardial ischemia are usually accompanied by prolongation of QT interval. In the hyperacute phase of myocardial infarction, prominent T waves are accompanied by elevation of ST segment. True posterior wall myocardial infarction produces prominent R wave with prominent T wave in leads V1 and V2 as a reciprocal change of prominent Q wave and negative T waves in posterior leads. Recovering inferior infarction produces prominent T wave in leads I and aVL as a reciprocal change. Left bundle branch block produces prominent T wave in leads V1 to V3. Chronic severe aortic regurgitation produces prominent T wave with tall R waves in leads V5 and V6. Moderate left ventricular hypertrophy due to systemic hypertension can produce prominent T waves in leads V1 and V2. Prominent T waves of acute pericarditis are associated with diffuse elevation of ST segment and depression of PR segment. Prominent ‘T’ waves with QT prolongation and bradycardia are seen in cerebro-vascular accident and following Stokes- Adam’s attacks. Hyperkalemia produces tall, narrow and peaked T waves.

Keywords z cerebro-vascular accident z electrocardiography z hyperkalemia z ischemic heart disease z t-wave

PROMINENT (TALL) T WAVEST wave amplitude > 0.5mv in limb leads and > 1.0mv in precordial leads is con-sidered as “tall”.1 T wave taller than the accompanying R wave is also considered abnormal except in leads V1 and V2.

CAUSES OF PROMINENT T WAVE(1) Vagotonia It can produce tall symmetrical T

waves with minimally elevated ST segment particularly in leads V4 to V6. There is relative bradycardia.

Dr. SR Mittal is Head, Department of Cardiology at Mittal Hospital and Research Centre, Ajmer, Rajasthan

(2) Early repolarization (Figure 1) Prominent T waves are accompanied

by J point elevation. (3) Ischemic heart disease (a) Acute subendocardial ischemia

(Figure 2) Prominent T wave is usually accom-

panied by lengthening of QT interval. (b) The hyperacute phase of myocardial

infarction (Figure 3 & 4) There is the concomitant elevation of

ST segment in the affected leads.


(c) True posterior wall myocardial in-farction (Figure 5)

Prominent T waves are seen in leads V1 & V2. These are a reciprocal change of T wave inversion in leads V7 to V9. R waves are also prominent in leads V1 and V2 as a reciprocal change of prominent Q wave in leads V7 to V9.

(d) Recovering inferior infarction Negative T waves in inferior leads

produce reciprocal tall positive and symmetrical T waves in leads I and aVL2. Prominent T waves in leads V1 to V3 suggest concomitant posterior infarction (Figure 6).

(e) High lateral infarction It can produce reciprocal prominent

T wave in inferior leads (Figure 7). (4) Left bundle branch block (Figure 8) Tall T waves are present in leads V1 to

V3. These are associated with deep and broad S waves in these leads. Leads V5 to V9 show broad and notched R waves with inverted T waves.

(5) Moderate LVH with chronic diastolic overload, e.g. chronic severe aortic re-gurgitation (Figure 9).

Tall T waves are associated with tall R waves in leads V5 and V6.

(6) Moderate LVH with chronic pressure

overload, e.g., systemic hypertension (Figure 10) T wave is prominent in leads V1 and V2.

(7) Acute pericarditis (Figure 11) Prominent T waves are associated

with diffuse elevation of ST segment in most of the leads (except leads aVR and V1). There are no reciprocal ST changes. PR segment depression in

leads II, V5 and V6 and elevation in lead aVR support the diagnosis of pericarditis.

(8) Post stokes- adam’s attack T waves are prominent and broad

with prolongation of QT interval. There is high degree A-V block.

(9) Non cardiac causes

Figure 1. Electrocardiogram from a case of early repolarization showing J point elevation (single arrow) and prominent T waves (double arrows).

Figure 3a. Electrocardiogram during hyperacute phase of anterior infarction showing prominent T wave in leads V2 to V5 (arrows).b. Electrocardiogram recorded after 24hrs showing evolved anterior infarction.

Figure 4a. Electrocardiogram during hyperacute phase of anterior infarction showing prominent T waves in leads V1 to V4 (arrows).b. Electrocardiogram recorded after 24hrs showing evolved anterior infarction.

Figure 2. Electrocardiogram from a case of acute subendocardial ischemia showing promi-nent T waves (arrows) with prolongation of QT interval.

Figure 5. Electrocardiogram showing infero-posterior infarction with reciprocal prominent T wave in leads V1 to V4 (arrows).


ECG OF THE MONTH

Figure 6. Electrocardiogram showing re-covering inferior infarction with promi-nent T waves in leads V2 to V4(arrows).

Figure 7. Electrocardiogram showing high lateral infarction (lead aVL) with promi-nent T waves in leads II, III, aVF(arrows).

Figure 8. Electrocardiogram showing left bundle branch block with prominent T waves in leads V1 to V5 (arrows).

Figure 9. Electrocardiogram from a case of chronic severe aortic regurgitation showing tall R wave in leads V3 to V6 and prominent T wave in leads V1 to V3 & V6 (arrows).

Figure 10. Electrocardiogram from a case of chronic systemic hypertension show-ing prominent T waves in leads V2 & V3

(arrows).

Figure 11. Electrocardiogram from a case of acute pericarditis showing diffuse ST segment elevation and depression of P-R segment in leads aVL and V2-V5 (arrows).

Figre 12. Electrocardiogram showing sinus bradycardia with prominent and broad T waves and prolonged QT interval.

Figure 13. Electrocardiogram from a case of hyperkalemia showing tall tented T waves in leads V4 to V6 (arrows).

Figure 14. Electrocardiogram from a case of hyperkalemia showing tall tented T waves in most of the leads (arrows). Rhythm strip of lead V1 shows prolonged P-R interval.

Figure 15. Electrocardiogram (rhythm strip of lead II) from a case of hyperkalemia showing disapporance of P wave and broad QRS fused with T wave.

Figure 16. Electrocardiogram from a case of hyperkalemia showing absence of P wave, broad QRS fusing with T wave and bradycardia.

Figure 17. Electrocardiogram from a case of hyperkalemia showing high degree AV block.


(a) Cerebrovascular accidents (Figure 12)

There is a widening of T wave with prolongation of QT interval. U wave is usually, increased in amplitude. Usually there is bradycardia.

(b) Hyperkalemia Earliest change is narrowing and

peaking (tenting) of T waves (Figure 13, 14). Progressive hyperkalemia results in widening of QRS and de-crease in amplitude of P wave. PR in-terval may prolong (Figure 14). Sub-

sequently, there is a complete loss of P wave with further broadening and merging of QRS and T waves (Figure 15). Sometimes advanced AV block may appear (Figure 16, 17).

REFERENCES1. Wagner GS and Lim TH. Insufficient Blood supply. In

Wagner GS(ed). Marriot’s Practical electrocardiography. Wolters Kluwer, New Delhi; 2001:163-207.

2. de Luna AB, Goldwasser D, Fiol M, Bayes- Genis A. Surface electrocardiography. In Fuster V, Walsh RA, Har-rington RA(eds). Hurst’s The Heart. Mc Graw Hill, New York; 2011:307-70.


PICTORIAL CME

Q1. T wave in limb leads is consid-ered “tall” if amplitude is more than

(A) 0.5mv(B) 1.0mv(C) 1.5mv(D) Amplitude of accompanying R

wave

Q2. T wave in precordial leads is con-sidered tall if amplitude is more than

(A) 1.0mv(B) 1.5mv(C) 2.0mv(D) Amplitude of accompanying R

wave

Q3. Normally T can be taller than R in leads

(A) II, III, aVF (B) V1, V2,V3(C) V5, V6(D) None

Q4. Prominent T waves in lead V5V6 can be seen in

(A) Vagotonia (B) Anxiety (C) Hyperventilation (D) Hypoxia

Q5. In early repolarization syndrome (A) J point is elevated(B) ST segment is depressed(C) T wave is prominent (D) QT interval is prolonged

Q6. Prominent T waves are seen in

MCQs(A) Chronic severe aortic regurgita-

tion (B) Severe aortic stenosis (C) Hyperacute lateral infarction (D) Chronic severe mitral regurgita-

tion

Q12. Acute pericarditis produces (A) Diffuse ST segment elevation (B) Reciprocal ST depression in leads

II, III, aVF(C) P-R segment elevation (D) All Q13. Prominent and broad T waves

with prolonged QT interval are seen in

(A) Cerebrovascular accident (B) Following Stokes Adam’s attack(C) Acute subendocardial ischemia (D) All

Q14. Hyperkalemia produces (A) Tall and pointed T waves(B) Broad T waves(C) QT prolongation (D) All

Q15. Hyperkalemia produces (A) Prolongation of P-R interval (B) Disappearance of P wave (C) A-V block(D) All

Q16. Hyperkalemia produces (A) Widening of QRS (B) Fusion of QRS and T wave(C) Narrowing of QRS(D) Increase in QT interval

(A) Subendocardial ischemia (B) Subendocardial infarction (C) Hyperacute phase of myocardial

infarction (D) Healed myocardial infarction

Q7. Prominent T waves in leads V1 and V2 are seen in

(A) LBBB(B) True posterior infarction (C) Anterior subendocardial infarc-

tion (D) Right ventricular infarction

Q8. Prominent T waves in leads I and aVL are seen in

(A) Recovering inferior infarction (B) Recovering high lateral infarction (C) Postero-lateral infarction (D) Acute anterior infarction

Q9. Healing high lateral infarction can produce prominent T waves in

(A) Leads I and aVL(B) Leads III and aVF(C) Leads V5 and V6(D) Leads V1 to V4

Q10. Moderate left ventricular hyper-trophy due to systemic hyperten-sion can produce prominent T wave in

(A) Leads V1 V2(B) Leads V5 V6 (C) Leads V7 to V9(D) None

Q11. Prominent T waves in leads V5 and V6 can be seen in

Prominent (Tall) T waves

Answers:(1) A,D, (2) A,D, (3) D, (4) A, (5) A,C, (6) A,C (7) A,B, (8)A, (9)B, (10) A,C (11)A, (12) A, (13) D, (14) A, (15) D, (16) A,B.

ECG OF THE MONTH


PICTORIAL CME

MONIKA MAHESHWARI

Dr. Monika Maheshwari is Professor at Jawahar Lal Nehru Medical College, Ajmer, Rajasthan

Interrupted Aortic Arch

Interrupted aortic arch is the absence or discontinuation of a portion of the aortic arch. It is a very rare genetic heart defect affecting 3 per million live births. More than 97% of the cases have associated cardiac anomalies like Ventricular Septal Defect (VSD), Patent Ductus Arteriosus (PDA). There are three types of interrupted aortic arch. In type A interruption occurs just beyond the left subclavian artery, in type B interruption is between the left carotid artery and the left subclavian artery and in type C interruption is between the innominate artery and the left carotid

Figure 1. Aortogram (RAO :1° Cranial : 0° view) showing interrupted aortic arch with developed collaterals.

Figure 2. Aortogram (LAO : 0.1° Cranial: 0° view) showing interrupted aortic arch with pig tail catheter in situ.

artery. Therapeutic plan consists of medical treatment for biventricular failure and prostaglandin E1 (PGE1) infusion to maintain ductal patency, and surgical correction via (1) direct aortic to aortic anastomosis bridging the gap, (2) “turndown” or “turnup” of one of the arch vessels to the aorta across the gap, or (3) bypass of the interruption with graft material.

One such case of interrupted aortic arch encountered by us (Figure 1,2) is picturised herein, who was then referred to higher centre for surgery.

Cardiology TodayCover May-June 2018 - CIMS · Andrew M Tonkin, Bhagwan Koirala, Carlos A Mestres,...

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Transcript of Cardiology TodayCover May-June 2018 - CIMS · Andrew M Tonkin, Bhagwan Koirala, Carlos A Mestres,...