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Cardiology TODAY

VOLUME XXII No. 2MARCH-APRIL 2018

PAGES 37-72

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EDITORIALWalk India Walk: Get your butts off ..... 39OP YADAVA

REVIEW ARTICLECan We Use Information Technology (IT) for Blood Pressure Control in India? 41KAVITA SINGH, DEVRAJ JINDAL, VAMADEVAN S AJAY, DORAIRAJ PRABHAKARAN

REVIEW ARTICLEImproving CV Outcomes in Diabetes with New Antidiabetic Medications: A New Era has Begun 46PC MANORIA, NIDHI MISHRA, PANKAJ MANORIA

REVIEW ARTICLEChallenges in Heart Failure Management 53RAJEEV RATHI

Cardiology Today VOL.XXII NO. 2 MARCH-APRIL 2018 37

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CLINICAL OPINIONHypoglycemia & Cardiovascular Risk 61VINOD K GUJRAL

IMAGEAtrial Septal Aneurysm 68SR MITTAL

ECG OF THE MONTHFlat T wave 71SR MITTAL

PICTORIAL CMEAnomalies of Mitral Valve 72MONIKA MAHESHWARI

38 Cardiology Today VOL.XXII NO. 2 MARCH-APRIL 2018

Cardiology Today VOL. XXII NO. 2 MARCH-APRIL 2018 39

Walk India Walk: Get your butts off …

EDITORIAL

For any guidelines for health to succeed, the recommendations should be such that they are practically implementable and pragmatic. Therefore, with changing times and the priorities of modern lifestyle, as also the whims and fancies of the society as a whole and an individual in specifi c, the guidelines need to be modifi ed and even personalized to an extant. Age old recommendation of walking briskly for 40 minutes has not succeeded. Current business tycoons and young IT enabled technologists are virtually glued to their desks and computers, all their working hours, and can hardly fi nd a 40 minute slot at a stretch. This rather stringent requirement on time evolved into a more user-friendly recommendation of moderate to vigorous activity performed in aliquots of 10 minutes and was endorsed by the American Heart Association/American College of Sport Medicine in 2007. However, these recommendations too fell short. As very succinctly put and challenged by Prof.William E Kraus of the Duke University School of Medicine, ‘That fl ies in the face of public health recommendations, like taking the stairs instead of elevator, and parking farther from your destination. These don’t take 10 minutes, so why were they recommended ?’1

Saint - Maurice et al from Kraus’s group therefore looked at data from 4,840 individuals from the National Health and Nutritional Examination Survey between 2003 and 2006, who were more than 40 years of age.1 They found that even short trips lasting less than ten minutes, for example, walking up and down the stairs, counted towards accumulated exercise time and reduced health risks as well as mortality. However, the caveat here is that the intensity of exercise has to be more than or equal to moderate. Moderate exertion has been defi ned in rather subjective terms as brisk walking at such a pace that it makes it hard to sustain a verbal conversation. Escalating it to a jog would make the exercise vigorous, but this would vary from individual to individual based on the level of physical conditioning. Current guidelines, which are almost a decade old, having been issued in 2008 by US department of health and human services, recommended 150 minutes of moderate exercise or 75 minutes of vigorous activities per week, preferably spread over a minimum of 5 days in a week and ideally all seven days. There is a dose-response relationship of exercise. However, as pointed out by Saint-Maurice et al, the most dramatic improvements in the overall risk of death and disease can occur with a relatively small amount of eff ort and the more you do, the better the benefi ts. In their study, those individuals who got more than 60 minutes per day of moderate or vigorous activity, reduced their mortality by 57% and if the duration was escalated to 100 minutes of moderate or vigorous activity per day, it cut the risk of death by a whopping 76%.1

DR. OP YADAVACEO and Chief Cardiac Surgeon

National Heart Institute,New Delhi

40 Cardiology Today VOL. XXII NO. 2 MARCH-APRIL 2018

‘Bharat’ can not be ‘Aayushman’ till we keep chasing disease. We shall have to spare a thought for preventing disease and not by some arduous techniques or methods, but by simple, practical and cost neutral (infact fi nancially benefi cial) techniques, like just walking and carrying out small events and chores on the two pedes, as often and as frequently as humanly possible. Infact in an another recent study, even light intensity activity, specially in older people, was found to be universally related to all cause mortality.2 This habit of walking has to be cultured and as they say initially ‘Man makes habits’ but subsequently ‘Habits make man’. Once cultured deliberately and willfully, this would become a second nature and may not need any subsequent reinforcement but for the initial phase, one needs to be coaxed and cajoled by the peers.

Its high time that revised guidelines should be issued and all new data should be incorporated and released for public consumption. It doesn’t matter how intensely and how long you are active, more importantly - Just be Active.

REFERENCES:1. Saint-Maurice PF, Troiano RP, Matthews CE, Kraus WE. Moderate-to-vigorous physical activity and all-cause mortality: do

bouts matter? J Am Heart Assoc. 2018;7:e007678. DOI: 10.1161/JAHA.117.007678.2. Jefferis BJ, Parsons TJ, Sartini C et al. Objectively measured physical activity, sedentary behaviour and all-cause mortality in

older men: does volume of activity matter more than pattern of accumulation? Br J Sports Med. 2018. Available at: http://bjsm.bmj.com/content/early/2018/01/19/bjsports-2017-098733.


Can We Use Information Technology (IT) for Blood Pressure Control in India?

REVIEW ARTICLE

KAVITA SINGH, DEVRAJ JINDAL, VAMADEVAN S AJAY, DORAIRAJ PRABHAKARAN

Keywords information technology tools health system high blood pressure m-Power Heart cardiovascular disease virtual classrooms

Dr. Kavita Singh, Dr. Devraj Jindal, Dr. Vamadevan S Ajay, are Consultant & Dr. Dorairaj Prabhakaran is Executive Director, Centre for Chronic Disease Control, New Delhi, India; Public Health Foundation of India, Gurgaon, India; London School of Hygiene and Tropical Medicine, UK

AbstractTelehealthcare management is a widely accepted strategy for improving outcomes of people with noncommunicable diseases (NCDs). For hypertensive patients, home blood pressure (BP) monitoring is particularly effective when linked with telehealth follow-up. Even in low-resource countries, most adults have access to a telephone, and studies in Latin America indicate that nurse telemanagement can improve NCD outcomes. Unfortunately, frequent telehealth education and monitoring by clinicians are labor intensive and rarely available in low-income and middle-income countries (LMICs).mHealth/e-Health based clinical decision-support systems integrated with electronic health records and task-shifting approaches signifi cantly improves blood pressure control, reduces cardio-metabolic risks and improves quality-of-life. Decision-support systems designed and implemented in India were simple and easy to use with low cost features (example: use of generic medicines). These low-cost improved care delivery model can be replicated at primary care centres, and in other low-income settings. Moving forward, we recommend for a three-pronged strategy, fi rst, we need to develop low-cost yet robust health management information systems, which will provide platforms for big data analytics. Second, collaboration with Google and survey of India to develop state of the art maps and updating them frequently particularly about health infrastructure to support surveillance programs and to understand the association between neighborhood built environment and health. Third, information technologies can also be used for creating virtual classrooms (e.g. ECHOES program) and for mass delivery of training programs at low-cost.


INTRODUCTIONCardiovascular disease continues to be the leading cause of death and disability In India and other low-and middle-income countries. High blood pressure contributes to majority of these deaths either through stroke, myocardial infarction, heart failure and other vascular complications.1 Screening, diagnosis, and care for people with hypertension in India, a country of more than 1.2 billion people that accounts for 7% of the world’s population with hypertension (140 million), is suboptimal.2-3 A recent survey suggests that less than 20% of the people with hypertension in India have adequate blood pressure control.2,3 Inadequate and overburdened care providers, fallible infrastructure, non-adherence to the management plan and several other patient, provider and health-system-level barriers further explain the suboptimal blood pressure control4-5 (Figure 1). Treatment of high blood pressure requires lifelong therapy and long-term maintenance of patient records. Also, clinical management guidelines evolve rapidly and given, the insuffi cient national clinical guidelines and wide variation in clinical practice for hypertension in India, there is great potential to bridge these gaps using information technology tools.

TECHNOLOGY AND NON-COMMUNICABLE DISEASESA large number of technological innovations have been successfully used in disease surveillance, data collection, screening/diagnosis and disease management. Few examples of the use of technology in disease surveillance to management include: use of geographic information systems, computerized cardiovascular risk assessment, portable diagnostic equipment (lab on chip,

portable ECG), the use of biomedical sensors that are integrated with global positioning system (GPS) to provide accurate estimation of physical activity and electronic health records - decision support system.

There are several benefi ts of using information technology (IT) in disease surveillance, screening/diagnosis, and management. IT tools enable real time data access, ensure data accuracy (with inbuilt checks), data security (back-up), big data analytics, improves timelines, and is eco-friendly (paper less and re-useable) and allow application of processes in multi-language mode. An example of innovative use of GIS (geographic information system) technology is in mapping clusters of high blood pressure and neighborhood built environment. Figure 2 depicts neighborhood systolic blood pressure (SBP) and road traffi c in Delhi from the CARRS GIS study (unpublished data). It shows that SBP is higher in areas with high traffi c density. While the high BP could be attributed to noise pollution other reasons such as lack of physical activity and unhealthy diet, have to be explored with adjustments for socioeconomic status of the individuals studied.

REVIEW ARTICLE

Figure 1. Barriers to optimal care for high-blood pressure

Figure 2. Neighborhood systolic blood pressure and road traffic in Delhi.


NEED FOR INFORMATION TECHNOLOGY TO MANAGE HIGH BLOOD PRESSURESubstantial evidence shows that meeting blood pressure control (<130/80 mmHg) is associated with sizeable reductions in cardiovascular mortality and morbidity.6-8 Therefore, there is a need to seriously consider practical and simple eff orts at improving healthcare delivery, to reduce hypertension-related deaths and disability in India. Given the gap between high burden of hypertension in India and unprepared health services, there is a need to augment the health system with innovative solutions, such as the use of health information technology. Over the last few years, coverage of information technology and mobile phones have expanded and so has the scope; leading to an amazing adoption of technology in health-sector for management and control of chronic conditions (hypertension, diabetes, depression, cardiovascular diseases) and improving overall quality-of-care. Computerized decision support systems and electronic health records off er delivery of evidence-based management tailored to individual patients. Computerization and automation of reminders is known to improve adherence and eventually help in controlling blood pressure. These systems may also be useful in sending text messages/ prompts for behaviour modifi cation. Such an arrangement sets up a virtual healthcare system which helps overcome the physical and economic constraints of visiting a conventional health facility as chronic conditions require continuous tracking and follow-up. Longitudinal records or electronic health records digitize patient’s health information, allowing monitoring patient-outcomes by diff erent physicians and seamless exchange of information.

Several patients (reminders; education; motivation by non-physician “care coordinators,” provider- (reminders; audit and feedback), and system-focused intervention strategies (structured or team-based care; electronic decision support systems), individually or in combination, have shown promise in improving blood pressure control.

However, long-term impact of electronic decision-support systems in blood pressure control and its consequent eff ect on cardiovascular disease mortality and morbidity needs empirical evaluation.

TECHNOLOGY ENABLED IMPROVED CARE DELIVERY MODELSHigh blood pressure and diabetes are the entry points (shared risk factors) for improving non-communicable disease care. mHealth technology has the potential to not only improve quality and access to care but also standardize care, reduce medical errors, help track patient outcome and aid in task/shifting or task-sharing (shifting of tasks traditionally undertaken by physicians to trained (less-specialized) non-physician health workers.9-10 Low-cost information technology such as mobile/eHealth platforms have been successfully implemented in improving screening, management, and follow-up of individuals with hypertension and diabetes. Below we describe two case studies where mHealth and decision-support electronic health records have been successfully implemented and found to be highly eff ective in managing

high blood pressure and reducing cardiovascular risk at the community health centre level and tertiary care hospitals in India. I. mPower Heart Project in Solan, Himachal Pradesh, India“m-Power Heart” project was carried out in the Solan District, Himachal Pradesh with primary objective of designing a feasible and sustainable evidence-based, decision support-enabled, healthcare delivery model for the management of hypertension and diabetes in the primary healthcare facilities of Himachal Pradesh.11

The specifi c components of the project were:

Setting up of non-communicable disease (NCD) clinic at eight out-patient clinics from fi ve Community Health Centers (CHCs) of Solan District

Quality improvement strategies for care delivery at CHCs through a structured training program for the healthcare team and use of clinical management guidelines

Deployment of laptop/smart-phone

Figure 3.mPower Heart Project Decision-Support System (DSS) model


based decision support system (DSS) at NCD clinics to facilitate evidence based care.

The mPower DSS was used by Nurses at the NCD clinics of CHCs and had the important features like screening for hypertension/diabetes and suggestions for diagnostic investigations; guidelines based management plan for hypertension and diabetes; longitudinal health records; lifestyle advices tailored to patient profi le; and quality assurance checks.

Trained nurses carried out opportunistic screening of 22,009 patients (aged 30 years or above) with the help of mPower DSS at NCD clinics over a period of 21 months and identifi ed 6797 patients either with hypertension and diabetes. A total of 6016 patients had hypertension (mean systolic blood pressure: 146.1 mm Hg, 95% CI: 145.7, 146.5; diastolic blood pressure: 89.52 mm Hg, 95% CI: 89.33, 89.72) and out of which 3152 (52%) individuals were newly detected. Similarly, 1516 patients had diabetes (mean fasting plasma glucose (FPG): 177.9 mg/dL, 95% CI: 175.8, 180.0) and out of which 450 (30%) individuals were newly detected. The changes in systolic blood pressure, diastolic blood pressure, and fasting plasma glucose observed at 18 months of follow-up were -14.6 mm Hg (95% CI: -15.3, -13.8), -7.6 mm Hg (CI: -8.0, -7.2), and -50.0 mg/dL (95% CI: -54.6, -45.5), respectively, and were statistically signifi cant even after adjusting for age, sex, and CHCs.

The mPower Heart project demonstrated that a nurse-facilitated, DSS enabled intervention is feasible and eff ective in the management of patients with hypertension and diabetes at primary care setting in India.

II. CARRS (Centre for Cardio-metabolic Risk Reduction in South Asia) Translation TrialThe CARRS Trial evaluated whether adding a multicomponent intervention (non-physician care coordinators [CC] to promote patient adherence and clinical decision-support software [DSS] to enhance physician responsiveness to treatment modifi cation) to usual

REVIEW ARTICLE

diabetes care was associated with better cardiometabolic profi les [Figure 4]. Ten hospitals in India and Pakistan randomized 1146 eligible patients (A1c≥8.0% and either systolic BP≥140 mmHg or Low Density Lipoprotein-cholesterol [LDL] ≥130mg/dL) to intervention (n=575) or usual care (n=571). At trial end

(median 28 months), we used intention to treat analysis to examine proportions (and 95% confi dence intervals [Cis] achieving multiple (A1c<7.0% and ≥1 of: BP<130/80 mmHg or LDL<100 mg/dL [or <70 mg/dL for those with cardiovascular disease] and single risk factor targets, and quality-of-life.

Figure 4. CARRS Trial Intervention Flow

Screenshot of Decision Support Software (DSS) – Management plan*The DSS management plan summarizes the glycaemic, blood pressure, and lipid values for the last three visits. The system generates a management plan (DSS prompt) for the physician based on the current visit blood reports. The physicians can accept/reject the DSS prompt at their discretion and are requested to provide a reason in case of rejecting the DSS prompt.


Baseline characteristics were similar in intervention and usual care arms: mean age (years) 54.2 vs. 54.2; males (%) 44.9 vs. 47.1; median duration of diabetes (years) 7 vs. 7; A1c (%) 9.9 vs. 9.9; BP (mmHg) 144.2/82.3 vs. 142.4/81.0; and LDL (mg/dl) 121.5 vs. 123.2, respectively. Over a median of 28 months, a greater percentage of intervention participants achieved the primary outcome (18.2% vs. 8.1%; relative risk, 2.24 [95% CI, 1.71 to 2.92]). Compared with usual care, intervention participants achieved larger reductions in HbA1c level (-0.50% [CI, -0.69% to -0.32%]), systolic BP (-4.04 mm Hg [CI, -5.85 to -2.22 mmHg]), diastolic BP (-2.03 mmHg [CI, -3.00 to -1.05 mmHg]), and LDL-c level (-7.86 mg/dL [CI, -10.90 to -4.81 mg/dL]) and reported higher quality-of-life and treatment satisfaction.12

This trial demonstrated that a health system approach involving DSS and CC signifi cantly improved cardiometabolic risks and quality-of-life, and may lower diabetes morbidity and mortality. WAY FORWARD AND CONCLUSIONIn conclusion, we quote Robert Frost, “The woods are lovely, dark and deep,

But I have promises to keep, and miles to go before I sleep, and miles to go before I sleep…”. “Two roads diverged in a wood, and I took the one less travelled by and that has made all the diff erence…” So, the innovative use of low-cost technology solutions (e/mHealth interventions) to manage chronic conditions including high blood pressure off ers much promise, and scale-up of proven eff ective interventions should be considered in near future. REFERENCES1. Global Status Report on NCDs -2014. http://www.

searo.who.int/india/topics/noncommunicable_diseases/ncd_situation_global_report_ncds_2014.pdf?ua=1 Acccessed on 10 July 2017.

2. Prabhakaran D, Jeemon P, Ghosh S, Shivashankar R, Ajay VS, Kondal D, et al. Prevalence and incidence of hypertension: Results from a representative cohort of over 16,000 adults in three cities of South Asia. Indian Heart J. 2017 Jul - Aug;69(4):434-41.

3. Anchala R, Kannuri NK, Pant H, Khan H, Franco OH, Di Angelantonio E, et al. Hypertension in India: a systematic review and meta-analysis of prevalence, awareness, and control of hypertension. Journal of hypertension. 2014 Jun;32(6):1170-7.

4. Devkota S, Dhungana RR, Pandey AR, Bista B, Panthi S, Thakur KK, et al. Barriers to Treatment and Control of Hypertension among Hypertensive Participants: A Community-Based Cross-sectional Mixed Method Study in Municipalities of Kathmandu, Nepal. Front Cardiovasc Med. 2016;3:26.

5. Khatib R, Schwalm JD, Yusuf S, Haynes RB, McKee M, Khan M, et al. Patient and healthcare provider barriers to hypertension awareness, treatment and follow up: a

systematic review and meta-analysis of qualitative and quantitative studies. PLoS One. 2014;9(1):e84238.

6. Patel P, Ordunez P, DiPette D, Escobar MC, Hassell T, Wyss F, et al. Improved Blood Pressure Control to Reduce Cardiovascular Disease Morbidity and Mortality: The Standardized Hypertension Treatment and Prevention Project. J Clin Hypertens (Greenwich). 2016 Dec;18(12):1284-94.

7. Bundy JD, Li C, Stuchlik P, Bu X, Kelly TN, Mills KT, et al. Systolic Blood Pressure Reduction and Risk of Cardiovascular Disease and Mortality: A Systematic Review and Network Meta-analysis. JAMA Cardiol. 2017 Jul 01;2(7):775-81.

8. Ettehad D, Emdin CA, Kiran A, Anderson SG, Callender T, Emberson J, et al. Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis. Lancet. 2016 Mar 05;387(10022):957-67.

9. Joshi R, Alim M, Kengne AP, Jan S, Maulik PK, Peiris D, et al. Task shifting for non-communicable disease management in low and middle income countries--a systematic review. PLoS One. 2014;9(8):e103754.

10. Rao KD, Bhatnagar A, Berman P. So many, yet few: Human resources for health in India. Hum Resour Health. 2012 Aug 13;10:19.

11. Ajay VS, Jindal D, Roy A, Venugopal V, Sharma R, Pawar A, et al. Development of a Smartphone-Enabled Hypertension and Diabetes Mellitus Management Package to Facilitate Evidence-Based Care Delivery in Primary Healthcare Facilities in India: The mPower Heart Project. Journal of the American Heart Association. 2016 Dec 21;5(12).

12. Ali MK, Singh K, Kondal D, Devarajan R, Patel SA, Shivashankar R, et al. Effectiveness of a Multicomponent Quality Improvement Strategy to Improve Achievement of Diabetes Care Goals: A Randomized, Controlled Trial. Annals of internal medicine. 2016 Sep 20;165(6):399-408.


Improving CV Outcomes in Diabetes with New Antidiabetic Medications:A New Era has Begun

REVIEW ARTICLE

P.C. MANORIA, NIDHI MISHRA, PANKAJ MANORIAKeywords DPP-4 inhibitors improved CV outcomes SGLT2 inhibitors glycemic control

Dr. P.C. Manoria is Director and Chief Cardiologist, Manoria Heart & Critical Care Hospital, Bhopal, (M.P.); Dr. Nidhi Mishra is Assistant Professor, Department of Biochemistry, Mahaveer Institute of Medical Sciences & Research, Bhopal, (M.P.); Dr. Pankaj Manoria is Chief Interventional Cardiologist, Manoria Heart & Critical Care Hospital, Bhopal, (M.P.).

AbstractA new era of improving cardiovascular (CV) outcomes in diabetes with new antidiabetic medications has begun. The new agents like sodium/glucose cotransporter 2 (SGLT2) inhibitors and Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RAs) in CV outcome trials (CVOTs) have shown improved CV outcomes in patients of diabetes with cardiovascular disease. In addition the above new agents also have the potential to decrease weight and blood pressure thereby improving comorbidities and on top of this they produce minimal or no hypoglycemia. Thus, we can kill three birds with the same stone, ie., optimizing glycemic control, minimizing comorbidities and above all improving CV outcomes.

With better control of infective and metabolic complications, Diabetes has emerged as a cardiovascular disease (CVD). 70% diabetics die because of CVD, particularly acute myocardial infarction. For close to 100 years, to be precise 93 years, since the introduction of insulin for clinical use in 1922, no medication designed to treat hyperglycemia associated with type 2 diabetes mellitus had demonstrated benefi t for cardiovascular risk in randomized cardiovascular clinical outcomes trials (CVOTs).

The Rosiglitazone controversy created a fl utter and the US Food Drug Administration (USFDA) in the year 2008, mandated that all new antidiabetic agents must undergo an adequately powered, glycemic-equipoise CVOTs in high-risk Type 2 diabetic patients, during postmarketing phase to demonstrate their safety by showing non-inferiority against placebo. The non-inferiority was defi ned as hazard ratio (HR) of <1.3 for the upper bound of 95% confi dence interval (CI), superiority can also be claimed if upper boundary of 95% CI is found to be <1.0


in a subsequent statistical analysis.1 In 2012, The European Medicines Agency also issued similar guidelines.2 As a consequence of this, since post–2008, all newer antidiabetic agents approved by USFDA and EMA have underwent or currently undergoing CVOT.

2015 came with a breaking news, when 3 new antidiabetic medications, Empaglifozin in the EMPA-REG OUTCOME, Liraglutide in LEADER and Semaglutide in SUSTAIN-6 trial showed cardiovascular benefi ts for the fi rst time in the history of diabetes. This represents a sea change in the treatment paradigm for type 2 diabetes with CVD. In addition

to CV benefi ts, these medications also improve upon other limitations of older antihyperglycemic medications, such as avoidance of weight gain and sodium retention and that too with minimal risk for hypoglycemia. In fact the new medications like SGLT2 inhibitors and GLP-1RA also decrease weight and blood pressure. In 2017 the CANVAS trial with canaglifozin also showed improved CV outcomes in diabetics with CVD.

CV OUTCOME TRIALS WITH NEWER AGENTSSeveral CVOTs had been initiated to assess the eff ect of newer anti-diabetic

medications on CV Outcomes. Eight trials have been completed and published while others are ongoing (Table -1). Indeed four CV outcome trials with newer agents i.e, EMPAREG OUTCOME, LEADER AND SUSTAIN-6 and CANVAS has shown improved CV outcomes.

The ongoing CVOT trials are outlined in Table 2.

MAJOR ADVERSE CARDIAC EVENTS IN CVOTSa. DPP-4 inhibitors trialsAll the three DPP-4 inhibitors trials, SAVOUR, EXAMINE and TECOS achieved the non-inferiority margin on major adverse cardiac event (MACE) endpoints as laid down by the FDA in 2008, thereby suggesting that saxagliptin, alogliptin, and sitagliptin all are CV neutral drugs. However, no superiority on MACE was observed with any of the three DPP-4 inhibitors.3-5

b. SGLT2 inhibitorsSurprisingly, empaglifl ozin in EMPA-REG OUTCOME6 trial not only achieved the non-inferiority but also demonstrated a substantial superiority against placebo. EMPA-REG found a signifi cant relative risk reduction in the primary outcome of 3P-MACE (composite of CV death, nonfatal myocardial infarction [MI], and nonfatal stroke) by 14% (HR = 0.86, 95% CI = 0.74–0.99, P = 0.04 for superiority) compared to the placebo.6

The CANVAS7 trial with canaglifozin also showed improved CV outcomes with exactly the same relative risk reduction of 14% in the primary outcome of similar 3P-MACE (HR=,0.86; 95% confi dence interval [CI], 0.75 to 0.97; P<0.001 for non-inferiority; P=0.02 for superiority) like the EMPA-REG OUTCOME trial. However, in CANVAS, while all three components of MACE moved in the right direction (i.e., HR<1.0), none actually achieved statistical signifi cance, perhaps refl ecting the fact that the study involved a sizable subgroup about one third of patients who had no prior history of CVD, unlike EMPA which did not included any such patients. Interestingly, in the CANVAS primary prevention subgroup,

Trials Drug Comparator Status Nu Established ResultsTrials Drug Comparator Status Nu Established Results CVD (%) CVD (%)

DPP-IV InhibitorsDPP-IV InhibitorsSAVORSAVOR33 Saxagliptin Placebo Declared 2013 16492 78% CV neutral, Saxagliptin Placebo Declared 2013 16492 78% CV neutral, hospitalization hospitalization for HF for HF EXAMINEEXAMINE44 Alogliptin Placebo Declared 2013 5380 100% CV neutral, Alogliptin Placebo Declared 2013 5380 100% CV neutral, numerical numerical HF HFTECOSTECOS55 Sitagliptin Placebo Declared 2015 14735 100% CV neutral, no Sitagliptin Placebo Declared 2015 14735 100% CV neutral, no increase in increase in hospitalization hospitalization for HF for HF

SGLT2 Inhibitors SGLT2 Inhibitors EMPA-REGEMPA-REG66 Empagliflozin Placebo Declared 2015 7020 99% Positive CV Empagliflozin Placebo Declared 2015 7020 99% Positive CV outcome outcomeCANVAS7 Canagliflozin Placebo Declared 2017 4330 67% Positive CVCANVAS7 Canagliflozin Placebo Declared 2017 4330 67% Positive CV outcome outcome

GLP1-RAGLP1-RALEADER8 Liraglutide Placebo Declared 2015 9340 81% Positive CVLEADER8 Liraglutide Placebo Declared 2015 9340 81% Positive CV outcome outcomeELIXA9 Lixisenatide Placebo Declared 2015 6068 100% CV neutralELIXA9 Lixisenatide Placebo Declared 2015 6068 100% CV neutralSUSTAIN 610 Semaglutide Placebo Declared 2016 3297 58.8% Positive CV SUSTAIN 610 Semaglutide Placebo Declared 2016 3297 58.8% Positive CV outcome outcome

Table 1. Large non-insulin completed CV outcome trials in T2DM

Trials Drug Comparator Status Nu.Trials Drug Comparator Status Nu.DPP-IV InhibitorsDPP-IV Inhibitors

CAROLINACAROLINA1111 Linagliptin Sulfonylurea Ongoing 6000 Linagliptin Sulfonylurea Ongoing 6000CARMELINACARMELINA1212 Linagliptin Placebo Ongoing 8300 Linagliptin Placebo Ongoing 8300

SGLT2 Inhibitors SGLT2 Inhibitors DECLARE TIMIDECLARE TIMI1313 Dapagliflozin Placebo Ongoing 17276 Dapagliflozin Placebo Ongoing 17276VERTIS CVVERTIS CV1414 Ertugliflozin Placebo Ongoing 12600 Ertugliflozin Placebo Ongoing 12600

GLP1-RAGLP1-RAEXSCELEXSCEL1515 Exenatide Placebo Ongoing 14000 Exenatide Placebo Ongoing 14000REWINDREWIND1616 Dulaglutide Placebo Ongoing 9622 Dulaglutide Placebo Ongoing 9622HARMONYHARMONY1717 Albiglutide Placebo Ongoing 7500 Albiglutide Placebo Ongoing 7500

Table 2. Large non-insulin ongoing CV outcomes trials in T2DM


the hazard ratio for the primary outcome was 0.98, suggesting that those without CVD do not experience the CV benefi t as those with CVD.

It should also be noted that while 3P-MACE reduction in EMPA-REG was mainly attributed to reduction in the CV death which was majorly due to the reduction in death from HHF; 3P-MACE reduction in LEADER8 was derived from summation of all CV end-points although here also reduction in the CV death contributed majorly. In contrast, the 3P-MACE reduction in SUSTAIN-610 was primarily attributed to a signifi cant reduction in the nonfatal stroke.

So, in summary, at the present state of time, the SGLT2 inhibitors, both empaglifozin and canglifozin show a clear and defi nite CV advantage in high-risk patients with T2DM and established macrovascular complications. The 'thumbprint,' however, of individual members of the class may be diff erent with regard to not only individual components of MACE but also with regard to adverse eff ect profi les.

The mechanistic underpinnings of the CV eff ects of SGLT2 inhibitors still remain to be fully elucidated. They potentially pertain to the drug's glucoretic-natriuretic properties.18 Another school of thought points to the tendency for these agents to shift fuel metabolism in favor of the consumption of ketones (instead of glucose and free fatty acids).19 Such a change, it has been proposed, may provide an energy advantage for cardiomyocytes. Clearly, more mechanistic studies are needed to better understand these concepts, which might have implications for the management of CVD.

The results of two ongoing CV outcome trials with other SGLT2 inhibitors in T2DM dapaglifozin in DECLARE (Dapaglifozin eff ect on CardiovascuLAR Events)13 and etruglfoozin in VERTIS CV [Cardiovascular Outcomes Following Ertuglifozin Treatment in Diabetes Mellitus Participants With Vascular Disease])14 are going to be released over the next several years. We will hopefully then have a better understanding of these issues at that time.

c.GLP-1RAs trialsFrom the three GLP-1RAs trials, ELIXA9 found lixisenatide to be noninferior (4P MACE, HR = 1.02; 95% CI = 0.89–1.17; P < 0.001 for noninferiority) to placebo while liraglutide in LEADER and semaglutide in SUSTAIN-6 trials showed superiority on similar 3P-MACE compared to placebo.

LEADER8 found 13% relative risk reduction (HR = 0.87; 95% CI = 0.78–0.97; P = 0.01) and SUSTAIN-6 demonstrated even a larger 26% relative risk reduction (HR = 0.74; 95% CI = 0.58–0.95; P = 0.02) in 3P-MACE.7-9

Interestingly, both LEADER and SUSTAIN-610 also demonstrated a signifi cant reduction on the expanded

composite outcome (death from CV causes, nonfatal MI, nonfatal stroke, revascularization or hospitalization for unstable angina, or heart failure) by 12% (HR = 0.88; 95% CI = 0.81–0.96; P = 0.005) and 26% (HR = 0.74; 95% CI = 0.62–0.89, P = 0.002), respectively, whereas EMP-REG could not demonstrate a signifi cant reduction (HR = 0.89; 95% CI = 0.78–1.01; P = 0.08) on expanded 4P-MACE (3P-MACE plus unstable angina). Figure 1 depicts the reduction in MACE in all eight CVOTs.

CV DEATH IN CVOTsNo benefi t was observed in reducing CV death in any CVOTs with DPP-4 inhibitors against placebo. Similarly, two

Figure 1: Primary major adverse cardiac events in cardiovascular outcome trials

Figure 2: Cardiovascular death in cardiovascular outcome trials

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CV death in all eight CVOTs.

NONFATAL MI IN CVOTsThere was a non-statistical trend in reduction of non-fatal MI in almost all CVOTs except EXAMINE and ELIXA. Figure 3 depicts this outcome. Silent MI was assessed in all patients in LEADER, and SUSTAIN-6 but only in 50% patient in EMPA-REG. Intriguingly, there was 28% increased trend of silent MI in EMPA-REG although statistically insignifi cant.

NONFATAL STROKES IN CVOTSTECOS had neutral outcome on nonfatal stroke. SAVOR-TIMI, ELIXA,

GLP-1RAs, lixisenatide, and semaglutide could not show any signifi cant reduction in the CV death in ELIXA and SUSTAIN-6, respectively. However, both empaglifl ozin in EMPA-REG and liraglutide in LEADER, signifi cantly reduced CV death by 38% (HR = 0.62; 95% CI = 0.49–0.77; P<0.0001) and 22% (HR = 0.78; 95% CI = 0.66–0.93; P = 0.007), respectively. This suggests that EMPA-REG showed much larger reduction in CV death compared to LEADER (38% vs. 22%) with more persuasive P value (<0.0001 vs. 0.007). The CANVAS trial published recently showed a trend towards reduction in CVD. Figure 2 depicts the outcome of

EMPA REG showed a non-signifi cant trend of increase in stroke. Stroke increased by 24% in empaglifl ozin arm (HR=1.24; 95% CI = 0.92–1.67; P = 0.16), although, it was statistically not signifi cant. EXAMINE, LEADER ,CANVAS all showed a non-signifi cant trend of decrease in stroke. Interestingly, SUSTAIN-6 showed a signifi cant 39% relative risk reduction in nonfatal stroke (HR = 0.61; 95% CI = 0.38–0.99; P=0.04). but its P value just reached statistical signifi cance (P=0.04). Figure 4 depicts the nonfatal stroke outcome of all eight CVOTs. Four subgroups of patients that had signifi cantly higher stroke in EMPA-REG in an independent analysis of FDA are:1. Patients with age <65 years of age

(HR = 1.6, 95% CI = 1.03–2.49)2. Patients from Europe (HR = 2.04,

95% CI = 1.26–3.29)3. Patients with baseline HbA1c ≥8.5%

(HR = 2.13, 95% CI = 1.21–3.74)4. Patients treated with insulin (HR =

1.57, 95% CI = 1.03–2.41).

Hospitalization Due to Unstable Angina in CVOTsNo statistically signifi cant diff erence in hospitalization due to unstable angina was observed in all eight CVOTs as shown in Figure 5.

ALL-CAUSE MORTALITY IN CVOTsEmpaglifl ozin reduced all-cause mortality by 32% (HR = 0.68; 95% CI = 0.57–0.82; P < 0.0001), while LEADER reduced it by 15% (HR = 0.85; 95% CI = 0.74–0.97; P = 0.02). This suggests that EMPA-REG had larger and robust reduction in all-cause mortality compared to LEADER (32% vs.15%, respectively) with persuasive P value (<0.0001 vs. 0.02, respectively).

The TECOS was neutral in all-cause mortality while SAVOR TIMI and SUSTAIN-6 showed a non signifi cant increase in it. The EXAMINE, ELIXA AND CANVAS showed a non-signifi cant decrease in all cause mortality. Figure 6 depicts the all cause mortality across all eight CVOTs.

Figure 3: Nonfatal myocardial infarction in cardiovascular outcome trials

Figure 4: Nonfatal stroke in cardiovascular outcome trials


with a history of heart failure and renal disease.20-22 Curiously, a post-hoc analysis of EXAMINE also suggested a signifi cant increase in HHF in patients without any history of heart failure (HR = 1.76, 95% CI = 1.07–2.90; P = 0.026).23 On the contrary, sitagliptin in TECOS found no signal of HHF. Further extensive analysis of TECOS also could not fi nd any signal of the heart failure, regardless of time, subgroups and method of statistical analysis applied.24,25 Meanwhile, FDA put a warning on April 5, 2016 which states that “safety review has found that Type 2 diabetes medicine containing saxagliptin and alogliptin may increase the risk of heart failure particularly in the patients who already have heart or kidney disease.26 It should be noted that HHF was neither a primary or secondary objective of these studies and thus any sub-analysis could be subjected to statistical error or may be a play of chance.

However, empaglifl ozin showed a robust reduction in HHF by 35% (HR = 0.65, 95% CI=0.50–0.85; P=0.002) in EMPA-REG. interestingly the CANVAS showed identical trend in reduction in HF hospitalization (HR=.67;95% CI 0.52- 0.67).

LEADER had a nonsignifi cant reduction in HHF, which defi nitely sounds encouraging for liraglutide as earlier two trials conducted in patients with exclusive heart failure subjects, had disappointing results. While functional impact of GLP-1

HEART FAILURE HOSPITALIZATIONS IN CVOTSHospitalization due to heart failure (HHF) was an exploratory end-point in all the trials. Saxagliptin in SAVOR-TIMI showed a statistically signifi cant 27% increase in the relative risk of HHF (HR=1.27; 95% CI=1.07–1.51, P=0.007). This HHF in SAVOR-TIMI was more pronounced within its fi rst year of randomization. Similar trend of increase (19%) was also observed with alogliptin in EXAMINE (HR = 1.19; 95% CI = 0.89–1.58; P=0.24), although, it was statistically insignifi cant. Intriguingly, the post hoc analyses from both SAVOR-TIMI and EXAMINE found that certain subgroups had a signifi cant increase in HHF that included, patients

Figure 5: Unstable angina hospitalization in cardiovascular outcome trials

Figure 6: All-cause mortality in cardiovascular outcome trials

Figure 7: Heart failure hospitalization in cardiovascular outcome trials

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for heart failure treatment (n = 300) conducted in patient with advanced heart failure (median left ventricular ejection fraction of 25%) with liraglutide (FIGHT) had a non-signifi cant trend of increase in HHF (HR = 1.30; 95% CI = 0.89–1.88; P = 0.17) and death (HR = 1.10; 95% CI = 0.57–2.14; P = 0.78), the eff ect of liraglutide on left ventricular function in chronic heart failure patients with and without Type 2 diabetes mellitus (LIVE) also had a signifi cant increase in serious adverse cardiac events when compared to placebo (12 vs. 3, respectively, P = 0.04).27,28 Intriguingly, SUSTAIN-6 had a non-signifi cant increase in trend of HHF. Figure 7 depicts the HHF in all CVOTs.

The CVD-REAL study,29 the fi rst large real-world study assessed data from more than 300,000 patients across six countries, 87% of whom did not have a history of CV disease. The data showed that across this broad population of patients with T2DM, treatment with SGLT-2i dapaglifl ozin, canaglifl ozin, empaglifl ozin reduced the rate of hospitalization for heart failure by 39% (p<0.001) and death from any cause by 51% (p<0.001), compared to other T2DM medicines. For the composite endpoint of hospitalization for heart failure and death from any cause, the reduction was 46% (p<0.001).

Safety analysis of CVOTsAll six CVOTs conducted with incretin-based therapy almost ruled out any real increase in pancreatitis or pancreatic cancer as was perceived earlier. However, there was a slight trend of increase in pancreatitis in DPP-4 inhibitors arm compared to the placebo. The only adverse eff ect observed in the trial was a tripling of genital infections, predominately due to candida, a well-recognized complication of glucosuria. However CANVAS showed two new side eff ects not seen in the EMPA ,i.e, an increase in lower limb amputations and bone fractures in the canaglifozin group While LEADER showed a signifi cant increase in acute gallstone disease (P<0.001) and acute cholecystitis (P=0.046), SUSTAIN-6 showed a signifi cant increase (HR=1.76; 95% CI=1.11–2.78, P=0.02) in retinopathy

complication (includes vitreous hemorrhage, onset of diabetes-related blindness, and the need for treatment with an intravitreal agent or retinal photocoagulation). It should also be noted that liraglutide in LEADER also reported an increased trend in retinopathy complication (HR=1.15; 95% CI=0.87–1.52; P=0.33), although it was nonsignifi cant.

From the existing data, it is clear that all the three DPP-4 inhibitors saxagliptin,alogliptin and sitagliptin are CV neutral drugs. Saxagliptin had undoubted increase in HHF in certain subgroups of patients. Alogliptin showed numerical increase in HHF. Sitagliptin in TECOS trial showed no signal of HHF. Among the GLP-RAs trials, lixisenatide was found to be CV neutral without any obvious safety signals. LEADER had a concordant reduction in all the CV end-points, some statistically signifi cant and some nonsignifi cant. SUSTAIN-6 had the largest reduction in 3P-MACE but no reduction in the CV death, all-cause death, and HHF. EMPA-REG had the largest and the most robust reduction in the CV death, all-cause death, and HHF, but a discordant nonsignifi cant increase in silent MI (assessed in half patients only) and nonfatal stroke.

The progression of kidney disease decreased by 39% (p<0.001) in the EMPA trial and interestingly, the progression of CKD in the CANVAS trial was almost identical to it.

Several CVOT trials are ongoing with linagliptin (CARMELINA, CAR-OLINA), canaglifl ozin (CANVAS-R), dapaglifl ozin (DECLARE-TIMI), ertug-lifl ozin (VERTIS-CV), exenatide once weekly (EXCEL), dulaglutide (RE-WIND) and albiglutide (HARMONY) which will further enlighten us in future.

CONCLUSIONThus the new agents SGLT2i and GLA-1 RA have paved the way for a new therapeutic path for diabetes of optimizing glycemic control, minimizing co-morbidities and improving CV outcomes coupled with minimal or no hypoglycemia. Indeed this is the beginning of a new revolution which we have desired for many years.

REFERENCES1. Center for Drug Evaluation and Research. Guidance for

Industry Diabetes Mellitus: Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes; 2008. Available from: http://www.fda.gov/downloads/Drugs/ Guidance Compliance Regulatory Information /Guidances /ucm071627.

2. European Medicines Agency. Guideline on Clinical Investigation of Medicinal Products in the Treatment or Prevention of Diabetes Mellitus. Available from: http://www.ema.europa.eu/docs/ en_GB/document_library/Scientific_guideline/2012/06/WC500129256.

3. Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013;369:1317-26.

4. White WB, Cannon CP, Heller SR, Nissen SE, Bergenstal RM, Bakris GL, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 2013;369:1327-35.

5. Green JB, Bethel MA, Armstrong PW, Buse JB, Engel SS, Garg J, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2015;373:232-42.

6. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117-28.

7. Zinman B, Wanner C, Lachin JM, et al. Empagli�ozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117-28.

8. Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016;375:311-22.

9. Pfeffer MA, Claggett B, Diaz R, Dickstein K, Gerstein HC, Køber LV, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med 2015;373:2247-57.

10. Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jódar E, Leiter LA, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2016.

11. Marx N, Rosenstock J, Kahn SE, Zinman B, Kastelein JJ, Lachin JM, et al. Design and baseline characteristics of the CARdiovascular Outcome Trial of LINAgliptin Versus Glimepiride in Type 2 Diabetes (CAROLINA®). Diab Vasc Dis Res 2015;12:164-74.

12. CARMELINA: Cardiovascular and Renal Microvascular Outcome Study With Linagliptin in Patients with Type 2 Diabetes Mellitus. Available from: https://www.clinicaltrials.gov/ct2/show/ NCT01897532.

13. DECLARE-TIMI: Dapagliflozin Effects on Cardiovascular Events. Available from: https://www. clinicaltrials.gov/ct2/show/ NCT01730534.

14. VERTIS-CV: Cardiovascular Outcomes Following Ertugliflozin Treatment in Type 2 Diabetes Mellitus Participants with Vascular Disease. Available from: https://www.clinicaltrials.gov/ct2/ show/ NCT01986881.

15. EXSCEL: Exenatide Study of Cardiovascular Event Lowering Trial. Available from: https://www. clinicaltrials.gov/ct2/show/ NCT01144338.

16. REWIND: Researching Cardiovascular Events with a Weekly Incretin in Diabetes. Available from: https://www.clinicaltrials.gov/ct2/show/

17. HARMONY: Effect of Albiglutide, when Added to Standard Blood Glucose Lowering Therapies, on Major Cardiovascular Events in Subjects with Type 2 Diabetes Mellitus. Available from: https://www. clinicaltrials.gov/ct2/show/NCT02465515. [Last accessed on 2016 Oct 20].


18. Sattar N, McLaren J, Kristensen SL, Preiss D, McMurray JJ. SGLT2 inhibition and cardiovascular events: why did EMPA-REG outcomes surprise and what were the likely mechanisms? Diabetologia 2016;59:1333-9.

19. Ferrannini E, Baldi S, Frascerra S, et al. Shift to fatty substrate utilization in response to sodium-glucose cotransporter 2 inhibition in subjects without diabetes and patients with type 2 diabetes. Diabetes 2016;65:1190-5.

20. Scirica BM, Braunwald E, Raz I, Cavender MA, Morrow DA, Jarolim P, et al. Heart failure, saxagliptin, and diabetes mellitus: Observations from the SAVOR-TIMI 53 randomized trial. Circulation 2014;130:1579-88.

21. Briefing Material, NDA 22350: Saxagliptin (Onglyza). NDA 200678: Saxagliptin/Metformin (Kombiglyze XR). April, 2015. http://www.fda. gov/downloads/Advisory Committees/Committees Meeting Materials/Drugs/ Endocrinologic and Metabolic - Drugs Advisory Committee/ UCM442060.

22. EMDAC Briefing Document Cardiovascular Outcomes

Trial EXAMINE/NDAs 022271, 022426, & 203414 Nesina (Alogliptin), Oseni (Alogliptin/Pioglitazone), & Kazano (Alogliptin/ MetforminHCl); 2015. Available from: http://www.fda.gov/ downloads/Advisory Committees/Committees Meeting Materials/Drugs/Endocrinologic and Metabolic Drugs Advisory Committee/UCM442062.

23. Zannad F, Cannon CP, Cushman WC, Bakris GL, Menon V, Perez AT, et al. Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE: A multicentre, randomised, double-blind trial. Lancet 2015;385:2067-76.

24. McGuire DK, Van de Werf F, Armstrong PW, Standl E, Koglin J, Green JB, et al. Association between sitagliptin use and heart failure hospitalization and related outcomes in type 2 diabetes mellitus: Secondary analysis of a randomized clinical trial. JAMA Cardiol 2016;1:126-35.

25. Scirica BM. The safety of dipeptidyl peptidase 4 inhibitors and the risk for heart failure. JAMA Cardiol 2016;1:123-5.17.

26. Available from: http://www.fda.gov/downloads/Drugs/DrugSafety/UCM493965.

27. Margulies KB, Hernandez AF, Redfield MM, Givertz MM, Oliveira GH, Cole R, et al. Effects of liraglutide on clinical stability among patients with advanced heart failure and reduced ejection fraction: A randomized clinical trial. JAMA 2016;316:500-8.

28. Jorsal A. Effect of Liraglutide, a Glucagon-like Peptide-I Analogue, on Left Ventricular Function in Chronic Heart Failure Patients with and Without Diabetes: The LIVE Study. European Society of Cardiology (ESC) Heart Failure 2016; May 22, 2016; Florence, Italy. Presentation 599; 2016.

29. Kisiborod M, Cavender MA, Fu AZ, et al Lower Risk of Heart Failure and Death in Patients Initiated on SGLT-2 Inhibitors Versus Other Glucose-Lowering Drugs: The CVD-REAL Study. Circulation 2017;136(3):249-259.

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Challenges in Heart Failure Management

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RAJEEV RATHI

Keywords heart failure with reduced ejection

fraction heart failure with preserved ejection

fraction guideline-recommended medications palliative care quality-of-life

Dr. Rajeev Rathi, Director & Head Transradial Interventional Programme, Max Super Speciality Hospital, Saket, New Delhi, India

We are at a crucial juncture in the war against heart failure, a time analogous to 1942, midway through World War 2, when after several major defeats the Allied forces won an important battle. The indomitable Winston Churchill could have been speaking about the war against heart failure, when he declared: “Now, this is not the end. It is not even the beginning of the end. But it is, perhaps, the end of the beginning.1”

Eugene Braunwald, 2015

AbstractThe management of chronic heart failure (HF) with low ejection fraction (EF) has changed considerably over the past 30 years: the introduction of angiotensin-converting enzyme inhibitors (ACEIs), -blockers, angiotensin-receptor blockers, mineralocorticoid-receptor antagonists and recently, the If blocker, ivabradine, has led to a signifi cant reduction in overall mortality and HF mortality. Recently, a trial testing a dual inhibitor blocking the angiotensin-II receptor and neprilysin, the enzyme responsible for B-type natriuretic peptide degradation, showed that this complex molecule improved clinical outcomes compared with the ACEI enalapril. However, challenges remain in the management of HF, with a suboptimal implementation of guideline-recommended therapies, a changing profi le of patients who are older and have multiple comorbidities and a high rate of early rehospitalization for HF. Use of devices such as implantable cardiac defi brillators and cardiac resynchronization therapy is also associated with an improvement in outcomes in this condition. HF with preserved EF (HFpEF), a growing fraction of the HF population, remains a clinical dilemma: no pharmacological intervention has so far demonstrated any convincing benefi t on an outcome. Heterogeneity of the people tested, the role of comorbidities, diffi culties in identifying patients with HFpEF, as well as a mismatch between the clinical phenotypes and the treatments tested, can explain the failure to fi nd benefi cial interventions. Overall, the management of HF after discharge remains fragmented and concerted action by all professionals concerned is needed.


Heart failure (HF) is a major health problem all across the globe with a pandemic like situation aff ecting 26 million people worldwide.2 However, the data across the globe is sparsely available from low-mid socio-economic nations in the world. The estimated prevalence of heart failure in India is 1.3-4.6 million people who are based on risk factor models.3 Heart failure with reduced ejection fraction (HFrEF) has been a success story when seen in trials however, heart failure with preserved ejection fraction (HFpEF) has been an unconquered challenge so far. The

magnitude of heart failure is increasing with increasing longevity. India has undergone rapid epidemiological and demographic transitions in the last 2 decades. As a result, the burden of HF in India has increased by nearly 140% from 1990 to 2013.2

The management of heart failure (HF) has changed considerably during the past 30 years with the introduction of both major classes of drugs and devices. Angiotensin-converting enzyme inhibitors (ACEIs), β-adrenergic blockers, angiotensin-receptor blockers (ARBs), mineralocorticoid- receptor

antagonists (MRAs), “funny” channel (If) blockers and more recently, dual inhibitors blocking neprilysin and angiotensin receptors have been shown to improve mortality and morbidity in large randomized clinical trials including patients with mild to moderate chronic HF and reduced ejection fraction (EF). (Table 1). Apart from drug therapy, implantable cardiac defi brillators (ICDs) and cardiac resynchronization therapy (CRT) have shown benefi t in preventing sudden cardiac death (SCD) in patients with mild to moderate HF with low systolic function, and in cardiovascular mortality and morbidity in both severe and moderate HFrEF (Table 2).

Unlike what is observed for HFrEF, all attempts to reduce the mortality and morbidity rates of HFpEF have failed (Table 3). There has not been a single trial with any therapy which shows a signifi cant mortality benefi t. HFpEF accounts for 55% of all the heart failure cases as per recent reports.4 Current treatment includes preventive management of HFpEF risk factors and diuretics for symptom control. Patients with HFpEF are usually older and have multiple comorbidities, which makes them more complicated to manage. The principal diffi culty in management of HFpEF is the timely diagnosis of the disease as the diagnosis is usually made at an advanced stage of disease when signs and symptoms of heart failure develop with a “preserved” EF >50% and objective evidence of abnormal distensibility, left ventricular fi lling or relaxation either by biomarkers or 2D Echocardiography.5 The understanding of the pathophysiology of HFpEF remains suboptimal and a uniform approach to its management may not work, because of several phenotypes of this condition have been described.6,7 Therefore, HFpEF remains a challenging condition with imperfectly understood pathophysiology, diffi cult diagnosis and heterogeneous phenotypes, all factors that make the management of this condition diffi cult and which explain why no progress has been made in improving patients’ outcome.8

The progress made in the management

Table 3: Clinical trials for drug therapy of Heart failure with preserved ejection fraction28-33

Trials Drugs Effect on Mortality Effect on morbidityTrials Drugs Effect on Mortality Effect on morbidity

DIG Digoxin - -DIG Digoxin - -

PEP-CHF Perindopril - +*PEP-CHF Perindopril - +*

I-PRESERVE Irbesartan - -I-PRESERVE Irbesartan - -

CHARM-PRESERVE Candesartan - +*CHARM-PRESERVE Candesartan - +*

SENIORS Nebivolol - +*SENIORS Nebivolol - +*

TOP-CAT Spironolactone - +*TOP-CAT Spironolactone - +*

RELAX Sildenafil - -RELAX Sildenafil - -+*: present in HF related hospitalization; - : absent+*: present in HF related hospitalization; - : absent

Table 1: Drugs used in heart failure with reduced ejection fraction9-22 Drugs Landmark Trial Mortality Decrease Drugs Landmark Trial Mortality Decrease

benefit in Morbidity benefit in Morbidity

ACE inhibitors CONSENSUS, SOLVD + +ACE inhibitors CONSENSUS, SOLVD + +

Angiotensin receptor CHARM-ALTERNATIVE, + +Angiotensin receptor CHARM-ALTERNATIVE, + +

blockers Val-HeFTblockers Val-HeFT

-Blockers Carvedilol US + +-Blockers Carvedilol US + +

Programme, CIBIS II, Programme, CIBIS II,

MERIT HF, COPERNICUS MERIT HF, COPERNICUS

Mineralocorticoid RALES, EMPHASIS + +Mineralocorticoid RALES, EMPHASIS + +

receptor antagonistsreceptor antagonists

Ivabradine SHIFT - +Ivabradine SHIFT - +

Sacubitril/Valsartan PARADIGM-HF + +Sacubitril/Valsartan PARADIGM-HF + +

(LCZ696)(LCZ696)

Digoxin DIG - +Digoxin DIG - +

Combination of A-HeFT + +Combination of A-HeFT + +

Hydralazine and Hydralazine and

Isorbide dinitrate Isorbide dinitrate

(Blacks)(Blacks)

Diuretics - +Diuretics - +

+: present; - :absent+: present; - :absent

Table 2: Devices used in Heart failure with reduced ejection fraction23-27

Device Landmark trial Effect on Mortality/MorbidityDevice Landmark trial Effect on Mortality/Morbidity

CRT COMPANION, CARE HF +CRT COMPANION, CARE HF +

ICD SCD-HEFT +ICD SCD-HEFT +

CRT plus ICD MADIT CRT, RAFT +CRT plus ICD MADIT CRT, RAFT +

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of HFrEF so far in diff erent path-breaking landmark trials are unfortunately not refl ected on situation on ground. In the absence of the mortality improving drugs, 5-year mortality of Heart failure patients was 50% in Framingham Heart study in late 1990s.34 It continues to be around 50% in THIN database, despite a structured drug therapy in place for almost a decade.35 The biggest registry of heart failure from India, Trivandrum Heart Failure registry came up with its one year data and showed that 1 out of 3 patients died after 1-year of diagnosis of heart failure.36 Survival of heart failure patients is worse than in many common cancers.37 Therefore, heart failure management remains one of the biggest challenges in contemporary medicine. In this review, we shall be focusing on challenges in management of otherwise well understood heart failure with reduced ejection fraction (HFrEF).

Heart failure is expected to be managed by physicians across the world by guideline-directed medical therapy (GDMT) for Heart failure which includes angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), -blockers, loop diuretics, aldosterone antagonists, hydralazine/isosorbide dinitrate (HYD/ISDN); angiotensin receptor-neprilysin inhibitor (ARNI) and the hyperpolarization channel blocker ivabradine.38 However, the biggest challenge in the management of HF is the inability to give GDMT to our patients. The results of QUALIFY survey which included around 7200 patients of heart failure from 36 countries was a substantial proof that GDMT is a tough task to achieve even at the best of the centres. In this study, good adherence was found in only 67% of the patients, with >50% target dose achieved in very less patients.39 The TSOC-HFrEF registry demonstrated the under-prescription of guideline-recommended medications and reluctance of physicians to up-titrate medications to target dose.40 In India, the condition is even worse. In PIINACLE India Quality Improvement Program (PIQIP), use of ACEIs/ARBs, β-blockers, and both were documented in only 33.5%, 34.9%, and 29.6% of patients,

respectively.41 Therefore inability to provide GDMT to heart failure patients remains the biggest challenge for physicians across the world. The common problems faced by physicians to pro ide guideline-directed medical therapy are:

HOW TO INITIATE AND WHICH DRUG TO INITIATE?There have been many randomized clinical trials proving effi cacy of diff erent drugs in heart failure, however, no clinical trials have specifi cally evaluated the potential for greater benefi t or excessive risk of indicated therapies among patients with multimorbidity.

When a newly diagnosed HF patient

presents with acute heart failure, how to start GDMT becomes a big question without any clear answer in the literature. Usually, physicians start with diuretics and ACE inhibitor/ARB and then add a -blocker. Data from the randomized CIBIS (Cardiac Insuffi ciency Bisoprolol) III trial suggest that in mild to moderate heart failure, initiation of treatment either with enalapril or bisoprolol is safe.42 However, physicians are reluctant to start -ablockers in moderate heart failure patient and prefer to do so on once patient gets stabilized.

The addition of angiotensin receptor neprilysin inhibitor (ARNI) in our arsenal has increased the confusion. Sacubitril/

Table 4: Starting dose and target doses of drugs in Guideline-directed medical therapy38

Drugs Starting dose Target doseDrugs Starting dose Target dose

-Blockers-Blockers

Bisoprolol 1.25 mg once daily 10 mg once dailyBisoprolol 1.25 mg once daily 10 mg once daily

Carvedilol 3.125 mg twice daily 25 mg twice daily for weight Carvedilol 3.125 mg twice daily 25 mg twice daily for weight

<85 kg and 50 mg twice daily for <85 kg and 50 mg twice daily for

weight > 85 kg weight > 85 kg

Metoprolol succinate 12.5–25 mg/d 200 mg dailyMetoprolol succinate 12.5–25 mg/d 200 mg daily

ARNIARNI

Sacubitril/valsartan 24/26 mg–49/51 mg 97/103 mg twice dailySacubitril/valsartan 24/26 mg–49/51 mg 97/103 mg twice daily

twice daily twice daily

ACE inhibitorACE inhibitor

Captopril 6.25 mg 3x daily 50 mg 3x dailyCaptopril 6.25 mg 3x daily 50 mg 3x daily

Enalapril 2.5 mg twice daily 10–20 mg twice dailyEnalapril 2.5 mg twice daily 10–20 mg twice daily

Lisinopril 2.5–5 mg daily 20–40 mg dailyLisinopril 2.5–5 mg daily 20–40 mg daily

Ramipril 1.25 mg daily 10 mg dailyRamipril 1.25 mg daily 10 mg daily

ARBARB

Candesartan 4–8 mg daily 32 mg dailyCandesartan 4–8 mg daily 32 mg daily

Losartan 25–50 mg daily 150 mg dailyLosartan 25–50 mg daily 150 mg daily

Valsartan 40 mg twice daily 160 mg twice dailyValsartan 40 mg twice daily 160 mg twice daily

Aldsterone antagonistsAldsterone antagonists

Eplerenone 25 mg daily 50 mg dailyEplerenone 25 mg daily 50 mg daily

Spironolactone 12.5–25 mg daily 25–50 mg dailySpironolactone 12.5–25 mg daily 25–50 mg daily

VasodilatorsVasodilators

Fixed-dose 20 mg/37.5 mg 2 tabs 3dailyFixed-dose 20 mg/37.5 mg 2 tabs 3daily

combination (one tab)combination (one tab)

isosorbide dinitrate/ 3x dailyisosorbide dinitrate/ 3x daily

hydralazine hydralazine

Ivabradine 2.5–5 mg twice Maximum doseIvabradine 2.5–5 mg twice Maximum dose

daily 7.5 mg twice daily daily 7.5 mg twice daily

Titrate to heart Titrate to heart

rate 50–60 bpm rate 50–60 bpm


Valsartan was tested in randomized trial, PARADIGM-HF which demonstrated a 20% reduction in the primary outcome of cardiovascular death or HF hospitalization (hazard ratio: 0.80; 95% confi dence interval: 0.73 to 0.87; p < 0.001) in patients treated with sacubitril/valsartan. The number needed to treat to prevent 1 primary endpoint over 27 months was 21.20 These diff erences in outcomes included a 20% reduction in sudden cardiac death.

Current guidelines have placed ARNI as class I agent for management of heart failure.43

HOW TO TITRATE THERAPY?Once the medical therapy is initiated with ACEi/ARB and -blocker, the next challenge is to uptitrate the dose to the recommended or maximal tolerated dose and adding other drugs to the regimen (Table 4). In some instances, it may not be possible to titrate GDMT to the target doses achieved in clinical trials. Patients in clinical practice may diff er substantially from those enrolled in the trials, they have more comorbidities and side eff ects. Hypotension, deranged renal function and hyperkalemia are the most common barriers in titrating GDMT to the target dose.

Drugs should be titrated every 2 weeks and regular physical examination and blood tests should be done to look for adverse eff ects. All other commonly prescribed drugs which have not shown any mortality benefi t like digoxin, nitrates should be stopped so that target dose of GDMT can be reached. All eff orts should be done to achieve the doses achieved in clinical trials in order to get the similar benefi t. For patients, who are on maximally tolerated dose of beta blockers, are in sinus rhythm and NYHA class II or III, with heart rate more than 70, Ivabradine should be added. Likewise Ivabradine should not be used in those with atrial fi brillation, patients who are 100% atrial paced, or in unstable patients. From a safety standpoint, patients treated with ivabradine had more bradycardia and developed more atrial fi brillation as well as transient blurring of vision.19

FEAR OF ADVERSE EFFECTS AND UNDERDOSING OF THERAPYFear of adverse eff ects during initiation or dose escalation of guideline-recommended medications is an important reason for not escalating to the target dose of the drugs. -blockers are feared in COPD/Asthma patients and ACEi/ARB/ARNI are feared for hyperkalemia and deranged renal function. Physicians frequently under dose the drugs and thus, optimal

results are not achieved. Therapy should be started at low doses and up-titrated based on tolerability. Patient education and frequent contact will shorten the time to achieve optimal therapy. COPD is not an absolute contraindication for -blocker use. They should be started in low doses and careful monitoring of signs of airway obstruction should be done to use -blockers eff ectively in obstructive pulmonary diseases.44 Renal function

Stable Renal Function Stable Renal Function Check Renal function every six months Check Renal function every six months

Stable Renal dysfunctionStable Renal dysfunction

Initiation or up-titration Initiation or up-titration of ACEI/ARB of ACEI/ARB

Worsening of renal function (WRF)Worsening of renal function (WRF)Rise in Sr Creat < 50% of the baseline and Rise in Sr Creat < 50% of the baseline and

Creatinine is not more than 3 mg%Creatinine is not more than 3 mg%eGFR is not less than 25ml/min/1.73meGFR is not less than 25ml/min/1.73m22

Yes No Yes No

Pseudo-worsening of renal function Either reduce the dose of drug to half Pseudo-worsening of renal function Either reduce the dose of drug to half OR OR Stop if hypotension, hyperkalemia Stop if hypotension, hyperkalemia of extreme rise in serum creatinine of extreme rise in serum creatinine Accept Changes Accept Changes Chase renal functions regularly Chase renal functions regularly

Pseudo WRF True WRF Pseudo WRF True WRF • • If possible, • Stop if dose is If possible, • Stop if dose is re-challenge already halved re-challenge already halved with ACEi/ARB • Refer to with ACEi/ARB • Refer to • Consider decrease Nephrologist • Consider decrease Nephrologist in dose of diuretic • Consider Renal in dose of diuretic • Consider Renal Artery Stenosis Artery Stenosis

Figure 1. Chronic heart failure with renal dysfunction47

Improvement Improvement in renal in renal function function

No No Improvement Improvement

in renal in renal function function

Table 5: Comorbidities affecting clinical outcome in Heart failure.49-51

Cardiovascular Non cardiovascularCardiovascular Non cardiovascular

• Coronary artery disease • Obesity• Coronary artery disease • Obesity

• Valvular heart disease • Diabetes Mellitus• Valvular heart disease • Diabetes Mellitus

(Aortic stenosis, Mitral regurgitation) (Aortic stenosis, Mitral regurgitation)

• Hypertension • Metabolic syndrome• Hypertension • Metabolic syndrome

• Dyslipidemia • Iron deficiency• Dyslipidemia • Iron deficiency

• Atrial fibrillation • Anaemia• Atrial fibrillation • Anaemia

• Chronic kidney disease • Chronic kidney disease

• Chronic lung disease • Chronic lung disease

• Thyroid disease • Thyroid disease

• Sleep disordered breathing • Sleep disordered breathing

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and potassium should be assessed within 1 to 2 weeks of the initiation or dose increase of ACEI/ARB/ARNI (Figure 1). In patients with preserved renal function or mild to moderate renal impairment, renal function and potassium should be reassessed within 2 to 3 days and again at 7 days after initiation and titration of aldosterone antagonists. During initiation and titration of agents that aff ect renal function, a decrease in eGFR of >30% or development of hyperkalemia should alert the clinician that a reduction in doses may be necessary, even though short-term changes in eGFR during intense diuretic therapy or with the initiation of ACEI or ARB do not predict longer-term adverse outcomes.45 In patients with evidence of hypovolemia, the dose of diuretics should be reduced. Monitoring should occur at least monthly for the fi rst 3 months and every 3 months thereafter.46

MANAGEMENT OF COMORBIDITIESManagement of various cardiovascular

and non cardiovascular comorbidities in patients with heart failure is yet another challenge for the physicians. There is a bidirectional relationship between HF and comorbidities whereby, the presence of one increases the risk of incident development of the other, and prognosis is worse if both are present simultaneously (Table 5).48

Coronary artery disease is one of the most common etiology and comorbidity of heart failure. It should be investigated, evaluated and revascularization should be done in appropriate patients. Diabetes should be managed according to ADA guidelines and the newer antidiabetic drugs SGLT2 inhibitors should be preferably used in heart failure patients.52 Iron defi ciency should be corrected with intravenous iron therapy.53 All other comorbidities should also be aggressively managed with referrals to appropriate specialties. There is signifi cant overlap between respiratory infections and exacerbation of underlying HF.

Vaccination against respiratory infections like infl uenza and pneumococcal infections in patients with HF could serve as a potential cost-eff ective intervention to improve patients’ quality-of-life and clinical outcomes.54

COST OF THE TREATMENT AND RE-HOSPITALIZATIONThe economic burden of HF is substantial and is expected to increase markedly in parallel with increases in HF prevalence. Between 2012 and 2030, in United states, total direct medical costs for HF are projected to increase from $21 billion to $53 billion, while total costs (including indirect outlay) are estimated to increase from $31 billion to $70 billion.55 Apart from the cost of hospitalization, the cost of cardiovascular medications has the biggest fi nancial burden on patients with HF, accounting for almost 15.6% of direct costs of the treatment.56 Health expenditures are a major fi nancial burden for many persons in low and middle-income countries, where individuals often lack health insurance. India, has a huge burden of cardiovascular diseases including HF and cost of their drug therapy alone has the potential to cause huge fi nancial burden to a signifi cant proportion of people.57 These costs increase the likelihood that patients will forego needed treatment and thus, will not be able to achieve the benefi ts of GDMT. Despite ARNI being a very potent new weapon in our arsenal, we are unable to utilize it widely in our country due to cost constraints (Table 6). Uniform government controlled pricing for all the heart failure drugs and a subsidized program for GDMT of heart failure is the need of the hour.

Rehospitalization of heart failure patients due to decompensation is yet another big challenge. Rehospitalization not only adds to the cost of heart failure management but also aff ects survival. Patients admitted for HF have a high event rate (> 50%), with a mortality rate between 10 and 15% and a rehospitalization rate within 6 months after discharge of 30 to 40%.58 The worsening in HF symptoms results in hospitalization and is associated with a high mortality rate

Table 6: Cost of commonly used drugs in Heart failure patients in India59

Treatment Price (Treatment Price (₹))

Total daily cost of GDMT in target doses without ARNI 56.07Total daily cost of GDMT in target doses without ARNI 56.07

(keeping cheapest options among these) (keeping cheapest options among these)

Total daily cost of GDMT in target doses with ARNI 226.39Total daily cost of GDMT in target doses with ARNI 226.39

(keeping cheapest options among these) (keeping cheapest options among these)

Total daily cost of GDMT in target doses with ARNI 294.39Total daily cost of GDMT in target doses with ARNI 294.39

and antidiabetes drugsand antidiabetes drugs

Table 7. "I need help" acronym for markers of advanced heart failure48,61,62

I Inotropes Previous or ongoing requirement forI Inotropes Previous or ongoing requirement for

dobutamine, milrinone, dopamine or dobutamine, milrinone, dopamine or

levosimendan levosimendan

N NYHA class/Natriuretic peptides Persisting NYHA Class III or IV and/orN NYHA class/Natriuretic peptides Persisting NYHA Class III or IV and/or

persistently high BNP or NT-pro-BNP persistently high BNP or NT-pro-BNP

E End organ dysfunction Worsening renal or liver dysfunction in E End organ dysfunction Worsening renal or liver dysfunction in

the setting of heart failure the setting of heart failure

E Ejection fraction Very low ejection fraction of 20%E Ejection fraction Very low ejection fraction of 20%

D Defibrillator shocks Recurrent appropriate defibrillator shocksD Defibrillator shocks Recurrent appropriate defibrillator shocks

H Hospitalizations More than 1 hospitalization with heartH Hospitalizations More than 1 hospitalization with heart

failure in the last 12 months failure in the last 12 months

E Edema/Escalating diuretics Persisting fluid overload and/or E Edema/Escalating diuretics Persisting fluid overload and/or

Increasing diuretic requirement Increasing diuretic requirement

L Low blood pressure Consistently low BP with systolic L Low blood pressure Consistently low BP with systolic

90 to 100 mm Hg 90 to 100 mm Hg

P Prognostic medications Inability to up-titrate (or need to decrease/P Prognostic medications Inability to up-titrate (or need to decrease/

cease) ACEI, B-blockers, ARNIs or MRAs cease) ACEI, B-blockers, ARNIs or MRAs


In Trivandrum Heart Failure registry as well, 1-year hospital readmission rate was 30.2% (n =333) among the 1,103 participants discharged from the index hospitalization.36 Therefore, decreasing heart failure readmissions should be an important target in heart failure management. The multidisciplinary approach associated with the implementation of good practices based on scientifi c evidence can reduce the risk of hospitalization.

WHEN TO REFER TO A HEART FAILURE SPECIALIST FOR TREATMENT OF ADVANCED HEART FAILURE? Heart failure is treated mostly by general physicians and general cardiovascular physicians however, appropriate and timely referral to an HF specialist and/or HF program is essential in selected patients to optimize their therapy and evaluate advanced HF care options. Late referral of heart failure patients increases the risks of right heart failure, renal and liver dysfunction, pulmonary hypertension and often cardiac cachexia.45 These factors are associated with poorer outcomes after advanced heart failure therapies, or can result in patients being considered too unwell to undergo these treatments.60 The ideal time to refer patients for consideration of advanced heart failure therapies are when they progress from stable heart failure to advanced heart failure. The “I Need Help” acronym encompasses many of the core components for defi ning advanced heart failure, as recommended by the American and European Heart Failure Guidelines and Consensus Statements (Table 7).48,61,62

PALLIATIVE/END OF LIFE CARE IN HEART FAILUREAdvances in care have delayed the progression of disease but rarely lead to a cure, such that the palliative care needs of patients, caregivers, and healthcare systems are as high as ever.

Palliative care is one component of holistic, supportive care of patients throughout the disease, intensifi ed at the end of life and extending into the bereavement phase for their caregivers.

Team-based palliative care for heart failure implies a multidisciplinary approach, including primary care, cardiology, and palliative care, each represented by various providers (e.g. physicians, advanced practitioners, nurses, case managers, and pharmacists). PAL-HF trial has shown that palliative care improves health-related quality-of-life in end-stage HF patients. Patients receiving palliative care have lesser depression and anxiety and better spiritual wellbeing. Palliative care represents an important component of the holistic management of patients with advanced HF.63

PATIENT-RELATED FACTORSHeart failure management is a two pronged strategy to fi ght the disease where the participation of patient is equally important as that of the physician treating it. There are many patient related factors which pose an obstacle to successful therapy (Table 7). Patients are not aware of their disease due to poor knowledge about the symptoms and complications. Medical management includes too many drugs and this leads to poor adherence. The fi nancial burden due to cost of the treatment has already been discussed. Regular follow up with regular investigations is also a big challenge in developing country like India where patients from rural area have to travel to bigger cities for follow up visits. These factors are one of the most important reasons for poor adherence to guideline directed medical treatment, failing which leads to increased number of heart failure exacerbations, reduced physical activity, increased hospitalizations and mortality.64 Special heart failure clinics should be set up providing dedicated care for heart failure. Structured program should have telephone contacts of all the patients and medication adjustment should be done by a nurse of primary health giver

after consultation with a cardiologist. All eff orts should be made to provide help to patients in their domestic environment by using digital medical care through mobile pplications helplines. And fi nally all eff orts should be made to make treatment as cost eff ective as possible.65

CONCLUSIONHeart failure is the most diffi cult cardiovascular disease to be managed on a long-term basis. Heart failure with preserved ejection fraction continues to be an enigma with nothing substantial to off er to our patients. There has been signifi cant success achieved in clinical trials of management of heart failure with reduced ejection fraction, however, there are challenges in application of the management learned from those trials. Increasing prevalence, increasing cost of health care and multiple comorbidities have made HF a public health challenge. The HF syndrome requires a multidisciplinary specialist based approach with full political will of the governments to make sure that each patient receives full benefi ts of all the research done so far. Treatment of advanced heart failure by dedicated specialists and palliative care to the terminally ill patients should be encouraged to make sure holistic heart failure treatment. Heart failure is the last major battle being fought by cardiologists across the globe and we should win this as well.

REFERENCES1. Braunwald E. The war against heart failure: the Lancet

lecture. Lancet. 2015 Feb 28;385(9970):812-24. doi: 10.1016/S0140-6736(14)61889-4. Epub 2014 Nov 16.Review. PubMed PMID: 25467564.

2. GBD 2015 Mortality and Causes of Death Collaborators. Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet (Lond Engl) 2016;388(10053):1459-544

3. Huffman MD, Prabhakaran D. Heart failure: epidemiology and prevention in India. Natl Med J India 2010;23(5):283-8.

4. Mozaffarian D, Benjamin EJ, Go AS, et al. Executive summary: heart disease and stroke statistics—2016 update: a report from the American Heart Association. Circulation. 2016;133(4):447–454.

5. Campbell RT, Jhund PS, Castagno D, et al. What have we learned about patients with heart failure and preserved ejection fraction from DIG -PEF , CHARM -PRESERVED , and I-PRESERVE? J Am Coll Cardiol 2012; 60: 2349 – 2356.

Table 8: Patient related factors of poor adherence to GMDT• Lack of awareness about the disease• Lack of awareness about the disease

• Polypharmacy• Polypharmacy

• Financial burden• Financial burden

• Self-adjustment of the doses• Self-adjustment of the doses

• Regular follow-up and investigations• Regular follow-up and investigations

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6. Shah SJ. Matchmaking for the optimization of heart failure with preserved ejection fraction clinical trials: No laughing matter. J Am Coll Cardiol 2013; 62: 1339 – 1342.

7. Guazzi M, Vicenzi M, Arena R, et al. Pulmonary hypertension in heart failure with preserved ejection fraction: A target of phosphodiesterase-5 inhibition in a 1-year study. Circulation 2011; 124: 164 – 174.

8. Komajda M, Lam CS. Heart failure with preserved ejection fraction: A clinical dilemma. Eur Heart J 2014; 35: 1022 – 1032.

9. The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure: Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 1987; 316: 1429 – 1435.

10. The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991; 325: 293 – 302.

11. Granger CB, McMurray JJ, Yusuf S, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: The CHARM-Alternative trial. Lancet 2003; 362: 772 – 776.

12. Maggioni AP, Anand I, Gottlieb SO, et al. Effects of valsartan on morbidity and mortality in patients with heart failure not receiving angiotensin-converting enzyme inhibitors. J Am Coll Cardiol 2002; 40: 1414 – 1421.

13. Shusterman NH. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure: U.S. Carvedilol Heart Failure Study Group. N Engl J Med 1996; 334: 1349 – 1355

14. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): A randomized trial. Lancet 1999; 353: 9 – 13.

15. Hjalmarson A, Goldstein S, Fagerberg B, et al. Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure: The Metoprolol CR/XL Randomized Intervention Trial in congestive heart failure (MERIT-HF): MERIT-HF Study Group. JAMA 2000; 283: 1295 – 1302.

16. Krum H, Roecker EB, Mohacsi P, et al. Effects of initiating carvedilol in patients with severe chronic heart failure: Results from the COPERNICUS Study. JAMA 2009; 289: 712 – 718.

17. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure: Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999; 341: 709 – 717.

18. Zannad F, McMurray JJ, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011; 364: 11 – 21.

19. Swedberg K, Komajda M, Bohm M, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): A randomised placebo-controlled study. Lancet 2010; 376: 875 – 885.

20. McMurray JJV, Packer M, Desai AS, et al; for the PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014; 371: 993 – 1004.

21. Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med. 1997 Feb 20;336(8):525-33.

22. Taylor AL, Ziesche S, Yancy C, et al. African-American Heart Failure Trial Investigators. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med. 2004 Nov 11;351(20):2049-57. Epub 2004 Nov 8. Erratum in: N Engl J Med. 2005 Mar 24;352(12):1276.

23. Bristow MR, Saxon LA, Boehmer J, et al. Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) Investigators. Cardiac-resynchronization

therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med. 2004 May 20;350(21):2140-50.

24. Cleland JG, Daubert JC, Erdmann E, et al. Cardiac Resynchronization-Heart Failure (CARE-HF) Study Investigators. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med. 2005 Apr 14;352(15):1539-49. Epub 2005 Mar 7.

25. Bardy GH, Lee KL, Mark DB, et al. Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) Investigators. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med. 2005 Jan 20;352(3):225-37. Erratum in: N Engl J Med. 2005 May 19;352(20):2146.

26. Moss AJ, Hall WJ, Cannom DS, et al. Cardiac-resynchronization therapy for the prevention of heart failure events. N Engl J Med 2009; 361: 1329 – 1338.

27. Tang AS, Wells GA, Talajic M, et al. Cardiac-resynchronization therapy for mild-to-moderate heart failure. N Engl J Med 2010; 363: 2385 – 2395

28. Cleland JGF, Tendera M, Adamus J, et al. The Perindopril in Elderly People with Chronic Heart Failure (PEP-CHF) Study. Eur Heart J. 2006;27:2338.

29. Massie BM, Carson PE, McMurray JJ, et al. Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med. 2008;359:2456.

30. Yusuf S, Pfeffer MA, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. Lancet. 2003;362:777.

31. Flather MD, Shibata MC, Coats AJ, et al. Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS). Eur Heart J. 2005;26:215.

32. Pitt B, Pfeffer MA, Assmann SF, et al; TOPCAT Investigators. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med. 2014;370:1383–1392.

33. Redfield MM, Chen HH, Borlaug BA, et al. Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial. JAMA. 2013;309:1268.

34. Levy D, Kenchaiah S, Larson MG, Benjamin EJ, et al. Long-term trends in the incidence of and survival with heart failure. N Engl J Med. 2002 Oct 31;347(18):1397-402.

35. Taylor CJ, Ryan R, Nichols L, et al. Survival following a diagnosis of heart failure in primary care, Family Practice, Volume 34, Issue 2, 1 April 2017, Pages 161–168, doi.org/10.1093/fampra/cmw145

36. Harikrishnan S, Sanjay G, Agarwal A, et al. One-year mortality outcomes and hospital readmissions of patients admitted with acute heart failure: Data from the Trivandrum Heart Failure Registry in Kerala, India. Am Heart J. 2017 Jul;189:193-199. doi: 10.1016/j.ahj.2017.03.019. Epub 2017 Apr 2.

37. Mamas MA, Sperrin M, Watson MC, et al. Do patients have worse outcomes in heart failure than in cancer? A primary care-based cohort study with 10-year follow-up in Scotland. Eur J Heart Fail. 2017 Sep;19(9):1095-1104. doi: 10.1002/ejhf.822.

38. Yancy CW, Jessup M, Bozkurt B, et al. 2016 ACC/ AHA/HFSA focused update on new pharmacological therapy for heart failure: an update of the 2013 ACCF/ AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. J Am Coll Cardiol. 2016;68:1476–88.

39. Komajda M, Anker SD, Cowie MR, et al. QUALIFY Investigators. Physicians' adherence to guideline-recommended medications in heart failure with reduced ejection fraction: data from the QUALIFY global survey. Eur J Heart Fail. 2016 May;18(5):514-22. doi: 10.1002/ejhf.510. Epub 2016 Apr 20.

40. Chang HY, Wang CC, Wei J, et al. Gap between guidelines and clinical practice in heart failure with reduced ejection fraction: Results from TSOC-HFrEF registry. J Chin Med Assoc. 2017 Dec;80(12):750-757. doi:10.1016/j.jcma.2017.04.011.

41. Pokharel Y, Wei J, Hira RS, et al. Guideline-Directed Medication Use in Patients With Heart Failure With Reduced Ejection Fraction in India: American College of Cardiology's PINNACLE India Quality Improvement Program. Clin Cardiol. 2016 Mar;39(3):145-9. doi:10.1002/clc.22519.

42. Willenheimer R, van Veldhuisen DJ, Silke B, et al. Effect on survival and hospitalization of initiating treatment for chronic heart failure with bisoprolol followed by enalapril, as compared with the opposite sequence: results of the randomized Cardiac Insufficiency Bisoprolol Study (CIBIS) III. Circulation. 2005; 112:2426–35.

43. 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. J Am Coll Cardiol 2017

44. Ponikowski P, Voors AA, Anker SD, et al. Authors/Task Force Members; Document Reviewers. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2016 Aug;18(8):891-975.

45. Testani JM, Stevens SR, Brisco MA, et al. Influence of diuretic dose and route of administration on loop diuretic efficiency: insights from the Diuretic Optimization Strategies Evaluation in Acute Heart Failure (DOSE-AHF) trial. J Card Fail. 2014;20:S40.

46. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACC/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;62:e147–239.

47. Damman K, Testani JM. The kidney in heart failure: an update. Eur Heart J.2015 Jun 14;36(23):1437-44. doi: 10.1093/eurheartj/ehv010.

48. Yancy CW, Januzzi JL Jr., Allen LA, et al. 2017 ACC Expert Consensus Decision Pathway for Optimization of Heart Failure Treatment: Answers to 10 Pivotal Issues About Heart Failure With Reduced Ejection Fraction: A Report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol. 2018 Jan 16;71(2):201-230. doi: 10.1016/j.jacc.2017.11.025. Epub 2017 Dec 22.

49. Ather S, Chan W, Bozkurt B, et al. Impact of noncardiac comorbidities on morbidity and mortality in a predominantly male population with heart failure and preserved versus reduced ejection fraction. J Am Coll Cardiol. 2012;59:998–1005. doi: 10.1016/j.jacc.2011.11.040

50. Yancy CW, Lopatin M, Stevenson LW, et al. ADHERE Scientific Advisory Committee and Investigators. Clinical presentation, management, and in-hospital outcomes of patients admitted with acute decompensated heart failure with preserved systolic function: a report from the Acute Decompensated Heart Failure National Registry (ADHERE) Database [published correction appears in J Am Coll Cardiol. 2006;47:1502]. J Am Coll Cardiol. 2006;47:76–84. doi: 10.1016/j.jacc.2005.09.022.

51. Braunstein JB,Anderson GF, Gerstenblith G, et al. Noncardiac comorbidity increases preventable hospitalizations and mortality among Medicare beneficiaries with chronic heart failure. J Am Coll Cardiol. 2003;


52. Zinman B, Wanner C, Lachin JM, et al. EMPA-REG OUTCOME Investigators. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015 Nov 26;373(22):2117-28. doi: 10.1056/NEJMoa1504720.

53. Drozd M, Jankowska EA, Banasiak W, et al. Iron Therapy in Patients with Heart Failure and Iron Deficiency: Review of Iron Preparations for Practitioners. Am J Cardiovasc Drugs. 2017 Jun;17(3):183-201. doi: 10.1007/s40256-016-0211-2.

54. Bhatt AS, DeVore AD, Hernandez AF, et al. Can Vaccinations Improve Heart Failure Outcomes?: Contemporary Data and Future Directions. JACC Heart Fail. 2017 Mar;5(3):194-203. doi: 10.1016/j.jchf.2016.12.007.

55. Heidenreich PA, Albert NM, Allen LA, et al. Forecasting the impact of heart failure in the United States:a policy statement from the American Heart Association.Circ Heart Fail. 2013;6:606–19.

56. Mozaffarian D, Benjamin EJ, Go AS, et al. Heart

disease and stroke statistics–2016 update: a report From the American Heart Association. Circulation.2016;133:e38–360.

57. Pandey KR, Meltzer DO. Financial Burden and Impoverishment Due to Cardiovascular Medications in Low and Middle Income Countries: An Illustration from India. PLoS One. 2016 May 9;11(5):e0155293. doi: 10.1371/journal.pone.0155293.

58. Cotter G, Metra M, Davison BA, et al. Worsening heart failure, a critical event during hospital admission for acute heart failure: results from the VERITAS study. Eur J Heart Fail. 2014;16(12):1362-71.

59. Medicines. www.1mg.com. Last accessed on 4th May,2018

60. Mehra MR, Canter CE, Hannan MM, et al. The 2016 International Society for Heart Lung Transplantation listing criteria for heart transplantation: a 10- year update. J Heart Lung Transplant 2016;35:1-23.

61. Baumwol J. “I Need Help”—a mnemonic to aid timely referral in advanced heart failure. J Heart Lung Transplant. 2017;36:593–4.

62. Metra M, Ponikowski P, Dickstein K, et al. Advanced chronic heart failure: a position statement from the Study Group on Advanced Heart Failure of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 2007;9:684-94.

63. Rogers JG, Patel CB, Mentz RJ, et al. Palliative Care in Heart Failure: The PAL-HF Randomized, Controlled Clinical Trial. J Am Coll Cardiol. 2017 Jul 18;70(3):331-341. doi: 10.1016/j.jacc.2017.05.030.

64. Ruppar TM, Cooper PS, Mehr DR, et al. Medication Adherence Interventions Improve Heart Failure Mortality and Readmission Rates:Systematic Review and Meta-Analysis of Controlled Trials. J Am Heart Assoc. 2016 Jun 17;5(6).

65. Unverzagt S, Meyer G, Mittmann S, et al. Improving Treatment Adherence in Heart Failure. Dtsch Arztebl Int. 2016 Jun 24;113(25):423-30. doi: 10.3238/arztebl.2016.0423.

REVIEW ARTICLE


Hypoglycemia & Cardiovascular Risk

CLINICAL OPINION

VINOD K GUJRAL

Diabetes is a major risk factor for cardiovascular disease. Patients having coronary artery disease (CAD) and diabetes have higher risk of mortality and morbidity than patients without diabetes. Hypoglyce-mia is a very common side effect associated with insulin therapy and treatment with sulfonylureas. Severe hypoglycemia can precipitate adverse cardiovascular outcomes such as myocardial ischemia and cardiac arrhythmia. Thus very good glycemic control is associated with fewer cardiovascular events. However, tight glycemic control may increase the risk of hypoglycemia.

Keywords cardiovascular disease diabetes hypoglycemia coronary artery disease

Late Dr Vinod K Gujral was Senior Consultant CardioDiabetologist, National Heart Institute, New Delhi

Diabetes is a major risk factor for cardiovascular disease.1 Patients with coronary artery disease

(CAD) and diabetes have higher mortal-ity and morbidity than patients without diabetes. Data from studies such as the UK Prospective Diabetes Study suggest that very good glycemic control is asso-ciated with fewer cardiovascular events.2 However, tight glycemic control may in-crease the risk of hypoglycemia.

Hypoglycemia is a very common side eff ect of insulin therapy and, to a lesser extent, of treatment with sulfonylureas. (Table 1) Severe hypoglycemia can pre-cipitate adverse cardiovascular outcomes such as myocardial ischemia and cardiac arrhythmia.

Risk factors for severe hypoglycemia include

Age Duration of diabetes Strict glycemic control Sleep

Impaired awareness of hypoglyce-mia,

Renal impairment, C-peptide negativity and Previous history of severe hypogly-

cemia.3,4

The adverse Cardiovascular events are mainly secondary to autonomic activa-tion which result in (Figure 1)

Hemodynamic changes, Vasoconstriction and Rise in intravascular coagulability

and viscosity.

Acute hypoglycemia provokes pro-nounced physiological responses, the important consequences of which are to maintain the supply of glucose to brain and promote hepatic production of glu-cose. Blood fl ow is increased to the myo-cardium, splanchnic circulation and the brain.

Hypoglycemia and the rapid changes in blood glucose have been shown to


increase counter-regulatory hormones such as epinephrine and nor-epinephrine, which may induce vasoconstriction and platelet aggregation, thereby precipitat-ing myocardial ischemia.5,6

Autonomic activation, principally of the sympatho-adrenal system, results in end-organ stimulation and the profuse release of epinephrine which precipitates hemodynamic changes like tachycardia, increased peripheral systolic blood pres-sure, decreased central blood pressure and increased myocardial contractility with an increased ejection fraction.7,8

The increased activity of sympathetic nervous system and secretion of other hormones and peptides such as the po-tent vasoconstrictor endothelin have pro-nounced eff ects on intravascular coagu-lability and viscosity.9 Increased plasma viscosity occurs during hypoglycemia because of an increase in erythrocyte con-centration, while coagulation is promoted by platelet activation and an increment in factor VIII and Von-Willebrand factor. Endothelial functions may be compro-

mised during hypoglycemia because of an increase in C-reactive protein, mobi-lization and activation of neutrophils and platelet activation.

The catecholamine-induced increased myocardial contractility may induce isch-emia in the myocardium in patients with CAD. The greater oxygen demand is not met because of not only the rigid vessels, but also endothelial dysfunction with fail-ure to vasodilate.

Several studies have shown that the hypoglycemia is associated with a sig-nifi cant lengthening of the corrected QT interval (QTC) in subjects with and with-out diabetes.10,11 These changes are likely seen because of increased catecholamine release during hypoglycemia, and QTC prolongation, in particular, could lead to a high risk of ventricular tachycardia and sudden death.12 Hyperinsulinemia and in-creased secretion of catecholamines may lead to hypokalemia during hypoglyce-mia, thus potentiating cardiac repolariz-ing abnormalities. These eff ects can be reversed by β-blockade and potassium replacements.12

Infl ammation has been associated with cardiovascular disease and diabetes. Epi-

Table 1. Hypoglycemia associated with glucose-lowering medicationMedicationMedication Proposed MechanismProposed Mechanism NotesNotes

MetforminMetformin Decreased hepatic glucose production/GI Decreased hepatic glucose production/GI

glucose absorption; increased peripheral glucose absorption; increased peripheral

glucose uptake/insulin-tissue sensitivityglucose uptake/insulin-tissue sensitivity

May induce hypoglycaemia if used concurrently May induce hypoglycaemia if used concurrently

with other hypoglycaemic agents, increased ex-with other hypoglycaemic agents, increased ex-

ercise, decreased caloric intakeercise, decreased caloric intake

Sulfonylureas/Sulfonylureas/

meglitinidesmeglitinides

Increased insulin secretion/sensitivityIncreased insulin secretion/sensitivity Hypoglycaemia, especially in malnourished state Hypoglycaemia, especially in malnourished state

or if take without food; caution in renal/hepatic or if take without food; caution in renal/hepatic

insufficiency, adrenal/pituitary insufficiency, ad-insufficiency, adrenal/pituitary insufficiency, ad-

vanced age, concurrent use of other hypoglycae-vanced age, concurrent use of other hypoglycae-

mic medications/alcoholmic medications/alcohol

GLP-1GLP-1 Incretin mimetic enhances glucose-depen-Incretin mimetic enhances glucose-depen-

dent insulin secretion; reduces glucagon dent insulin secretion; reduces glucagon

circulation; slows GI emptyingcirculation; slows GI emptying

Hypoglycaemic risk increases with other hypo-Hypoglycaemic risk increases with other hypo-

glycemic agents; may require dose adjustmentglycemic agents; may require dose adjustment

TZDsTZDs Enhance peripheral glucose utilization/tis-Enhance peripheral glucose utilization/tis-

sue uptakesue uptake

Hypoglycaemic risk increases with other hypo-Hypoglycaemic risk increases with other hypo-

glycemic agents; may require dose adjustmentglycemic agents; may require dose adjustment

Alpha-glucosi-Alpha-glucosi-

dase inhibitorsdase inhibitors

Lower postparendial serum glucose by Lower postparendial serum glucose by

slowing GI absorption of starches/sugarsslowing GI absorption of starches/sugars

Hypoglycaemic risk increases with concurrent Hypoglycaemic risk increases with concurrent

sulfonylurea usesulfonylurea use

DPP-4 inhibitorsDPP-4 inhibitors Preserve/enhance action of endogenous Preserve/enhance action of endogenous

incertin hormones (GIP and GLP-1); in-incertin hormones (GIP and GLP-1); in-

crease glucose-dependent insulin secre-crease glucose-dependent insulin secre-

tion; decrease glucoagon circulation; slow tion; decrease glucoagon circulation; slow

GI emptyingGI emptying

Reserved for T2DM; hypoglycaemic risk increas-Reserved for T2DM; hypoglycaemic risk increas-

es wih other hypoglycaemic agents; may require es wih other hypoglycaemic agents; may require

dose adjustmentdose adjustment

Amylinomimet-Amylinomimet-

icsics

Lower postparandial serum glucose by Lower postparandial serum glucose by

slowing GI Absorption of starches/sugars; slowing GI Absorption of starches/sugars;

may decrease glucagon secretionmay decrease glucagon secretion

Hypoglycaemic risk may be outweigh benefits/Hypoglycaemic risk may be outweigh benefits/

increases with other concurrent hypoglycaemic increases with other concurrent hypoglycaemic

agentsagents

DPP-4: dipeptidyl peptidase-4' GI: gastrointestinal; GIP: glucose-dependent insulinotropic polypeptide; GLP-1: gluca-DPP-4: dipeptidyl peptidase-4' GI: gastrointestinal; GIP: glucose-dependent insulinotropic polypeptide; GLP-1: gluca-

gon-like peptide-1; T2DM: type 2 diabetes mellitus; TZDs: thiadoldinediones.gon-like peptide-1; T2DM: type 2 diabetes mellitus; TZDs: thiadoldinediones.

Figure 1. The various mechanisms of cardio vascular events caused by severe hypoglycemia

HYPOGLYCEMIA (Blood Glucose <70mg%) &HYPOGLYCEMIA (Blood Glucose <70mg%) &RAPID CHANGES IN BLOOD GLUCOSERAPID CHANGES IN BLOOD GLUCOSE

INCREASED INCREASED CARDIOVASCULAR CARDIOVASCULAR

MORBIDITY & MORBIDITY & MORTALITYMORTALITY

AUTONOMIC ACTIVATIONAUTONOMIC ACTIVATION(Epinephrine, Endothelin, Coagulants, Cytokines)(Epinephrine, Endothelin, Coagulants, Cytokines)

• • TachycardiaTachycardia• • Rise in Syst.BPRise in Syst.BP• • Fall in Cent.BPFall in Cent.BP• • Rise in Myocar-Rise in Myocar-

dial Contractilitydial Contractility

HEMODYANAMICHEMODYANAMICINSTABILITY &INSTABILITY &

MYOCARDIAL MYOCARDIAL ISCHEMIAISCHEMIA

• • Increased Increased EndothelinEndothelin

VASO-VASO-CONSTRICTIONCONSTRICTION

• • High Erythrocyte High Erythrocyte concentrationconcentration

• • High Platelet High Platelet AggregationAggregation

• • High Factor-VIIIHigh Factor-VIII• • High VW FactorHigh VW Factor

HIGH Intravascular HIGH Intravascular Coagulation & ViscocityCoagulation & Viscocity

• • Increased QTC Increased QTC • • Decreased K+Decreased K+

VentricularVentricularArrhythmia & Arrhythmia &

SUDDEN DEATHSUDDEN DEATH

• • High CRPHigh CRP• • High Neutrophil ActivationHigh Neutrophil Activation• • Platelet ActivationPlatelet Activation• • High CytokinesHigh Cytokines

ENDOTHELIAL ENDOTHELIAL DYSFUNCTION & DYSFUNCTION &

VESSEL STIFFNESSVESSEL STIFFNESS

CLINICAL OPINION


sodes of hypoglycemia have been found to be associated with rise in infl ammatory cytokines including interleukin (IL)-6, IL-8, tumor necrosis factor (TNF)-α, C-reactive protein and endothelin-1.13 These infl ammatory cytokines result in endothe-lial injury and abnormalities in coagula-tion, resulting in rise of cardiovascular events. Infl ammatory cytokines like IL-1 have also been shown to increase the se-verity of hypoglycemia, thus perpetuating a positive feedback cycle.14 Studies have suggested that endothelial function may be compromised during acute hypogly-cemia. Vessel wall stiff ness was found to be increased during hypoglycemia in pa-tients with type-1 diabetes of longer du-ration than those with shorter duration of diabetes.15

Thus, hypoglycemia may increase the risk of cardiovascular events, especially in subsets of patients with longer dura-tion of diabetes. Infl ammation and endo-thelial dysfunction could potentially be the aggravating factors that contribute to increased cardiovascular risk with severe hypoglycemia, especially in the subset of patients with pre-existing cardiovascular disease, diabetes, and severe autonomic neuropathy.

In the adult human, acute hypogly-cemia causes pronounced physiological responses as a consequence of autonomic activation, principally of the sympatho-adrenal system, and results in end-organ stimulation and a profuse release of epi-nephrine (adrenaline). This profound au-tonomic stimulus provokes hemodynamic changes, the important consequences of which are to maintain the supply of glu-cose to the brain and promote the hepat-ic production of glucose. Blood fl ow is therefore increased to the myocardium, the splanchnic circulation (to provide pre-cursors of gluconeogenesis to the liver), and the brain. The hemodynamic changes associated with hypoglycemia include an increase in heart rate and peripheral sys-tolic blood pressure, a fall in central blood pressure, reduced peripheral arterial resis-tance (causing a widening of pulse pres-sure), and increased myocardial contrac-tility, stroke volume, and cardiac output.9 The workload of the heart is therefore temporarily but markedly increased. This

transient cardiac stress is unlikely to be of serious functional importance in healthy young people who have a normal CV system, but may have dangerous conse-quences in many older people with dia-betes, especially individuals with type 2 diabetes, many of whom have coronary heart disease.

In nondiabetic people, the arteries be-come more elastic during acute hypogly-cemia with a decline in arterial wall stiff -ness, but in people with type 1 diabetes of >15 years’ duration, arterial wall stiff ness per se is greater and arteries are less elas-tic in response to hypoglycemia, mani-festing in a lesser fall in central arterial pressure.15 Normal elasticity of the arteri-al wall ensures that the refl ected pressure wave from the high-pressure arterioles, generated during each myocardial con-traction, returns to the heart during early diastole, so enhancing coronary arterial perfusion, which occurs mainly during diastole. However, progressive stiff ening of the arterial walls (as occurs in most people with longstanding diabetes) ac-celerates the return of the refl ected wave causing its earlier arrival during late sys-tole. This pathophysiological eff ect may interfere with coronary arterial perfusion and promote myocardial ischemia.

Hypoglycemia has long been known to aff ect the electrocardiogram (ECG),16 causing ST wave changes with lengthen-ing of the QT interval12 and cardiac repo-larization.17 Both experimentally induced and spontaneous clinical hypoglycemic episodes prolong cardiac repolarization, the process whereby the heart prepares for coordinated contraction during diastole and where abnormalities in other condi-tions can increase the risk of cardiac ar-rhythmias. These changes are refl ected by changes in the T wave of the electrocar-diogram (Figure 1). Hypoglycemia leads to reduction in its amplitude with fl at-tening and lengthening of the T wave,18 which is quantifi ed by measuring the length of the QT interval (mathematical-ly corrected for the prevailing heart rate [QTc]). Electrophysiological changes are related to hypokalemia, which is a con-sequence of the profuse secretion of cat-echolamines. These changes may increase the risk of cardiac arrhythmia; various ab-

normal heart rhythms, including ventricu-lar tachycardia and atrial fi brillation, have been reported during hypoglycemia. This phenomenon and its contribution to caus-ing sudden death after hypoglycemia are discussed in detail below.

HYPOGLYCEMIA AS A POTENTIAL RISK FACTOR FOR SUDDEN DEATH IN DIABETESCumulating clinical and experimental evi-dence has shown that hypoglycemia can cause abnormal electrical activity in the heart and has strengthened the premise that hypoglycemia can provoke sudden death. High-resolution electrocardiogra-phy, which measures the QT interval pre-cisely, in conjunction with hypoglycemic clamps to control the depth of hypoglyce-mia, has demonstrated lengthening of the QT interval both in diabetic and nondia-betic individuals.19,20 Clinical episodes of hypoglycemia have been shown to cause QT lengthening, measured using ambula-tory.

ECG monitoring and simultaneous measurement of blood glucose (by either intermittent venous sampling or continu-ous glucose monitoring).21

POTENTIAL ROLE OF CARDIAC AUTO-NOMIC NEUROPATHYIt is possible that an interaction between hypoglycemia-induced abnormalities of cardiac repolarization and autonomic neuropathy contributes to the risk of sud-den death in individuals with diabetes. Diabetic autonomic neuropathy is known to be associated with an increased mor-tality, and resting QT intervals are gen-erally longer in patients with autonomic neuropathy than in patients without.22 The recent demonstration that brief periods of experimental hypoglycemia impair CV autonomic function for up to 16 h is ad-ditional evidence for a clinically relevant interaction.23

A direct relationship between hypo-glycemia and fatal cardiovascular event is diffi cult to demonstrate as blood glucose and cardiac monitoring are seldom per-formed simultaneously. In the ACCORD study, excess of deaths was noted in the intensive treatment arm, which led to discontinuation of study.24 In the smaller


study of veterans with type-2 diabetes, Veterans Aff airs Diabetes Trial (VADT),25 severe hypoglycemia was found to in-crease the risk of adverse events and deaths.

The 4 trials conducted in people with type 2 diabetes mellitus diff ered with re-spect to the participants studied and the approach used. The UKPDS was con-ducted in people with newly diagnosed type 2 diabetes mellitus and relatively low cardiovascular risk; only 2% had

a history of preexisting cardiovascular disease.27,33 Conversely, the ACCORD, ADVANCE, and VADT were conducted in people with established diabetes of 10, 8, and 12 years duration, respectively, and with other risk factors for cardiovascular disease. Indeed, 35%, 32%, and 40% of participants in ACCORD, ADVANCE, and VADT had a previous cardiovascular event, respectively. These trials diff ered in the approach to glucose lowering. In the UKPDS, the 2 diff erent fasting glucose

levels were targeted by allocating people to an intensive glucose control policy that started with insulin or sulfonylurea ver-sus a conventional control policy based on diet, whereas in the ACCORD, AD-VANCE, and VADT trials, 2 diff erent lev-els of hemoglobin A1c were targeted with a similar, broad menu of drugs that were added or adjusted at regular visits. These glycemia intervention strategies achieved median hemoglobin A1c levels that var-ied from 6.4% to 7.0% in the intensive-therapy groups and from 7.3% to 8.4% in the standard-therapy groups.

A recent analysis from ACCORD (26) confi rmed that patients with baseline car-diac autonomic neuropathy were about twice as likely to die as patients without cardiac autonomic neuropathy.

In contrast to the ACCORD study, in VADT, a recent severe hypoglycemic event was an important predictor for CV death (HR 3.72; 95% CI 1.34–10.4; P < 0.01) and all-cause mortality (HR 6.37; 95% CI 2.57–15.8; P = 0.0001).

By contrast, in the ADVANCE study,27 in which the overall occurrence of severe hypoglycemia was much lower than in ACCORD, no increase in all-cause or CV mortality was observed in patients ran-domized to the intensive arm. (Table 2) Nevertheless, severe hypoglycemia was strongly associated with increased risks of various adverse clinical outcomes , and the authors suggested that whereas severe hypoglycemia may contribute to these outcomes, it may alternatively be a marker of vulnerability to these events.

According to a recent meta-analysis, the benefi cial eff ect of strict glycemic control on CV events28 seems to be lim-ited for patients who are free from CVD, a less stringent glycemic target should be recommended for diabetic patients with longer duration of the disease, shorter life expectancy, advanced macrovascular complications, and chronic kidney dis-ease and patients who are prone to hypo-glycemia.28

A meta-analysis of various studies revealed that severe hypoglycaemia defi -nitely & signifi cantly increases the ad-verse cardiovascular events (Table 3).

Hypoglycemia may render high-CV-risk patients with type 2 diabetes sus-

Table 2. Differences between the ACCORD and ADVANCE studies

Characteristic Characteristic ACCORD ACCORD ADVANCEADVANCE

Baseline data Baseline data

Participants, n Participants, n 10 25110 251 11 14011 140

Mean age (y)Mean age (y) 6262 6666

Duration of diabetes (median [ACCORD]/mean [AD-Duration of diabetes (median [ACCORD]/mean [AD-VANCE]) (y)VANCE]) (y)

1010 88

Mean HbA1c at baseline (%) Mean HbA1c at baseline (%) 8.18.1 7.27.2

History of macrovascular disease (%)History of macrovascular disease (%) 3535 3232

Intervention Intervention

Target HbA1c value (%)Target HbA1c value (%) <6.0<6.0 £6.5£6.5

Mean duration (y)Mean duration (y) 3.43.4 5.05.0

Treatments at study completion Treatments at study completion (intensive vs standard) (%)(intensive vs standard) (%)

--Insulin--Insulin 77 vs 5577 vs 55 41 vs 2441 vs 24

--Metformin--Metformin 95 vs 8795 vs 87 74 vs 6774 vs 67

--Secretagogue (sulfonylurea or glinide) --Secretagogue (sulfonylurea or glinide) 87 vs 7487 vs 74 94 vs 6294 vs 62

--TZD--TZD 92 vs 5892 vs 58 17 vs 1117 vs 11

--Incretin --Incretin 18 vs 518 vs 5 Not reported Not reported

--Statin --Statin 88 vs 8888 vs 88 46 vs 4846 vs 48

--Any antihypertensive --Any antihypertensive 91 vs 9291 vs 92 89 vs 8889 vs 88

--ACE inhibitor --ACE inhibitor 70 vs 7270 vs 72 Not reportedNot reported

--Aspirin --Aspirin 76 vs 7676 vs 76 57 vs 5557 vs 55

Outcome (intensive vs standard)Outcome (intensive vs standard)

Median HbA1c at study end (%)Median HbA1c at study end (%) 6.4 vs 7.5*6.4 vs 7.5* 6.4 vs 7.0*6.4 vs 7.0*

Death from any cause (%)Death from any cause (%) 5.0 vs 4.0*5.0 vs 4.0* 8.9 vs 9.68.9 vs 9.6

Death from cardiovascular cause (%)Death from cardiovascular cause (%) 2.6 vs 1.8*2.6 vs 1.8* 4.5 vs 5.24.5 vs 5.2

Nonfatal MI (%)Nonfatal MI (%) 3.6 vs 4.6*3.6 vs 4.6* 2.7 vs 2.82.7 vs 2.8

Nonfatal stroke (%)Nonfatal stroke (%) 1.3 vs 1.21.3 vs 1.2 3.8 vs 3.83.8 vs 3.8

Major/severe hypoglycemia (%/y)Major/severe hypoglycemia (%/y) 3.1 vs 1.0*3.1 vs 1.0* 0.7 vs 0.40.7 vs 0.4

Weight gain (kg)Weight gain (kg) 3.5 vs 0.43.5 vs 0.4 0.0 vs -1.0*0.0 vs -1.0*

Current smoking (%)Current smoking (%) 10 vs 10 10 vs 10 8 vs 88 vs 8

*The comparison between the intensive and the standard arms was signifi cant.*The comparison between the intensive and the standard arms was signifi cant.

Adapted from the New England Journal of Medicine. ©2008 New England Journal of MedicineAdapted from the New England Journal of Medicine. ©2008 New England Journal of Medicine

CLINICAL OPINION


ceptible to serious arrhythmias, possibly because the condition alters cardiac auto-nomic tone and promotes abnormal repo-larizations, suggests a small observational study.29

In 25 such patients on insulin therapy for at least four years, who wore 12-lead Holter monitors and continuous glucose monitors for fi ve days while conducting normal daily activities, the devices docu-mented a variety of ECG abnormalities associated with episodes of silent hypo-glycemia, which occurred mostly at night. The ECG abnormalities included atrial ectopic beats, ventricular premature beats (VPBs), bradycardia, and ventricular tachycardia (VT), as well as T-wave ab-normalities and prolonged QT intervals.(Figure 2).

In addition to the sharp jump in brady- arrhythmias during nocturnal hypoglyce-mia (p=0.02), atrial ectopic beats went up during hypoglycemia at night but not dur-ing the day; VPBs were more prevalent during hypoglycemia, especially at night, but the rate of complex VPBs didn't rise with hypoglycemia during either day or night.

Moreover, the daytime corrected QT

(QTc) interval averaged 402 ms during hypoglycemia and 384 ms during eugly-cemia (p=0.05). At night, the levels were statistically similar at 440 ms and 432 ms, respectively. "Two individuals had QTc >500 ms during hypoglycemia," accord-ing to the group.30

Hypoglycaemia caused by glucose-lowering therapy has been linked to car-diovascular (CV) events. The ORIGIN trial provides an opportunity to further assess this relationship.31

This analysis of data collected during the ORIGIN trial shows that both severe

hypoglycaemia and nocturnal severe hy-poglycaemia independently predicted car-diovascular events and mortality in people having cardiovascular risk factors and ear-ly type 2 diabetes or with dysglycemia.31 As reported previously, participants allo-cated to insulin glargine vs. standard care experienced a higher incidence of severe and non-severe hypoglycaemia. Despite this diff erence, the present analysis also shows that the relationship between se-vere hypoglycaemia and these outcomes was substantially higher in individuals al-located to standard glycaemic control vs. those who targeted normal glucose levels with insulin glargine (Table 4).

Explanations for the observed rela-tionship between severe hypoglycaemia and cardiovascular outcomes include the pathophysiological mechanisms noted above. However, it is also possible that people who are prone to hypoglycae-mic episodes have some other attribute that puts them at risk for cardiovascular outcomes. Indeed the fi nding of a sub-stantially stronger relationship between severe hypoglycaemia and outcomes in the standard care group, within which guideline suggested, but not normal, fast-ing glucose levels were being sought, than in the insulin glargine-mediated normo-glycaemic group supports the possibil-ity that severe hypoglycaemia may be a marker rather than an accelerator of future cardiovascular outcomes. If this assump-tion were true, a stronger relationship to cardiovascular outcomes would indeed be expected when severe hypoglycaemia occurs in response to standard approaches to glucose lowering than when it appears

Table 4. Hypoglycemia: Origin trial

Glargin (n= 6264)Glargin (n= 6264) Standard (n=6273)Standard (n=6273) P ValueP Value

Any non severeAny non severe

1 or more1 or more 5757 1717 2525 55 <0.001<0.001

NoneNone 4343 7575 <0.001<0.001

Confirmed non severeConfirmed non severe

1 or more1 or more 4242 1010 1414 33 <0.001<0.001

NoneNone 5858 8686 <0.001<0.001

SevereSevere

1 or more1 or more 66 0101 22 0.30.3 <0.001<0.001

Table 3. Major Hypoglycemia Significantly Increases Adverse Cardio Vascular Outcomes in Type2 DM Patients28

Clinical outcomeClinical outcome No. of eventsNo. of events Hazard ratio adjusted Hazard ratio adjusted

for treatment assignedfor treatment assigned

P- valueP- value

Macrovascular EventsMacrovascular Events 11471147 4.054.05 <.001<.001

Microvascular EventsMicrovascular Events 11311131 2.392.39 <.001<.001

Death From CV CauseDeath From CV Cause 542542 4.864.86 <.001<.001

Death from Non CVDeath from Non CV 489489 4.824.82 <.001<.001

Figure 2. Effect of experimental hypoglycaemia on QT interval

5.0mm 2.5mm


in response to targeting lower blood glu-cose levels even, as in the insulin glargine arm of ORIGIN.31 This is because people with a lower threshold for severe hypo-glycaemia (i.e. those who develop it when targeting higher glucose levels) may also share other risk factors for cardiovascular outcomes. In support of this possibility, the following arguments can be made: fi rst, although previous trials have linked severe hypoglycaemia with cardiovascu-lar prognosis, they have not shown that this is related to the intensity of glucose lowering; second meta-analyses of trials comparing more vs. less intensive glycae-mic control suggested a decrease in ma-jor cardiovascular events in the intensive groups despite an increased number of se-vere hypoglycaemic episodes; and third, a similar fi nding was reported in the Action to Control Cardiovascular Disease in Dia-betes (ACCORD) trial,24 in which people

allocated to intensive glucose lowering who had a severe hypoglycaemic event had a lower risk of death than people in the standard arm with a severe hypogly-caemic event. The fact that we observed such an eff ect within the ORIGIN trial within which glucose lowering was me-diated by insulin glargine (as opposed to the menu of drugs used in ACCORD) pro-vides further support for this possibility.

Other alternative or supplementary explanations are possible. One is the much higher use of sulfonylureas in the standard arm (Table 1). This may be par-ticularly relevant in light of the small between-group diff erence in HbA1c noted in the trial. In addition to promot-ing hypoglycaemia, sulfonylureas stimu-late insulin secretion from the pancreatic beta cells by binding to ATP-dependent potassium channels. Such channels are located in many tissues, among them the

heart and they are involved in myocar-dial adaptation to ischaemia. The use of sulfonylurea may therefore worsen the consequences of any ischaemic episode. Another is the possibility that the greater frequency of non-severe hypoglycaemia in the glargine arm might have induced a greater tolerance for subsequent severe events in the glargine group, and this may have accounted for lower absolute inci-dence of events (and hazard) in people who had severe hypoglycaemic episodes in the glargine vs. standard group.32

THE CONCLUSIONS & CLINICAL GUIDELINES In view of the available convincing evi-dences , it would be fair and necessary to tailor make the targets of glycemic con-trol (HbA1C), the rate of lowering the blood glucose and the selection of oral or injectable anti hyperglycaemic agents for diff erent group of diabetes patients on the basis of their age, duration of diabetes, co-morbidities, life expectancy ,history of hypoglycaemias and their existing cardio-vascular status (Fig. 3) (Table 5).

The American Diabetes Association (ADA), in 2013 Guidelines for standard of diabetes care suppliments, published three levels of glycemic control for diff er-ent CV & Hypoglycemia risk individuals with Diabetes. (Table 5)

REFERENCES1. Morrish NJ, Wang SL, Stevens LK, Fuller JH, Keen H.

Mortality and causes of death in the WHO Multinational Study of Vascular Disease in Diabetes. Diabetologia. 2001;44(Suppl 2):S14–21.

2. United Kingdom Prospective Diabetes Study Group. United Kingdom Diabetes Study 24: A 6-year, randomized,controlled trial comparing sulfonylurea, insu-lin, and metformin therapy in patients with newly diag-nosed type 2 diabetes that could not be controlled with diet therapy. Ann Intern Med. 1998;128:165–75.

3. Mühlhauser I, Overmann H, Bender R, Bott U, Berger M. Risk factors of severe hypoglycaemia in adult patients with type 1 diabetes: A prospective population based study. Diabetologia. 1998;41:1274–82.

4. Strachan MW. Frequency, causes and risk factors for hypoglycaemia in type 1 diabetes. In: Frier BM, Fisher M, editors. Hypoglycaemia in Clinical Diabetes. 2nd ed. Chichester: John Wiley and Sons; 2007. pp. 49–81.

5. DeFronzo RA, Hendler R, Christensen N. Stimulation of counterregulatory hormonal responses in diabetic man by a fall in glucose concentration. Diabetes. 1980;29:125–31.

6. Galassetti P, Davis SN. Effects of insulin per se on neuro-endocrine and metabolic counter-regulatory responses to hypoglycaemia. Clin Sci (Lond) 2000;99:351–62.

7. Hilsted J, Bonde-Petersen F, Norgaard MB, Grreniman M, Christsen NJ, Parving HH, et al. Haemodynamic changes Figure 3. The targets of glycemic control in type1 & type 2 diabetics

A target A1C A target A1C 6.5% may 6.5% may

be considered in some be considered in some

patients with type 2 dia-patients with type 2 dia-

betes to further lower the betes to further lower the

risk of nephropathy and risk of nephropathy and

retinopathy which must be retinopathy which must be

balanced against the risk of balanced against the risk of

hypoglycaemiahypoglycaemia

Consider 7.1-8.5% if:Consider 7.1-8.5% if:• • Limited life expectancyLimited life expectancy• • High level of functional dependencyHigh level of functional dependency• • Extensive coronary artery disease at high risk of Extensive coronary artery disease at high risk of

ischaemic eventsischaemic events• • Multiple co-morbiditiesMultiple co-morbidities• • History of recurrent severe hpoglycaemiaHistory of recurrent severe hpoglycaemia• • Hypoglycaemia unawarenessHypoglycaemia unawareness• • Longstanding diabetes for whom it is difficult to Longstanding diabetes for whom it is difficult to

achieve an A1C achieve an A1C 7%, despite effective doses of 7%, despite effective doses of multiple antihyperglycaemic agents, including multiple antihyperglycaemic agents, including intensified basal-bolus insulin therapy.intensified basal-bolus insulin therapy.

8.5%8.5%6.0%6.0%7%7%

7% >7%7% >7%

Most patients Most patients

with type 1 and with type 1 and

type 2 diabetestype 2 diabetes

Table 5. Glycemic goals in various CV risk groups33

GoalGoal Level of EvidenceLevel of Evidence

NEWLY DIAGNOSED : Lowering A1c to <7% has been shown to NEWLY DIAGNOSED : Lowering A1c to <7% has been shown to

reduce microvascular complications & long term reduction in mac-reduce microvascular complications & long term reduction in mac-

rovascular diseaserovascular disease

BB

For SELECTED PATIENTS <40 years age(short duration of diabetes), For SELECTED PATIENTS <40 years age(short duration of diabetes),

no existing CV disease : Lowering A1c to < 6.5% (without signifi-no existing CV disease : Lowering A1c to < 6.5% (without signifi-

cant hypoglycemia) is recommendedcant hypoglycemia) is recommended

CC

PATIENTS with H/O significant hypoglycemia, ELDERLY, long stand-PATIENTS with H/O significant hypoglycemia, ELDERLY, long stand-

ing diabetes, in presence of advanced micro & macrovascular com-ing diabetes, in presence of advanced micro & macrovascular com-

plications, extensive co-morbid conditions & those with limited life plications, extensive co-morbid conditions & those with limited life

expectancy A1c<8% is more appropriate and safeexpectancy A1c<8% is more appropriate and safe

BB

CLINICAL OPINION


in insulin-induced hypoglycaemia in normal man. Diabe-tologia. 1984;26:328–32.

8. Fisher BM, Gillen G, Hepburn DA, Dargie HJ, Frier BM. Cardiac responses to acute insulin-induced hypogly-cemia in humans. Am J Physiol Heart Circ Physiol. 1990;258:1775–9.

9. Wright RJ, Frier BM. Vascular disease and diabetes: Is hy-poglycaemia an aggravating factor? Diabetes Metab Res Rev. 2008;24:353–63.

10. Laitinen T, Lyyra-Laitinen T, Huopio H, Vauhkonen I, Ha-lonen T, Hartikainen J, et al. Electrocardiographic altera-tions during hyperinsulinemic hypoglycemia in healthy subjects. Ann Noninvasive Electrocardiol. 2008;13:97–105.

11. Gill GV, Woodward A, Casson IF, Weston PJ. Cardiac ar-rhythmia and nocturnal hypoglycaemia in type 1 diabe-tes: The ‘dead in bed’ syndrome revisited. Diabetologia. 2009;52:42–5.

12. Robinson RT, Harris ND, Ireland RH, Lee S, Newman C, Heller SR. Mechanisms of abnormal cardiac repolariza-tion during insulin-induced hypoglycemia. Diabetes. 2003;52:1469–74.

13. Galloway PJ, Thomson GA, Fisher BM, Semple CG. Insulin-inducedhypoglycemia induces a rise in C-reactive protein. Diabetes Care. 2000;23:861–2.

14. Fisher BM, Hepburn DA, Smith JG, Frier BM. Responses of peripheral blood cells to acute insulin-induced hypogly-caemia in humans: Effect of alpha-adrenergic blockade. Horm Metab Res Suppl. 1992;26:109–10.

15. Sommerfield AJ, Wilkinson IB, Webb DJ, Frier BM. Vessel wall stiffness in type 1 diabetes and the central hemody-

namic effects of acute hypoglycemia. Am J Physiol Endo-crinol Metab. 2007;293:E1274–9.

16. Judson WE, Hollander W. The effects of insulin-induced hypoglycemia in patients with angina pectoris; before and after intravenous hexamethonium. Am Heart J 1956;52:198–209

17. Koivikko ML, Karsikas M, Salmela PI, et al. Effects of controlled hypoglycaemia on cardiac repolarisation in pa-tients with type 1 diabetes. Diabetologia 2008;51:426–435

18. Graveling AJ, Frier BM. Does hypoglycaemia cause cardio-vascular events? Br J Diabetes Vasc Dis 2010;10:5–13

19. Marques JLB, George E, Peacey SR, et al. Altered ventricu-lar repolarization during hypoglycaemia in patients with diabetes. Diabet Med 1997;14:648–654

20. Landstedt-Hallin L, Englund A, Adamson U, Lins PE. Increased QT dispersion during hypoglycaemia in pa-tients with type 2 diabetes mellitus. J Intern Med 1999;246:299–307

21. Robinson RT, Harris ND, Ireland RH, Macdonald IA, Heller SR. Changes in cardiac repolarization during clinical epi-sodes of nocturnal hypoglycaemia in adults with type 1 diabetes. Diabetologia 2004;47:312–315

22. Adler GK, Bonyhay I, Failing H, Waring E, Dotson S, Free-man R. Antecedent hypoglycemia impairs autonomic car-diovascular function: implications for rigorous glycemic control. Diabetes 2009;58:360–366

23. Lee SP, Yeoh L, Harris ND, et al. Influence of autonomic neuropathy on QTc interval lengthening during hypogly-cemia in type 1 diabetes. Diabetes 2004;53:1535–1542

24. ACCORD study group. Effects of intensive glucose lower-ing in type 2 diabetes. N Engl J Med. 2008;358:2545–59.

25. Duckworth W, Abraira C, Moritz T, Redad D, Emmanuele M, Reaven PD, et al. Glucose control and vascular com-plications in veterans with type 2 diabetes. N Engl J Med. 2009;360:129–39.

26. Zoungas S, Patel A, Chalmers J, et al. Severe hypoglyce-mia and risks of vascular events and death. N Engl J Med 2010;363:1410–1418

27. Patel A, MacMahon S, Chalmers J, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358:2560–2572

28. Turnbull FM, Abraira C, Anderson RJ, et al. Intensive glu-cose control and macrovascular outcomes in type 2 dia-betes. Diabetologia 2009;52:2288–2298

29. Chow E, Bernjak A, Williams S, et al. Risk of cardiac ar-rhythmias during hypoglycemia in patients with type 2 diabetes and cardiovascular risk. Diabetes 2014; 63:1738–1747.

30. Clark AL, Best CJ, Fisher SJ. Even silent hypoglycemia induces cardiac arrhythmias. Diabetes 2014; 63:1457–1459.

31. ORIGIN Trial Investigators, Gerstein H, Yusuf S, et al. Ra-tionale, design, and baseline characteristics for a large international trial of cardiovascular disease prevention in people with dysglycemia: the ORIGIN Trial (Outcome Reduction with an Initial Glargine Intervention). Am Heart J 2008;155(1):26–32.

32. ORIGIN Trial Investigators, Gerstein H, Yusuf S, et al. Ox-ford JournalsMedicine European Heart JournalAdvance Access10.1093/eurheartj/eht332 .2013-10-21.

33. American Diabetes Association, Standards of Medical care in Diabetes—2013. Diabetes Care,2013:36S1-S10.

(Based on reader's interest, this article is a reprint from Mar-Apr 2014 Vol XVIII No.2 issue of Cardiology Today)


Atrial Septal Aneurysm

IMAGE

SR MITTAL

AbstractAn atrial septal aneurysm is defi ned as the area of excessive mobility of interatrial septum at least 10 mm in width and moving away from the normal plane of the septum by at least 10 mm. Nearly 75% of patients with atrial septal aneurysm have a patent foramen ovale. Usually, there is no or minimal left to right shunt due to higher pressure of left atrium. In conditions with raised right atrial pressure, right to left shunt may occur. Atrial septal aneurysm with patent foramen ovale is associated with higher incidence of cryptogenic stroke and migraine with aura. It is not clear if patent foramen ovale is responsible for these comorbidities. An atrial septal aneurysm is also associated with the higher incidence of mild to moderate mitral and aortic valve regurgitation and supraventricular arrhythmias.

Keywords atrial septum aneurysm cryptogenic stroke migraine right to left shunt supraventricular arrhythmias

ATRIAL SEPTAL ANEURYSMIt is an area of excessive mobility of atrial septum (Figure 1). As some mobility of atrial septum is normal, movement of at least 10 mm from the plane of the re-maining part of septum and at least 10mm in width is defi ned as atrial septal aneu-rysm1,2 (Figure 2). Movement of the aneu-rysm depends on relative pressures of the two atria. Usually it is displaced towards right atrium due to relatively higher pres-sure of the left atrium throughout the car-diac cycle (Figure 3A). During inspiration, there is increased fi lling of the right side of heart due to increased venous return. Th is may result in transient mild elevation of right atrial pressure and transient move-ment of the aneurysm towards left atrium

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

(Figure 3B). Other conditions that increase right atrial pressure also displace the atrial septal an-

Figure 1. Subcostal four chamber view showing aneurysm of interatrial septum (A). LA- Left atrium, RA- right atrium, LV- left ventricle, RV- Right ventricle.


eurysm to left during some part of the car-diac cycle. Th ese conditions include right ventricular hypertrophy (Figure 4), tricus-pid regurgitation (Figure 5) and tricuspid stenosis (Figure 6).

Th rombi may form on either side of the aneurysm and may result in thromboembolic events.2,3

CONCURRENT PATHOLOGIESPatent foramen ovaleNearly 75% of the cases of atrial septal aneurysm are associated with patent

Figure 2. Diagrammatic representation of definition of aneurysm of interatrial septum. LA- Left atrium, LV- Left ventricle, RA- Right atrium, RV- Right ventricle, A- Aneurysm.

Figure 3. Diagrammatic representation of effect of expiration (A) and inspiration (B) on right and left atrial pressures and position of atrial septal aneurysm, RAP- Right atrial pressure, ECG- electrocardiogram, LAP- Left atrial pressure, LA- Left atrium, RA- right atrium, LV – left ventricle, RV- right ventricle, A- aneurysm, a-atrial contraction, x- atrial relaxation, c- closure of atrio-ventricular valve, x’- ventricular systole, v- atrial filling, y- opening of atrioventricular valve and emptying of atria.

Figure 4. Diagrammatic representation of effect of right ventricular hypertrophy on right and left atrial pressures and position of atrial septal aneurysm. ECG- electrocardiogram, RAP- Right atrial pressure, LAP- left atrial pressure, LA- Left atrium, RA- right atrium, LV – left ventricle, RV- right ventricle, A- aneurysm, a-atrial contraction, x- atrial relaxation, c- closure of atrio-ventricular valve, x’- ventricular systole, v- atrial filling, y- opening of atrioventricular valve and emptying of atria.

Figure 5. Diagrammatic representation of effect of tricuspid regurgitation on right and left atrial pressures and position of atrial septal aneurysm. ECG- electrocardiogram, RAP- Right atrial pressure, LAP- left atrial pressure, LA- Left atrium, RA- right atrium, LV – left ventricle, RV- right ventricle, A- aneurysm, a-atrial contraction, x- atrial relaxation, c- closure of atrio-ventricular valve, x’- ventricular systole, v- atrial filling, y- opening of atrioventricular valve and emptying of atria.


Figure 7. Diagrammatic representation(A) closure of patent foramen ovale when left atrial pressure is more than right atrial pressure (B) opening of patent foramen ovale with right to left shunt when right atrial pressure is more than left atrial pressure. LA- Left atrium, RA- right atrium, LV – left ventricle, RV- right ventricle, SP- septum primum, SS- septum secundum.

foramen ovale (PFO).1,2 PFO represents failure of the primum and secundum septa to fuse. Septum appears structurally intact but some left to right shunting can be demonstrated by either contrast or colour fl ow imaging.1 Release phase of valsalva maneuver and cough transiently increase right heart pressure and may produce small right to left shunt.4 Other conditions that raise right atrial pressure also push septum primum to left and open patent foramen ovale with right to left shunt (Figure 7 A, B).

Patients with a large PFO (>4 mm) with substantial right to left shunt are considered to be at risk of paradoxical embolism.4,5 However, randomized trials have not shown any clear benefi t of PFO closure.6

Association of PFO and atrial septal aneurysm is associated with higher incidence of stroke than PFO alone.2 Exact mechanism is not clear. Th rombus formation in aneurysm could be responsible for higher incidence of stroke in patients with PFO with aneurysm of interatrial septum.2,3 Higher incidence of supraventricular arrhythmias in these patients could also contribute to higher incidence of embolic stroke. Atrial septal aneurysm with PFO has also been observed to be associated with

Figure 6. Diagrammatic representation of effect of tricuspid stenosis on right and left atrial pressures and position of atrial septal aneurysm. ECG- electrocardiogram, RAP- Right atrial pressure, LAP- left atrial pressure, LA- Left atrium, RA- right atrium, LV – left ventricle, RV- right ventricle, A- aneurysm, a-atrial contraction, x- atrial relaxation, c- closure of atrio-ventricular valve, x’- ventricular systole, v- atrial filling, y- opening of atrioventricular valve and emptying of atria.

platypnoea-orthodeoxia syndrome.8 Th is rare syndrome is characterized by dyspnea and arterial oxygen desaturation induced by upright position and relieved by supine position. Preferential fl ow of blood from inferior vena cava through PFO is considered responsible for oxygen desaturation in upright position.

Association of PFO and atrial septal aneurysm is also associated with higher incidence of migraine with aura.9 It is not clear if it has any etiologic correlation or it is a comorbidity.10

Mild to moderate mitral and aortic valve regurgitation11Higher than normal incidence of atrio-ventricular valve prolapse has been observed in association with atrial septal aneurysm.12

Supraventricular arrhythmias11Atrial conduction heterogenecity has been observed in cases of atrial septal aneu-rysms and supraventricular arrhythmias.13

REFERENCES1. Lesson P, Augustine D, Mitchell ARJ, Becher H. Transtho-

racic anatomy and pathology: chambers and vessels. In Lesson P, Augustine D, Mitchell ARJ, Becher M(eds). Echo-cardiography. Oxford, UK; 2012: 191-341.

2. Armstrong WF, Ryan T. Left and right atrium and right ventricle. In Armstrong WF, Ryan T (eds). Feigenbaum’s

Echocardiography. Wolters Kluwer, Philadelphia; 2010; 185-215.

3. Adauy JV, Gabrielli L, Cordava S, Saavedra R, Mc Nab P. Big thrombus “sitting” in an atrial septal aneurysm. Echocardiography 2017; 34 : 1396-8.

4. Armstrong WF, Ryan T. Contrast echocardiography. In Armstrong WF, Ryan T (eds). Feigenbaum’s Echocardiog-raphy. Wolters Kluwer, Philadelphia; 2010; 67-90.

5. Schuchlenz HW, Weihs W, Horner S, et al. The association between the diameter of a patent foramen ovale and the risk of embolic cerebrovascular events. Am J Med 2000; 109: 456-62.

6. Meier B, Kalesan B, Mattle HP, et al. PC Trial Investigators. Percutaneous closure of patent foramen ovale in crypto-genic embolism. N Engl J Med 2013;368:1083-91.

7. Bonati LH, Kessel – Schaefer A, Linka AZ, et al. Diffu-sion – weighted imaging in stroke attributable to patent foramen ovale : significance of concomitant atrial septum aneurysm. Stroke 2006;37:2030-34.

8. Boudart C, Tabolcea I, Strachinaru M, et al. Acute coro-nary syndrome and platypnoea- orthodeoxia with thoracic and interauricular septal aneurysm. European review for Medical and Pharmacolagiel Sciences 2016; 20:301-4.

9. Snizder RJ, Leurmans JS, de Heiz AH, et al. Patent foramen ovale with atrial septal aneurysm is strongly associated with migraine with aura: A large observational study. J Am Heart Assoc 2016 Dec 1; 5 (12). Pill:e003771.

10. Falanga G, Carerj S, Oreto G, Khandheria BK, Zito C. How to understand patent foramen ovale clinical significance Part I. J Cardiovasc Echogr 2014;24:114-21.

11. Yetkin E, Atalay H, Lleri M. Atrial septal aneurysm. Prevalence and covariates in adults. Int J Cardiol 2016; 223:656-9.

12. Hanley PC, Tajik AJ, Hynes JK, et al. Diagnosis and clas-sification of atrial septal aneurysm by two – dimensional echocardiography: report of 80 consecutive cases. J Am Coll Cardiol 1985;6:1370-82.

13. Russo V, Rago A, DiMeo F, et al. Atrial septal aneurysms and supraventricular arrhythmias: The role of electrome-chanical delay. Echocardiography 2015; 32 : 1504-14.

IMAGE


Flat T wave

ECG OF THE MONTH

SR MITTAL

AbstractDiffuse fl attening of T wave is seen in pericardial effusion and myxoedema. Flattening in leads V5& V6 is seen in left ventricular hypertrophy.

Keywords left ventricular hypertrophy myxoedema pericardial effusion

FLAT T WAVEDiff use fl attening of T wave is observed in 1. Pericardial eff usion (Figure 1)It is associated with sinus tachycardia and low voltage QRS. 2. Myxoedema (Figure 2)It is associated with sinus bradycardia and low voltage QRS. 3. Left ventricular hypertrophy Flattening of T wave in lead V5 & V6 is observed in left ventricular hypertrophy (Figure 3).

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

Figure 1. Electrocardiogram from a case of pericardial effusion showing sinus tachycardia, low voltage QRS and diffuse flattening of T wave.

Figure 2. Electrocardiogram from a case of myxoedema showing diffuse flattening of T wave in precordial leads.

Figure 3. Electrocardiogram from a case of systemic hypertension showing flattening of T wave in lead V6.


PICTORIAL CME

MONIKA MAHESHWARI

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

Anomalies of Mitral Valve

ANOMALIES OF MITRAL VALVEVarious congenital and acquired malformations of mitral valve encountered by us is picturised herein.

Figure 1. Trans thoracic echocardiogram (apical five chamber view) showing prolapsed posterior mitral valve leaflet.

Figure 2. Trans thoracic echocardiogram (apical four chamber view) showingvegetation on mitral valve

Figure 3. Transthoracic echocardiogram (parasternal long axis view) showing domed and thickened anterior mitral valve leaflet in rheumatic mitral stenosis.

Figure 4. Transthoracic echocardiogram (parasternal long axis view) showing double orificed mitral valve

Figure 5. Trans thoracic echocardiogram (apical four chamber view) showing mitral valve regurgitation flow.

Figure 6. Transthoracic echocardiogram (parasternal long axis view) showing flail mitral valve leaflet.

Figure 7. Transthoracic echocardiogram (M–mode) showing systolic anterior mo-tion of mitral valve leaflet in hypertrophic obstructive cardiomyopathy

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