Asian journal of clinical cardiology january march 2015

www.ijcpgroup.com

In This Issue — Polypill: Inception, Conception and Adoption — Evaluation and Treatment of Severe Asymptomatic Hypertension — TURP Syndrome: A Quick Review and Update — Prevalence of Metabolic Syndrome in Patients with Essential Hypertension — A Rare Case of Cor Triloculare Biventriculare Detected in a Postpartum Female — A Rare Case of Diencephalic Seizures Secondary to Hemorrhagic Stroke

Volume 17, Number 3, January-March 2015 Pages 1-40

Asian

Journal of

IJCP Group of Publications

CLINICAL CARDIOLOGY

Dr Sanjiv Chopra Prof. of Medicine & Faculty Dean Harvard Medical School Group Consultant Editor

Volume 17, Number 3, January-March 2015

Dr Deepak Chopra Chief Editorial Advisor

Padma Shri, Dr BC Roy and National Science Communication Awardee Dr KK Aggarwal Group Editor-in-Chief Dr Veena Aggarwal MD, Group Executive Editor

from the desk of the group editor-in-chief 5

Nonobstructive Heart Blockages not Benign

KK Aggarwal

Dr Sameer Srivastava Editor, AJCC Assistant Editors: Dr Nagendra Chouhan, Dr Dharmendar Jain

AJCC Specialty Panel Advisory Board

International Dr Fayoz Shanl Dr Alain Cribier Dr Kohtian Hai Dr Tanhuay Cheem Dr Ayman Megde Dr Alan Young Dr Gaddy Grimes Dr Jung bo Geg Dr Rosli Mohd. Ali Dr S Saito National Dr Mansoor Hassan Dr RK Saran Dr SS Singhal Dr Mohd. Ahmed

Dr PK Jain Dr PK Gupta Dr Naresh Trehan Dr Sameer Shrivastava Dr Deepak Khurana Dr Ganesh K Mani Dr K S Rathor Dr Rajesh Kaushish Dr Sandeep Singh Dr Yugal Mishra Faculty Dr GK Aneja Dr Ramesh Thakur Dr Balram Bhargava Dr HK Bali Dr HM Mardikar

Dr Sanjay Mehrotra Dr Vivek Menon Dr Keyur Parikh Dr Ajit Mullasari Dr Kirti Punamiya Dr MS Hiramath Dr VS Narain Dr SK Dwivedi Dr Raja Baru Panwar Dr Vijay Trehan Dr Rakesh Verma Dr Suman Bhandari Dr Ravi Kasliwal Dr Atul Abhyankar Dr Tejas Patel Dr Samir Dani

review article 7

Polypill: Inception, Conception and Adoption

Bhosle S, Maseeh A, Parikh AO

IJCP Editorial Board

Obstetrics and Gynaecology Dr Alka Kriplani, Dr Thankam Verma, Dr Kamala Selvaraj Cardiology Dr Praveen Chandra, Dr SK Parashar Paediatrics Dr Swati Y Bhave Diabetology Dr CR Anand Moses, Dr Sidhartha Das, Dr A Ramachandran, Dr Samith A Shetty ENT Dr Jasveer Singh, Dr Chanchal Pal Dentistry Dr KMK Masthan, Dr Rajesh Chandna Gastroenterology Dr Ajay Kumar, Dr Rajiv Khosla Dermatology Dr Hasmukh J Shroff, Dr Pasricha, Dr Koushik Lahiri Nephrology Dr Georgi Abraham Neurology Dr V Nagarajan, Dr Vineet Suri Journal of Applied Medicine & Surgery Dr SM Rajendran, Dr Jayakar Thomas Orthopedics Dr J Maheshwari Advisory Bodies Heart Care Foundation of India Non-Resident Indians Chamber of Commerce & Industry World Fellowship of Religions

17 Evaluation and Treatment of Severe Asymptomatic Hypertension

Chad S. Kessler, Yazen Joudeh

22 TURP Syndrome: A Quick Review and Update

Parinita C Hazarika

clinical study Published, Printed and Edited by Dr KK Aggarwal, on behalf of

27 Prevalence of Metabolic Syndrome in Patients with Essential Hypertension

IJCP Publications Ltd. and Published at

E - 219, Greater Kailash, Part - 1

D Makwana, S Bagga, M Nandal

New Delhi - 110 048 E-mail: editorial@ijcp.com Printed at Print Vision, Ahmedabad Š Copyright 2015 IJCP Publications Ltd. All rights reserved.

The copyright for all the editorial material contained in this journal, in the form of layout, content including images and design, is held by IJCP Publications Ltd. No part of this publication may be published in any form whatsoever without the prior written permission of the publisher.

Editorial Policies The purpose of IJCP Academy of CME is to serve the medical profession and provide print continuing medical education as a part of their social commitment. The information and opinions presented in IJCP group publications reflect the views of the authors, not those of the journal, unless so stated. Advertising is accepted only if judged to be in harmony with the purpose of the journal; however, IJCP group reserves the right to reject any advertising at its sole discretion. Neither acceptance nor rejection constitutes an endorsement by IJCP group of a particular policy, product or procedure. We believe that readers need to be aware of any affiliation or financial relationship (employment, consultancies, stock ownership, honoraria, etc.) between an author and any organization or entity that has a direct financial interest in the subject matter or materials the author is writing about. We inform the reader of any pertinent relationships disclosed. A disclosure statement, where appropriate, is published at the end of the relevant article.

Note: Asian Journal of Clinical Cardiology does not guarantee, directly or indirectly, the quality or efficacy of any product or service described in the advertisements or other material which is commercial in nature in this issue.

case report 30 A Rare Case of Cor Triloculare Biventriculare Detected in a Postpartum Female

Parneet Kaur, Khushpreet Kaur, Rama Garg, Isha Gupta

33 A Rare Case of Diencephalic Seizures Secondary to Hemorrhagic Stroke

Muhammed Zohaib Ghatala, Swamikannu Murugan, Shriraam Mahadevan, Booma Soundarajan

ArounD the Globe 36 News and Views

IJCP’s Editorial & Business Offices Delhi

Mumbai

Kolkata

Bangalore

Chennai

Hyderabad

Dr Veena Aggarwal 9811036687 E - 219, Greater Kailash, Part - I, New Delhi - 110 048 Cont.: 011-40587513 editorial@ijcp.com drveenaijcp@gmail.com Subscription Dinesh: 9891272006 subscribe@ijcp.com Ritu: 09831363901 ritu@ijcp.com

Mr. Nilesh Aggarwal 9818421222

Ritu Saigal Sr. BM 9831363901

H Chandrashekar GM Sales & Marketing 9845232974

Chitra Mohan Sr. BM 9841213823 40A, Ganapathypuram Main Road Radhanagar Chromepet Chennai - 600 044 Cont.: 22650144 chitra@ijcp.com

Venugopal GM Sales & Marketing 9849083558

Pravin Dhakne 8655611025, 24452066 Unit No. 210 2nd Floor Shreepal Complex, Suren Road, Near Cine Magic Cinema Andheri (E) Mumbai - 400 093 nilesh.ijcp@gmail.com

Flat 7E Merlin Jabakusum 28A, SN Roy Road Kolkata - 700 038 Cont.: 24452066 ritu@ijcp.com

Sr.: Senior; BM: Business Manager; GM: General Manager

Arora Business Centre, 111/1 and 111/2, Dickenson Road (Near Manipal Centre) Bangalore - 560 042 Cont.: 25586337 chandra@ijcp.com

H. No.16-2-751/A/70 First Floor Karan Bagh Gaddiannaram Dil Sukh Nagar Hyderabad 500 059 venu@ijcp.com

from the desk of the group editor-in-chief

Dr KK Aggarwal

Padma Shri, Dr BC Roy and National Science Communication Awardee Group Editor-in-Chief, IJCP Group and eMedinewS

Nonobstructive Heart Blockages not Benign

I

n a retrospective study of patients undergoing elective coronary angiography, nonobstructive coronary artery disease (CAD) (heart blockages), compared with no apparent CAD (no blockages), was associated with a significantly greater 1-year risk of heart attack and all-cause mortality.

After risk adjustment, there was no significant association between 1- or 2-vessel nonobstructive CAD (blockages in one or two arteries) and mortality, but there were significant associations with mortality for 3-vessel nonobstructive CAD (blockages in all three arteries).

Veterans with evidence of nonobstructive CAD on elective coronary angiography had a 2- to 4.5-fold greater risk for heart attack compared with those with no evidence of blockages and 1-year heart attack risk was found to increase progressively by the extent of blockages, rather than increasing abruptly when blockages became obstructive.

The results of this study are published in Nov. 5 JAMA.

Never tell your patients "that your coronaries are fine and they have nothing to worry about," but one should say "There is evidence of atherosclerosis and while there is no need to panic, we need to address it. Remember there is nothing like "mild coronary artery disease." Up to 1 in 4 angiograms show minimal plaque or blockages.

Nonobstructive blockage means presence of atherosclerotic plaque revealed during coronary angioplasty or angiography that does not appear to obstruct blood flow or result in angina symptoms.

These nonobstructive lesions occur in between 10% and 25% of patients undergoing elective angiography, and their presence has historically been characterized as 'insignificant' or 'no significant' blockages in the medical literature even though multiple studies have shown plaque ruptures leading to heart attack commonly come from nonobstructive plaques.

■■■■

Asian Journal of Clinical Cardiology, Volume 17, Number 3, January-March 2015

5

review article

Polypill: Inception, Conception and Adoption Bhosle S*, Maseeh A*, Parikh AO*

Abstract Cardiovascular disease (CVD) is a global epidemic and its risk factors are widely prevalent. Current prevention strategies are limited because of cumbersome and imperfect risk stratification algorithms to identify individuals at risk in primary prevention. The Prospective Urban Rural Epidemiological (PURE) study observed that effective preventive drugs for coronary heart disease and stroke are underused globally. The aggregated benefits of concurrently controlling common CVD risk factors, such as dyslipidemia and hypertension, in people at overall risk for CVD is postulated to be more efficient than treating each individual risk factor to target. Several different drugs are available to treat various CVD risk factors. Hence, combining them in one pill could reduce heart disease by 80%. Administration of a polypill consisting of cholesterol-lowering (statins), antihypertensive and antiplatelet agents together would simultaneously lower multiple risk factors, and applying such a population risk-reduction strategy would drastically reduce CVD incidence.

The polypill has the potential to control the global health epidemic of CVD by effectively reaching underdeveloped regions of the world, simplifying healthcare delivery, improving cost-effectiveness, increasing medication adherence and supporting a comprehensive prescription of evidence-based cardioprotective drugs.

Keywords: Cardiovascular disease, risk factors, dyslipidemia, hypertension, prevention strategies, polypill

Introduction Magnitude of the Problem Cardiovascular disease (CVD), which includes heart disease and stroke, is a major cause of death and disability globally.1,2 In addition to the morbidity and mortality associated with CVD, there is a significant financial cost related to hospitalization, medication and lost productivity.1 CVD is a global epidemic and its risk factors are widely prevalent.2 CVD (heart disease and stroke) accounts for 17 million deaths or about 30% of all global deaths and 39% of deaths in people under the age of 70 years. It is estimated that nearly 50% of the global population will suffer from CVD during their lifetime. And as many as 25 million people are projected to die of CVD by the year 2030.1 The CVD burden has decreased in developed countries as effective prevention and treatment strategies were implemented, although these gains are threatened by increasing obesity, sedentary lifestyles and diabetes mellitus. By contrast, CVD has increased in developing countries, and by the year 2020, 80% of the global CVD mortality is predicted to occur in low- and middle-income countries.2 Over 80% of deaths and 85% of disability from CVD occur in low- and middle-income countries. The Indian *Medical

Affairs, Cadila Pharmaceuticals Limited, India

subcontinent, including India, Pakistan, Bangladesh, Sri Lanka and Nepal is home to 22% (see UN http://www. unescap.org/sites/default/files/AWP%20No.%2026.pdf) of the world’s population and may be one of the regions with the highest burden of CVD in the world. In addition to the high rate of coronary heart disease (CHD) mortality in the Indian subcontinent, CHD manifests almost 10 years earlier on average in this region compared with the rest of the world.3 Therefore, reducing the burden of CVD requires strategies that are applied to entire or large segments of the population.2

Issues with Current Treatment Current prevention strategies are limited because of cumbersome and imperfect risk stratification algorithms to identify individuals at risk in primary prevention.2 Drug treatment to prevent is ischemic heart disease (IHD) events and stroke has generally been limited to single risk factors, to targeting the minority of patients with values in the tail of the risk factor distribution, and to reducing the risk factors to 'average' population values.

However, adopting this strategy only results in modest decline in disease. A large preventive effect would require intervention in everyone at increased risk irrespective of the risk factor levels; intervention on several reversible causal risk factors together and reducing these risk factors by as much as possible.4 Factors such as lack of systematic implementation of proven therapies in secondary prevention, high cost and low affordability of therapy and a misplaced fear that

Asian Journal of Clinical Cardiology, Volume 17, Number 3, January-March 2015

7

Review article the use of drugs may encourage unhealthy lifestyles also limit the impact of the current prevention strategies.2

India: Adherence Post-CHD/Stroke

The Prospective Urban Rural Epidemiological (PURE) study assessed the use of proven effective secondary preventive drugs (antiplatelet drugs, β blockers, angiotensin-converting enzyme [ACE] inhibitors or angiotensin receptor blockers [ARBs] and statins) in individuals with a history of CHD or stroke from rural and urban communities in countries at various stages of economic development.5 The study observed that effective preventive drugs for CHD and stroke are underused globally, with striking variation between countries at different stages of economic development. Even the use of accessible and inexpensive treatments such as aspirin (the most commonly used antiplatelet drug) varied 7-fold between low- and high-income countries, but the use of statins varied 20-fold. For every group of countries classified by economic development, rates of drug use were consistently lower in rural than urban settings.

For example in the high-income countries, only 64.6% of patients with CHD and 52.7% of patients who had a stroke were on an antiplatelet drug and only 72.2% and 52.2%, respectively, were on statins, with lower rates for ACE inhibitors or ARBs (53.2% CHD and 41.9% stroke) and β blockers (47.6% for CHD). Only 60.6% of patients who had a stroke received a blood pressure (BP)-lowering drug.5 In a study of rural communities from Andhra Pradesh in India, among individuals with either CHD or cerebrovascular disease, 14% reported taking aspirin, 41% took a BP-lowering medication and 5% reported using a cholesterol-lowering medication (Fig. 1).6 In another study from the same region, among the 7.6% (95% confidence interval [CI] 6.2-8.9%) with a high global CHD risk (>20% over 10 years), 29.5% (95% CI 19.5-39.5%) were on BP-lowering medication, 2.8% (95% CI 0-6.7%) were on cholesterol-lowering medication, 19.4% (95% CI 10.9-28%) had increased exercise and 24.8% (95% CI 15.8-33.8%) attempted to quit smoking.7

Lack of Adherence Nonadherence to medications has been documented to occur in >60% of cardiovascular patients.8 Self-reported adherence to cardiovascular medications in patients who have coronary artery disease (CAD) was found to be <40% for the combination of aspirin, β-blocker and a lipidlowering agent in both isolated and long-term follow-up surveys.8,9 Secondary prevention after acute myocardial infarction (MI) is achieved primarily through medications.

8

Lipid-lowering agent

Antihypertensive

Aspirin

95% 5% Adherent 59% 41%

Nonadherent 86%

14% 0%

20%

40%

60%

80% 100%

Figure 1. Adherence (Post-CHD/Stroke) of preventive drugs.

However, patients must take their medications to benefit.

Medication adherence research has focused primarily on continuation of medications rather than not filling the first prescription written (primary nonadherence).

The adjusted 1-year mortality rate was higher in patients who filled some versus all and none versus all of their discharge medications.10 Secondary nonadherence (failure to follow the instructions or to refill the prescription) has been shown to increase mortality, hospitalizations and costs.8 ÂÂ

Elderly patients with and without recent acute coronary syndrome (ACS) have low rates of adherence to statins. This suggests that many patients initiating statin therapy may receive no or limited benefit from statins because of premature discontinuation.10

ÂÂ

Patients with high adherence rates have a significantly lower risk of cardiovascular events compared with those with low adherence rates.11

ÂÂ

For all four conditions (diabetes, hypertension, hypercholesterolemia and congestive heart failure), hospitalization rates were significantly lower for patients with high medication adherence.12

Individuals who feel healthy several years after an acute CVD event or feel that they are at lower risk for an event reduce their use of drugs with time due to various reasons as enumerated in Table 1.5

The Concept of the Polypill For people who have had a CVD event or related disorders such as angina pectoris, combination treatment has been practised for many years, although apart from the use of aspirin, there has been a tendency to treat each risk factor rather than the overall risk of the disease. For example, until recently statins have been prescribed only if serum cholesterol is raised. BP-lowering drugs are given only

Asian Journal of Clinical Cardiology, Volume 17, Number 3, January-March 2015

Review article with values in the middle of risk-factor distribution curves. This concept proposed a shift in the paradigm of the prevention and treatment of CVD toward a more simplified, public health-orientated concept.1

Table 1. Reasons for Decline in Drug Use after an Acute Cardiovascular Disease Event5 zz

Restricted availability of these drugs in low- and middle-income countries, especially in rural areas

zz

Unaffordability of even generic drugs

zz

Side-effects from drugs

zz

Inconvenience

zz

Costs associated with visiting health practitioners

Rationale of the Study

Absence of transportation and long distances from clinics in some rural areas

The mortality risk increases with increase in number of risk factors. So, simultaneous modification of multiple risk factors is expected to reduce mortality due to these disorders more than the reduction of any individual risk factor. Based on the same rationale, the polypill strategy is based on utilizing a once-daily fixed-dose combination pill to reduce multiple cardiovascular risk factors simultaneously.17

zz

zz

The Cadila Polycap Project: Inception to Conception

Restricted access to healthcare providers in low-income countries

if a diagnosis of hypertension has been made. This is inappropriate and leads to many people not receiving preventive treatment who could benefit from receiving such treatment.13 Recognition that cardiovascular risk factors, such as hypertension, dyslipidemia and diabetes mellitus, often cluster together has focused attention on the concept of total cardiovascular risk.14 The aggregated benefits of concurrently controlling common CVD risk factors, such as dyslipidemia and hypertension, in people at overall risk for CVD is postulated to be more efficient than treating each individual risk factor to target.15 The term 'Polypill' describes a fixed-dose combination pill containing several components designed to lower several cardiovascular risk factors simultaneously.13 The concept of a polypill was first hypothesized by Dr Salim Yusuf in 2002 in The Lancet that a combination of four drugs (aspirin, a β-blocker, a statin and an ACE inhibitor) could reduce CVD events by 75% in those with established vascular disease.16 Then, in 2003, in the BMJ, Wald and Law proposed a six-drug combination polypill composed of three BP-lowering drugs from different classes each at half doses, aspirin, a statin and folic acid that could safely reduce IHD events by 88% and strokes by 80%, if taken by all individuals with established CVD and all those >55 years without CVD (regardless of risk profile).

They also suggested that the polypill be used without monitoring risk factor levels or biochemical safety parameters. One-third of people taking this pill from age 55 would benefit, gaining on average about 11 years of life free from an IHD event or stroke.4 According to Wald and Law, focusing treatment on those with the most extreme risk profiles would identify only about 15-24% of disease events, because on a population level, the majority of events occur in those individuals

The projected benefits of polypill proposed by Yusuf in 2002 and Wald and Law in 2003 were based on data extrapolated from studies conducted in patients with hyperlipidemia or hypertension. However, data regarding the extent to which this therapy would reduce BP and lipid levels in individuals with normal BP and lipid levels is lacking, so is data pertaining to long-term adherence to treatment or tolerability. TIPS (The Indian Polycap Study) aimed to test the hypothesis put forth by Wald and Law.18 Results of epidemiologic studies suggest that moderately elevated plasma or serum homocysteine levels are prevalent in the general population and are associated with an increased risk for CVD, independent of classic cardiovascular risk factors.19 However, use of folic acid to lower homocysteine levels did not reduce the risk of major cardiovascular events in patients with vascular disease.20 Hence, the Polycap did not include folic acid.18 ÂÂ

Antihypertensives: Half doses of three generic antihypertensives were included. The b-blocker atenolol was chosen because it is suitable for oncedaily use, the diuretic hydrochlorothiazide (HCTZ) was incorporated because it is cheap and effective at half dose, and the ACE inhibitor ramipril was included because good evidence exists that it improves patient's clinical outcomes.18

ÂÂ

Statin: Half dose simvastatin was included as it has proven efficacy and safety and it is also economical.18

ÂÂ

Antiplatelet: Aspirin was chosen because of its low price, widespread acceptance and ample evidence for benefit.18

TIPS enrolled subjects without CVD, aged 45-80 years.

CVD manifests a decade earlier in the Indian population

Asian Journal of Clinical Cardiology, Volume 17, Number 3, January-March 2015

9

Review article as compared to their western counterparts. Hence, the TIPS investigators specified a minimum age that is 10 years lower than that recommended by Wald and Law. The upper age limit of 80 years was specified to improve adherence to trial procedures and drug regimens without affecting the generalizability of the study's results.18 Individuals with at least one cardiovascular risk factor such as stable type 2 diabetes mellitus, hypertension, tobacco smoking within the last 5 years, a raised waist-tohip ratio (>0.85 for women and >0.9 for men) or moderately elevated low-density lipoprotein (LDL) cholesterol (>120 mg/dL) were chosen to increase acceptability of the study medication among the participants.18 A five-arm phase I crossover trial in healthy volunteers studied the pharmacokinetics (bioavailability and drug drug interactions) in a parallel pharmacokinetic trial involving healthy volunteers) to determine if the various drugs used in the polypill can be effectively and safely combined. Plasma concentrations of each drug and, where applicable, its active metabolite were measured using validated liquid chromatographytandem mass spectrometry and ultra-performance liquid chromatography. Mean pharmacokinetic parameters and their standard deviations were computed for each analyte.21 ÂÂ

ÂÂ

Aspirin, ramipril, atenolol and HCTZ from the Polycap were absorbed with a similar rate and extent to those of the single agent preparations. This resulted in comparable relative bioavailabilities.

Also, pharmacokinetic parameters for the ingredients of Polycap on average fell within the range of 80-125% for in-transformed Cmax, AUCt and AUC∞. This clearly indicates that there was no pharmacokinetic drugdrug interaction in vivo and that the bioavailabilty of ramipril, atenolol, HCTZ and aspirin is preserved in the five-ingredient Polycap.21

slight reduction in the efficacy of simvastatin was observed.21 This study in healthy volunteers established that Polycap is safe and well-tolerated, and that there is no evidence of pharmacokinetic drug-drug interactions for any of the ingredients, with their bioavailabilities being well-preserved thus explaining its reported efficacy pharmacokinetically.21 The study corroborates the hypothesis of reducing cardiovascular risk factors by the use of multiple ingredients in a single pill.21 Polypill: Primary and Secondary Prevention Completed trials

TIPS 1 Trial22 ÂÂ

Study design: Phase II, double-blind, randomized trial.

ÂÂ

Study centers: Fifty centers in India.

ÂÂ

Sample size: Two thousand fifty-three individuals without CVD, aged 45-80 years and with one risk factor.

ÂÂ

Primary outcome measures: Effect on lipids, BP, heart rate, urinary 11-dehydrothromboxane B2, antiplatelet effects, rates of discontinuation of drugs for safety.

ÂÂ

Intervention: Patients were randomized to the PolycapTM (n = 412) consisting of low doses of thiazide (12.5 mg), atenolol (50 mg), ramipril (5 mg), simvastatin (20 mg) and aspirin (100 mg) per day, or to eight other groups, each with about 200 individuals, of aspirin alone, simvastatin alone, HCTZ alone, three combinations of the two BP-lowering drugs, three BP drugs alone or three BP-lowering drugs + aspirin.

All patients were given lifestyle advice.

ÂÂ

Results

For simvastatin, there was a slight loss of bioavailability with the Polycap; the relative mean bioavailability parameters were 3-4% lower than the lower tolerance bound of 80%. However, there was an associated increase in the bioavailability of simvastatin acid with the Polycap versus reference drug. There are two aspects to the observed lower relative bioavailability of simvastatin. First despite the lower value, the active metabolite, simvastatin acid, showed a high relative bioavailability (>125%; the upper tolerance bound). Therefore, as an approximation, the overall bioavailability of active simvastatin and simvastatin acid is acceptable.

Second, the lower bioavailability of simvastatin mirrors the results of the TIPS trial, in which a

10

Asian Journal of Clinical Cardiology, Volume 17, Number 3, January-March 2015

Compared with groups not receiving BPlowering drugs, the Polycap reduced systolic BP by 7.4 mmHg and diastolic BP by 5.6 mmHg (4.7-6.4), which was similar when three BPlowering drugs were used, with or without aspirin. Reductions in BP increased with the number of drugs used (2.2/1.3 mmHg with one drug, 4.7/3.6 mmHg with two drugs and 6.3/4.5 mmHg with three drugs) (Fig. 2).

PolycapTM reduced LDL cholesterol by 0.70 mmol/L, which was less than that with simvastatin alone (0.83 mmol/L); both reductions were greater versus groups without simvastatin (p < 0.0001) (Fig. 3).

The reductions in heart rate with Polycap and other groups using atenolol were similar

Review article

1 BP-lowering

2 BP-lowering 3 BP-lowering

LDL cholesterol though slightly less than that with simvastatin. Hence, PolycapTM could be conveniently used in the management of CVD to reduce multiple risk factors and cardiovascular risk.

Polycap

0 −2.2 −2

−4.7

−1.3

−6.3

−7.4

TIPS 2 Trial23

−4 −6

−3.6

−8

−4.5

−10

ÂÂ

Study design: Randomized, double-blind.

ÂÂ

Study centers: Twenty-seven centers in India.

ÂÂ

Sample size: Five hundred eighteen individuals with previous vascular disease or diabetes mellitus.

ÂÂ

Primary outcome measures: Effect on BP, heart rate, serum lipids, serum and urinary potassium and tolerability were assessed using an intention-to-treat analysis.

ÂÂ

Intervention: Randomly assigned to a single capsule (low-dose) PolycapTM (3 BP-lowering drugs: HCTZ 12.5 mg, atenolol 50 mg, ramipril 5 mg + simvastatin 20 mg + aspirin 100 mg) or to 2 capsules (full-dose) of Polycap + potassium supplementation for 8 weeks.

−5.6

−12 DBP

−14

SBP

Figure 2. Comparison of BP reduction with 1, 2, 3 BP-lowering drugs and Polycap in the TIPS 1 trial.

0

Simvastatin

Polycap

−0.05 −0.15

ÂÂ

−0.25 −0.35

Results

The full-dose PolycapTM (plus potassium supplementation) reduced BP by a further 2.8 mmHg systolic and 1.7 mmHg diastolic, compared with that observed with the low-dose PolycapTM (p = 0.003; p = 0.001) (Fig. 4), but there were no differences in heart rate (0.1 bpm).

The differences in total and LDL cholesterol between the full-dose and low-dose PolycapTM was 7.2 mg/dL (p = 0.014) and 6.6 mg/dL (p = 0.006), respectively, but there were no differences in high-density lipoprotein (HDL) cholesterol or triglycerides.

The rates of discontinuation of the study drug after randomization were similar in the two groups (6.9% low-dose vs 7.8% full-dose).

The projected theoretical risk reduction in CHD and stroke with TIPS (low-dose PolycapTM) and TIPS 2 (full-dose PolycapTM) was 62%, 48% and 69%, 57%, respectively (Fig. 5).

−0.45 −0.55 −0.65 −0.75 −0.85

−0.70 −0.83

Simvastatin

Polycap

Figure 3. Comparison of LDL cholesterol reduction with the Polycap and simvastatin alone in the TIPS 1 trial.

(7.0 beats/min), and both were significantly greater versus groups without atenolol (p < 0.0001).

ÂÂ

The reductions in 11-dehydrothromboxane B2 were similar with the Polycap (283.1 ng/mmoL creatinine) versus the three BP-lowering drugs + aspirin (350.0 ng/mmoL creatinine, 294.6-404.0), and aspirin alone (348.8 ng/mmoL creatinine, 277.6-419.9) versus groups without aspirin.

Tolerability of the Polycap was similar to that of other treatments, with no evidence of increasing intolerability with increasing number of active components in one pill.

Conclusion: The study showed that the PolycapTM was noninferior to its individual components in lowering BP and hart rate. It also reduced

ÂÂ

Conclusion: The full-dose PolycapTM (plus potassium supplementation) reduces BP and LDL cholesterol to a greater extent compared with the low-dose, with similar tolerability. Therefore, the full-dose PolycapTM should potentially lead to larger benefits.

FOCUS Trial24,25 ÂÂ

Study design: Cross-sectional; Phase 1 (descriptive, noninterventional study); Phase 2 (interventional,

Asian Journal of Clinical Cardiology, Volume 17, Number 3, January-March 2015

11

Review article

Reduction in SBP (mmHg)

0

Morisky-Green Medication Adherence Questionnaire (MAQ) and pill count (patients had to meet both criteria for adherence at the in-person visit to be considered adherent).

Reduction in DBP (mmHg)

−5

ÂÂ −8.6

−10

−10.3

−15

−14.6

Results

In Phase 1, overall cardiovascular medication adherence, defined as an MAQ score of 20, was 45.5%. In a multivariable regression model, the risk of being nonadherent (MAQ <20) was associated with younger age, depression, being on a complex medication regimen, poorer health insurance coverage and a lower level of social support, with consistent findings across countries.

In Phase 2, the polypill group showed improved adherence compared with the group receiving separate medications after 9 months of followup: 50.8% versus 41% (p = 0.019; intentionto-treat population) and 65.7% versus 55.7% (p = 0.012; per-protocol population) when using the primary endpoint (Fig. 6), attending the final visit with MAQ = 20 and high pill count (80-110%) combined, to assess adherence.

Adherence also was higher in the fixeddose combination group when measured

by MAQ alone (68% vs 59%, p = 0.049). No treatment difference was found at follow-up in mean systolic BP (129.6 mmHg vs 128.6 mmHg), mean LDL cholesterol levels (89.9 mg/dL vs 91.7 mg/dL), serious adverse events (23 vs 21) or death (1, 0.3% in each group).

−17.4

−20 Single dose Polycap

Double dose Polycap

Figure 4. Comparison of BP reduction with single dose Polycap and double dose Polycap in the TIPS 2 trial.

Projected Risk Reduction TIPS (Low-dose Polycap) CHD

Stroke

TIPS 2 (Full-dose Polycap) CHD

Stroke

0% −10% −20% −30% −40% −50%

−48%

−60% −70%

−57%

−62%

−80%

−69%

Figure 5. The Projected risk reduction in CHD and stroke with TIPS (low-dose Polycap) and the TIPS 2 (full-dose Polycap).

ÂÂ

Follow-up: Nine months.

ÂÂ

Sample size: Phase 1 (n = 2,118; patients with a history of MI from five countries (Spain, Italy, Argentina, Brazil and Paraguay), Phase 2 (n = 695; patients from Phase 1 from four countries).

ÂÂ

ÂÂ

Intervention: Phase 1 analyzed factors that interfere with appropriate adherence to cardiovascular medications for secondary prevention after an acute MI. Patients were randomized to either the polypill (containing aspirin 100 mg, simvastatin 40 mg and ramipril 2.5, 5 or 10 mg) or three drugs separately for Phase 2.

Primary endpoint: Adherence to the treatment measured at the final visit by the self-reported

12

ÂÂ

Conclusion: FOCUS 1 identified the reasons that impede appropriate adherence to cardiovascular medications in a post-MI population. FOCUS 2 showed that compared with the three drugs

Polypill

Separate medications 65.70%

70.00 60.00 Adherence (%)

randomized trial with prospective economic evaluation) tested the effect of a polypill versus the three drugs given separately on adherence, BP and LDL cholesterol, safety and tolerability.

50.00

50.80%

55.70%

41%

40.00 30.00 20.00 10.00 0.00

Intention-to-treat population

Per-protocol population

Figure 6. Comparison of adherence in polypill group and group receiving separate medications after 9 months of follow-up.

Asian Journal of Clinical Cardiology, Volume 17, Number 3, January-March 2015

Review article given separately, the use of a polypill strategy met the primary endpoint for adherence for secondary prevention following an acute MI. FOCUS 2 is ongoing and will assess whether there are any differences between the two treatment arms in BP, blood cholesterol, safety or costs.

Polypill: Primary and Secondary Prevention Ongoing trials

TIPS-3 Trial26,27 The International PolycapTM Study 3 (TIPS-3) is a randomized, double-blind, placebo-controlled trial for the evaluation of a PolycapTM, low-dose aspirin and vitamin D supplementation in primary prevention of CVD, cancer and fractures. ÂÂ

Sample size: Five thousand subjects (women ≥60 years and men ≥55 years) from 11 countries without known heart disease or prior stroke and INTERHEART risk score of ≥10.

ÂÂ

Study design: Randomized, double-blind, placebocontrolled trial; 2 × 2 × 2 factorial design.

ÂÂ

Follow-up: Five years.

ÂÂ

Intervention: The Polycap contains thiazide (diuretic), atenolol (b-blocker), ramipril (ACE inhibitor) and simvastatin (statin). The trial will also separately dispense daily low-dose aspirin and monthly vitamin D to investigate their effects on CVD, cancer and osteoporosis.

ÂÂ

HOPE-3 Trial28 The Heart Outcomes Prevention Evaluation (HOPE)-3 trial is evaluating whether rosuvastatin 10 mg/day alone, a fixed-dose combination of candesartan 16 mg/HCTZ 12.5 mg/day alone, both or neither can reduce the risk of heart attacks, stroke and their sequelae in people without known heart disease and at average risk. All participants receive structured lifestyle advice. ÂÂ

Sample size: Twelve thousand seven hundred five individuals at moderate risk (men aged >55 years and women aged >65 years) with 1 risk factor or women aged >60 years with two risk factors.

ÂÂ

Study design: Randomized, 2 × 2 factorial design.

ÂÂ

Study centers: Two hundred fifty-six centers in 22 countries in North and South America, Europe, Africa, Asia and Australia.

ÂÂ

Follow up: Five years.

ÂÂ

Primary outcome measures

Primary outcome measures

ÂÂ

at 10 years of follow-up in participants taking vitamin D versus placebo (follow-up 10 years).

Composite of major CVD (cardiovascular death, nonfatal stroke, nonfatal MI) + heart failure, resuscitated cardiac arrest or revascularization with evidence of ischemia in participants taking Polycap versus placebo.

Composite of cardiovascular events (cardiovascular death, MI or stroke) and cancer in participants taking aspirin versus placebo.

Risk of fractures in participants taking vitamin D versus placebo.

Secondary outcome measures

Composite of cardiovascular death, nonfatal stroke and nonfatal MI in participants taking Polycap versus placebo.

Composite outcome of cardiovascular events and cancers after 10 years of follow-up in participants taking aspirin versus placebo (follow-up 10 years).

Composite outcome of cardiovascular events, fractures and cancers, and the risk of the falls

ÂÂ

To evaluate the effects of lipid modification (LDL cholesterol lowering and HDL cholesterol raising) with rosuvastatin 10 mg daily on major cardiovascular events.

To evaluate the effects of BP-lowering with combined candesartan 16 mg/HCTZ 12.5 mg daily on major cardiovascular events.

To evaluate the impact of combined lipid modification with rosuvastatin 10 mg/day and BP-lowering with candesartan 16 mg/HCTZ 12.5 mg daily on major cardiovascular events.

Secondary outcome measures

Total and cardiovascular mortality

CHD and cerebrovascular disease events

Heart failure

Revascularization procedures

Angina pectoris

Progression of renal disease

New diagnosis of diabetes

Poly-Iran Trial29 The purpose of this study is to determine the effects of polypill tablet (a fixed-dose combination of two antihypertensive medications, atorvastatin and aspirin) on primary and secondary prevention of CVD in Iranian adults >50. ÂÂ Study design: Pragmatic cluster randomized trial nested within the Golestan Cohort Study (GCS). The study comprises three arms as follows:

Asian Journal of Clinical Cardiology, Volume 17, Number 3, January-March 2015

13

Review article

Three thousand five hundred randomly selected participants receive polypill tablets once-daily and minimal care (which consists of direct education and pamphlet on cardiovascular risk reduction, biannual follow-ups and BP measurements).

Three thousand five hundred randomly selected participants receive only minimal care as described above.

Twenty-four thousand participants receive usual care (the basic primary healthcare provided by the local physicians and Community Health Workers for the whole participants of GCS consistent with the current Iranian Health Care System guidelines).

ÂÂ

ÂÂ

Primary outcome measures: Time to first major cardiovascular event within 5 years defined as nonfatal and fatal MI, unstable angina, sudden death, heart failure, coronary artery revascularization procedures and nonfatal and fatal stroke, hospitalization because of CVD. Secondary outcome measures: Change in BP, fasting blood sugar and lipid profile, adverse events leading to discontinuation of polypill, compliance, number of major cardiovascular events within 5 years.

Increasing numbers of elderly patients require polypharmacy for chronic diseases. Nonadherence to medications is common and is associated with adverse treatment outcomes. Reduced adherence means higher morbidity, adverse events and costs. The term ‘compliance’ has been replaced by the term ‘adherence’ because it reflects a less paternalistic doctor-to-patient relationship, and also includes the responsibility of the doctors in medical treatment.30 Several studies have shown that adherence to statin treatment is associated with reduction in acute MI,30,31 long-term mortality30,32 and all-cause mortality.30,33 In patients with chronic conditions, fixed-dose combinations are one approach to improve adherence to treatment and thereby improve clinical outcomes. Using a polypill in comparison with the different drugs taken separately can improve adherence.30 The UMPIRE (Use of a Multidrug Pill in Reducing Cardiovascular Events) randomized clinical trial

14

ÂÂ

The FOCUS trial found that the 3-drug polypill improved adherence on 9-month follow-up (50.8% vs 41% on an intention-to-treat analysis and 65.7% vs 55.7% in a per-protocol comparison).24,35

ÂÂ

The Kanyini Guidelines Adherence with the Polypill (Kanyini-GAP) study conducted in Australian patients, including indigenous and nonindigenous people, reported that after a median of 18 months, the polypill-based strategy was associated with greater self-reported use of combination treatment versus usual care; 70% versus 47%, respectively.36

Arms #1 and #2 are compared via a 2-armed open-labeled cluster randomized controlled trial.

Comparisons between arm #3 and the other 2 arms are also performed.

Global Scenario For A Polypill Strategy

ÂÂ

conducted in Europe and India showed 33% higher improved adherence to a polypill strategy versus usual care for prevention of CVD (86% vs 65%, respectively).

The trial randomized 2,004 participants with established CVD or at a high-risk for CVD, to a 4-drug fixed-combination in two variants: One containing 75 mg aspirin, 40 mg simvastatin, 10 mg lisinopril and 50 mg atenolol and the other a combination of 75 mg aspirin, 40 mg simvastatin, 10 mg lisinopril and 12.5 mg HCTZ.34-36

In an editorial comment in JACC, Dr K Srinath Reddy wrote, “the polypill, on its own, improves adherence. If other barriers to adherence also are removed or lowered (through improved affordability and social support as well as treatment of comorbidities such as depression), there are likely to be even higher benefits.”35 The UK Intellectual Property Office and Intellectual Property Office of New Zealand officially granted patents (UK Patent No. GB2482432; New Zealand Patent No. NZ595127) for Cadila Pharmaceuticals world’s first cardiovascular polypill 'Polycap', titled "Stable pharmaceutical composition for atherosclerosis." Polycap provides Multicomponent Composition (MCC) to improve adherence to therapy. (Source: http://www.google. as/patents/WO2010092450A1?cl=en) Challenges and future directions Although, the use of a polypill has shown beneficial effects in reducing CVD risk, there are several challenges yet to be met. Several questions need to be answered before long-term primary prevention trials are conducted with fixed-dose combination pill.37 A feasibility study of the World Health Organization (WHO) in Sri Lanka addressed some of these concerns and documented high acceptability of the polypill to patients and physicians. However, the centers in this feasibility trial were tertiary care hospitals37 and wider adoption of the polypill will provide 'real-world' user feedback and more insights.

Asian Journal of Clinical Cardiology, Volume 17, Number 3, January-March 2015

Review article Dose is another issue, which needs to be addressed.

The Polycap had just one dose (generally a moderate dose) of each agent. Currently for combination pills, regulatory authorities require that the pill be available in every dose combination of each drug, so the combination pill would not limit treatment. However, this approach would obviously not be feasible with a pill with five or six components and each having 2-4 doses.38 The polypill could potentially be widely used in secondary prevention and in selected high-risk individuals without CVD (e.g., those with severe hypertension or diabetes mellitus with additional risk factors), 50-75% proportional reduction in risk can be anticipated from prolonged therapy.2 But, in individuals without CVD and not at high-risk large trials are needed to quantify the benefits, potential risks, and cost-effectiveness of the polypill. If such trials will provide clear evidence that the polypill reduces the risks of major CVD events by at least 40-50% in moderate-risk individuals with good safety, tolerability and cost-effectiveness, then it could become a key component of both primary and secondary CVD prevention globally.2 Will the availability of a polypill take away the significance of lifestyle management? This is another challenge that should be of great concern to clinicians.38 The polypill should not be considered in isolation but as an integral part of a comprehensive CVD prevention strategy that includes efforts to reduce tobacco use, increase physical activity and increase consumption of heart-healthy diets. This approach could substantially reduce CVD by >80-90% globally in a highly cost-effective manner. Even if the uptake of these measures is only 50% of an 'ideal' target, a substantial reduction in CVD by half globally is possible within the next two decades.2 Conclusion Cardiovascular diseases (CVDs) are the leading causes of mortality in the world.39 What was once thought to be an endemic disease of high income countries has become a global epidemic, as low- and middle-income countries have adopted Western lifestyles, to the point that noncommunicable diseases are now the main cause of death in these regions, above and beyond communicable diseases, malnutrition and injury.40 More than 80% of CVD deaths occur in low- and middle-income countries.39 Current cardiovascular prevention strategies fail to achieve the full potential of risk modification.41 The aggregated benefits of concurrently controlling common CVD risk factors, such as dyslipidemia and hypertension, in people at overall risk for CVD is postulated to be more efficient than treating each individual risk factor to target.15

Several drugs are available to treat various CVD risk factors. Hence, combining them in one pill could reduce heart disease by 80%. Administration of a polypill consisting of cholesterol-lowering (statins), antihypertensive and antiplatelet agents together would simultaneously lower multiple risk factors, and applying such a population risk-reduction strategy would drastically reduce CVD incidence.15 TIPS was the first to systematically test the clinical application of the polypill; it included ramipril, HCTZ, atenolol, aspirin and simvastatin. BP and LDL levels were effectively lowered and antiplatelet function was demonstrated.

The prevention of CVD by using a polypill has gained increasing momentum as a strategy to contain progression of the disease. The polypill has the potential to control the global health epidemic of CVD by effectively reaching underdeveloped regions of the world, simplifying healthcare delivery, improving costeffectiveness, increasing medication adherence and supporting a comprehensive prescription of evidencebased cardioprotective drugs.42 References 1. Wiley B, Fuster V. The concept of the polypill in the prevention of cardiovascular disease. Ann Glob Health 2014;80(1):24-34.

2. Lonn E, Bosch J, Teo KK, Pais P, Xavier D, Yusuf S. The polypill in the prevention of cardiovascular diseases: key concepts, current status, challenges, and future directions.

Circulation 2010;122(20):2078-88.

3. Goyal A, Yusuf S. The burden of cardiovascular disease in the Indian subcontinent. Indian J Med Res 2006;124(3):235-44.

4. Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ 2003;326(7404):1419.

5. Yusuf S, Islam S, Chow CK, Rangarajan S, Dagenais G, Diaz R, et al; Prospective Urban Rural Epidemiology (PURE) Study Investigators. Use of secondary prevention drugs for cardiovascular disease in the community in highincome, middle-income, and low-income countries (the PURE Study): a prospective epidemiological survey. Lancet 2011;378(9798):1231-43.

6. Joshi R, Chow CK, Raju PK, Raju R, Reddy KS, Macmahon S, et al. Fatal and nonfatal cardiovascular disease and the use of therapies for secondary prevention in a rural region of India. Circulation 2009;119(14):1950-5.

7. Wood A, Pell J, Patel A, Neal B, Raju PK, Chow CK. Prevention of cardiovascular disease in a rural region of India and strategies to address the unmet need.

Heart 2011;97(17):1373-8.

8. Baroletti S, Dell'Orfano H. Medication adherence in cardiovascular disease. Circulation 2010;121(12):1455-8.

9. Newby LK, LaPointe NM, Chen AY, Kramer JM, Hammill BG, DeLong ER, et al. Long-term adherence to evidencebased secondary prevention therapies in coronary artery disease. Circulation 2006;113(2):203-12.

Asian Journal of Clinical Cardiology, Volume 17, Number 3, January-March 2015

15

Review article 10. Jackevicius CA, Li P, Tu JV. Prevalence, predictors, and outcomes of primary nonadherence after acute myocardial infarction. Circulation 2008;117(8):1028-36.

11. Mazzaglia G, Ambrosioni E, Alacqua M, Filippi A, Sessa E, Immordino V, et al. Adherence to antihypertensive medications and cardiovascular morbidity among newly diagnosed hypertensive patients. Circulation.

2009;120(16):1598-605.

12. Sokol MC, McGuigan KA, Verbrugge RR, Epstein RS. Impact of medication adherence on hospitalization risk and healthcare cost. Med Care 2005;43(6):521-30.

13. Wald NJ, Wald DS. Polypill concept. Postgrad Med J 2010;86(1015):257-60.

14. Mancia G. Total cardiovascular risk: a new treatment concept. J Hypertens Suppl 2006;24(2):S17-24.

15. Dabhadkar KC, Kulshreshtha A, Ali MK, Narayan KM. Prospects for a cardiovascular disease prevention polypill.

Annu Rev Public Health 2011;32:23-38.

16. Yusuf S. Two decades of progress in preventing vascular disease. Lancet 2002;360(9326):2-3.

17. Dabhadkar KC, Bellam N. Polypill strategy for primary prevention of cardiovascular disorders. Drugs Today (Barc) 2013;49(5):317-24.

18. Xavier D, Pais P, Sigamani A, Pogue J, Afzal R, Yusuf S; Indian Polycap Study (TIPS) Investigators. The need to test the theories behind the Polypill: rationale behind the Indian Polycap Study. Nat Clin Pract Cardiovasc Med 2009;6(2): 96-7.

19. Eikelboom JW, Lonn E, Genest J Jr, Hankey G, Yusuf S. Homocyst(e)ine and cardiovascular disease: a critical review of the epidemiologic evidence. Ann Intern Med 1999;131(5):363-75.

20. Lonn E, Yusuf S, Arnold MJ, Sheridan P, Pogue J, Micks M, et al; Heart Outcomes Prevention Evaluation (HOPE) 2 Investigators.

Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med 2006;354(15):1567-77.

21. Patel A, Shah T, Shah G, Jha V, Ghosh C, Desai J, et al.

Preservation of bioavailability of ingredients and lack of drug-drug interactions in a novel five-ingredient polypill (polycap): a five-arm phase I crossover trial in healthy volunteers. Am J Cardiovasc Drugs 2010;10(2):95-103.

22. Indian Polycap Study (TIPS), Yusuf S, Pais P, Afzal R, Xavier D, Teo K, Eikelboom J, et al. Effects of a polypill (Polycap) on risk factors in middle-aged individuals without cardiovascular disease (TIPS): a phase II, double-blind, randomised trial.

Lancet 2009;373(9672):1341-51.

23. Yusuf S, Pais P, Sigamani A, Xavier D, Afzal R, Gao P, et al.

Comparison of risk factor reduction and tolerability of a full-dose polypill (with potassium) versus low-dose polypill (polycap) in individuals at high risk of cardiovascular diseases: the Second Indian Polycap Study (TIPS-2) investigators. Circ Cardiovasc Qual Outcomes 2012;5(4): 463-71.

24. Castellano JM, Sanz G, Peñalvo JL, Bansilal S, FernándezOrtiz A, Alvarez L, et al. A polypill strategy to improve adherence: results from the FOCUS Project. J Am Coll Cardiol 2014;64(20):2071-82.

25. FOCUS trial. Available at: https://www.clinicaltrials.gov/ct2/ show/NCT01321255.

16

26. TIPS-3 trial. Available at: https://www.clinicaltrials.gov/ct2/ show/NCT01646437.

27. TIPS-3 - The International Polycap Study 3. Available at: http://www.coheart.ca/projects/tips3/.

28. HOPE-3 trial. Available at: https://clinicaltrials.gov/ct2/ show/NCT00468923?term=NCT00468923&rank=1.

29. Poly-Iran trial. Available at: https://clinicaltrials.gov/ct2/ show/NCT01271985.

30. Laufs U, Rettig-Ewen V, Böhm M. Strategies to improve drug adherence. Eur Heart J 2011;32(3):264-8.

31. Penning-van Beest FJ, Termorshuizen F, Goettsch WG, Klungel OH, Kastelein JJ, Herings RM. Adherence to evidence-based statin guidelines reduces the risk of hospitalizations for acute myocardial infarction by 40%: a cohort study. Eur Heart J 2007;28(2):154-9.

32. Rasmussen JN, Chong A, Alter DA. Relationship between adherence to evidence-based pharmacotherapy and longterm mortality after acute myocardial infarction. JAMA 2007;297(2):177-86.

33. Shalev V, Chodick G, Silber H, Kokia E, Jan J, Heymann AD. Continuation of statin treatment and all-cause mortality: a population-based cohort study. Arch Intern Med 2009;169(3):260-8.

34. Thom S, Poulter N, Field J, Patel A, Prabhakaran D, Stanton A, et al; UMPIRE Collaborative Group. Effects of a fixeddose combination strategy on adherence and risk factors in patients with or at high risk of CVD. The UMPIRE randomized clinical trial. JAMA 2013;310(9):918-29.

35. Reddy KS. Polypill opens a path for improving adherence.

J Am Coll Cardiol 2014;64(20):2083-5.

36. Patel A, Cass A, Peiris D, Usherwood T, Brown A, Jan S, et al; for the Kanyini Guidelines Adherence with the Polypill (Kanyini GAP) Collaboration. A pragmatic randomized trial of a polypill-based strategy to improve use of indicated preventive treatments in people at high cardiovascular disease risk. Eur J Prev Cardiol 2014 Mar 27.

[Epub ahead of print].

37. Soliman EZ, Mendis S, Dissanayake WP, Somasundaram NP, Gunaratne PS, Jayasingne IK, et al. A Polypill for primary prevention of cardiovascular disease: a feasibility study of the World Health Organization. Trials 2011;12:3.

38. Cannon CP. Can the polypill save the world from heart disease? Lancet 2009;373(9672):1313-4.

39. Huffman MD, Yusuf S. Polypills essential medicines for cardiovascular disease secondary prevention? J Am Coll Cardiol 2014;63(14):1368-70.

40. Castellano JM, Sanz G, Fuster V. Evolution of the polypill concept and ongoing clinical trials. Can J Cardiol 2014;30(5):520-6.

41. Lonn E, Yusuf S. Polypill: the evidence and the promise.

Curr Opin Lipidol 2009;20(6):453-9.

42. Castellano JM, Sanz G, Fernandez Ortiz A, Garrido E, Bansilal S, Fuster V. A polypill strategy to improve global secondary cardiovascular prevention: from concept to reality. J Am Coll Cardiol 2014;64(6):613-21.

Asian Journal of Clinical Cardiology, Volume 17, Number 3, January-March 2015

review article

Evaluation and Treatment of Severe Asymptomatic Hypertension CHAD S. KESSLER, YAZEN JOUDEH

Abstract Poorly controlled hypertension is a common finding in the outpatient setting. When patients present with severely elevated blood pressure (i.e., systolic blood pressure of 180 mm Hg or greater, or diastolic blood pressure of 110 mm Hg or greater), physicians need to differentiate hypertensive emergency from severely elevated blood pressure without signs or symptoms of end-organ damage (severe asymptomatic hypertension). Most patients who are asymptomatic but have poorly controlled hypertension do not have acute end-organ damage and, therefore, do not require immediate workup or treatment (within 24 hours). However, physicians should confirm blood pressure readings and appropriately classify the hypertensive state. A cardiovascular risk profile is important in guiding the treatment of severe asymptomatic hypertension; higher risk patients may benefit from more urgent and aggressive evaluation and treatment. Oral agents may be initiated before discharge, but intravenous medications and fast-acting oral agents should be reserved for true hypertensive emergencies. High blood pressure should be treated gradually. Appropriate, repeated follow-up over weeks to months is needed to reach desired blood pressure goals.

Keywords: Hypertensive emergency, end-organ damage, cardiovascular risk profile, asymptomatic hypertension

A

pproximately one third of adults in the United States have some degree of hypertension1-3 and up to 5 percent of patients presenting to the emergency department have severely elevated blood pressure.4 In one study, about one fourth of patients presenting with diastolic blood pressure of 110 mm Hg or greater were unaware of their hypertension, including 28 percent of those with severe asymptomatic hypertension and 8 percent of those with a hypertensive emergency.5 There are few prospective, randomized controlled trials on the treatment of severe asymptomatic hypertension. Physicians should not expect to reduce blood pressure to desired levels before discharge. Instead, gradual reduction is achieved over time with repeated follow-up visits.

pressure as less than 120 mm Hg systolic or less than 80 mm Hg diastolic; prehypertension as 120 to 139 systolic or 80 to 89 diastolic; stage 1 hypertension as 140 to 159 systolic or 90 to 99 diastolic; and stage 2 hypertension as 160 or greater systolic, or 100 or greater diastolic.6 However, there is no universal terminology to describe severe stages of hypertension.7

The Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) defines normal blood

For this article, we define severely elevated blood pressure as 180 mm Hg or greater systolic, or 110 mm Hg or greater diastolic.8 Severely elevated blood pressure can be classified as severe asymptomatic hypertension or hypertensive emergency.9-11 Severe asymptomatic hypertension is defined as severely elevated blood pressure without signs or symptoms of end-organ damage.

Hypertensive emergency (sometimes called hypertensive crisis12) is the point when signs or symptoms of end-organ damage occur. Although hypertensive emergency is usually associated with diastolic blood pressure greater than 120 mm Hg (except in children and pregnant women),5,13 it can occur at any hypertensive level.

CHAD S. KESSLER, MD, FACEP, is an assistant professor of medicine at the University of Illinois at Chicago College of Medicine, and is associate program director of the universityâ&#x20AC;&#x2122;s Internal Medicine/Emergency Medicine Residency Program. He is also director of emergency medicine at the Jesse Brown Veterans Affairs Medical Center in Chicago.

YAZEN JOUDEH, MD, is a fourth-year resident in the Medicine/Pediatrics Residency Program at the University of Illinois at Chicago College of Medicine.

Source: Adapted from Am Fam Physician. 2010;81(4):470-476.

Severe asymptomatic hypertension can be further classified as hypertensive urgency or severe uncontrolled hypertension, based on the patientâ&#x20AC;&#x2122;s medical history and global cardiovascular risk.

Hypertensive urgency is defined as the presence of risk factors for progressive end-organ damage (e.g., history of congestive heart failure, unstable angina, or preexisting renal insufficiency), whereas severe

Definitions

Asian Journal of Clinical Cardiology, Volume 17, Number 3, January-March 2015

17

Review article Severely elevated blood pressure: Systolic blood pressure of 180 mm Hg or greater, or diastolic blood pressure of 110 mm Hg or greater

Severe asymptomatic hypertension: Patient has no signs or symptoms of endorgan damage

Hypertensive urgency: Presence of risk factors for progressive end-organ damage (e.g., history of congestive heart failure, unstable angina, preexisting renal insufficiency)

Hypertensive emergency: Patient has signs or symptoms of end-organ damage

Severe uncontrolled hypertension: Absence of specific risk factors for end-organ damage, other than hypertension itself

Figure 1. Classification of severely elevated blood pressure.

uncontrolled hypertension is defined as the absence of these risk factors.8 The classification of severely elevated blood pressure is presented in Figure 1.

Pathophysiology Hypertension may be present for many years before it becomes an emergency.14 The rapidity of blood pressure elevation and severity of end-organ damage during an emergency are caused by the failure of normal autoregulatory function and abrupt increases in systemic vascular resistance. Moreover, there is concurrent endovascular injury with fibrinoid necrosis of arterioles.

This leads to a cycle of ischemia, platelet deposition, and further failure of autoregulation as vasoactive substances are released.

Normally, tissue perfusion in the brain, heart, and kidneys is tightly regulated at a constant level, despite fluctuations in systemic blood pressure.14 With severely elevated blood pressure, autoregulation shifts to the right over time (Figure 2).15 Thus, there is a lower threshold for hypoperfusion to occur if the current blood pressure abruptly decreases by more than 20 to 25 percent. Because of this, physicians should avoid the common practice of giving asymptomatic patients excessive doses of antihypertensives in an attempt to normalize blood pressure rapidly. This can lead to unnecessary delays in emergency department discharge for observation, or even admission for iatrogenic hypotension.

18

Evaluation A 2007 European guideline emphasizes the role of determining global cardiovascular risk in the evaluation of patients with hypertension.16 Treatment should be based on a complete cardiovascular risk profile that takes into account coexisting risk factors and any history of end-organ damage (Table 1).16 Risk can then be stratified as low, moderate, high, or very high. This risk stratification is dynamic, taking into account that a patient with lower blood pressure and multiple risk factors may have a similar prognosis to a patient with more poorly controlled hypertension and no risk factors.

History and Physical Examination After rechecking an elevated blood pressure reading, physicians should determine if the patient has symptoms or signs that suggest secondary causes of hypertension or the presence of end-organ damage. A thorough review of systems with an emphasis on neurologic, cardiac, and renal symptoms should be performed to detect new vision changes, mild confusion, dyspnea on exertion, and oliguria.17 A complete medication history should be obtained to review adherence to current antihypertensives, as well as the use of new drugs or nonprescription supplements (e.g., nonsteroidal anti-inflammatory drugs, herbal or dietary supplements, weight-loss drugs).

Orthostatic vital signs should be evaluated in older patients and in patients with diabetes or suspected postural hypotension. All patients should receive focused

Table 1. Risk Factors for End-organ Damage in Persons with Severely Elevated Blood Pressure Systolic blood pressure of greater than 160 mm Hg, with diastolic blood pressure of less than 70 mm Hg Diabetes mellitus Metabolic syndrome At least three cardiovascular risk factors (e.g., age older than 55 years for men or 65 years for women, smoking, dyslipidemia, impaired fasting glucose, obesity) One or more of the following findings associated with subclinical organ damage: Left ventricular hypertrophy on electrocardiography (particularly with strain) or echocardiography (particularly concentric) Reduced estimated glomerular filtration rate or creatinine clearance Microalbuminuria or proteinuria Established cardiovascular or renal disease Information from reference 16.

Asian Journal of Clinical Cardiology, Volume 17, Number 3, January-March 2015

Review article cardiopulmonary, neurologic, and funduscopic examinations. Mild retinal changes, such as arteriolar narrowing and arteriovenous nicking, are largely nonspecific except in younger patients. However, hemorrhages and exudates, and papilledema are associated with increased cardiopulmonary risk.16 Papilledema is a sign of hypertensive emergency, whereas hemorrhages may be caused by hypertensive emergency or diabetes.

Diagnostic Testing There is no consensus about the necessary laboratory workup of patients with severe asymptomatic hypertension. The JNC 7 recommends an array of testing only before initiating therapy in patients with newly diagnosed hypertension.6 Several studies have examined the usefulness of routine screening for end-organ damage in patients with severe hypertension.11,17,18 These studies did not show clear evidence that electrocardiography (ECG), complete blood count, basic metabolic profile, or urinalysis affects acute medical decisions or improves short-term outcomes. Until further guidelines are established, clinical judgment (and pretest probability) must be used to determine which tests may be useful.

Table 2 presents a suggested approach to the initial evaluation of patients with severely elevated blood pressure.

A urinalysis that is negative for proteinuria and hematuria is strong evidence against an acute elevation in serum creatinine level,19 although a basic metabolic profile may still be useful to calculate the glomerular filtration rate or creatinine clearance. Both measures are strong predictors of cardiovascular risk accompanying acute or chronic renal dysfunction.16 ECG is unlikely to influence acute care in the absence of signs and symptoms of acute coronary syndrome. However, ECG is recommended for any patient with indicators of cardiovascular disease, such as chest pain, arrhythmia, and shortness of breath. More extensive testing for secondary causes is not generally indicated, unless the clinical or laboratory evaluation strongly suggests an identifiable cause or blood pressure control has been refractory despite multiple treatments over time.6 In the absence of other signs of central nervous system dysfunction, an isolated, nonspecific headache has not been shown to be a risk factor for end-organ central nervous system damage; therefore, imaging is generally not recommended.8

Table 2. Suggested Initial Evaluation of Patients with Severely Elevated Blood Pressure Confirm elevated blood pressure reading in a quiet area after the patient sits upright for at least five minutes, with the arm supported at the level of the heart.

Inquire about medication history and compliance, as well as cardiovascular, pulmonary, and neurologic symptoms.

Perform focused cardiopulmonary, neurologic, and funduscopic examinations.

If the patient is at low risk of cardiovascular disease,* consider screening for acute renal failure with urinalysis. Check urine toxicology if drug use is suspected.

For a patient with moderate or high cardiovascular risk,* perform urinalysis and a basic metabolic profile.

Consider chest radiography and/or electrocardiography if the patient has clinical signs and symptoms that may suggest endorgan cardiopulmonary damage or cardiac ischemia.

Check hemoglobin levels only if anemia is suspected.

If initiating a new oral antihypertensive agent, particularly one that is renally metabolized, perform a basic metabolic profile to establish baseline renal function (via a calculated creatinine clearance), unless recent test results are available.

If a hypertensive emergency is diagnosed, treat accordingly.

Otherwise, treat the patient for severe asymptomatic hypertension (Table 3). *See Table 1 for risk factors.

Treatment

patients and may be harmful.6,17 There are no controlled studies demonstrating long-term improved outcomes with acute treatment of severe asymptomatic hypertension.

Severely elevated blood pressure likely does not develop abruptly, but rather over days, weeks, or months.

Aggressive dosing with intravenous medications or fastacting oral agents, such as nifedipine or hydralazine, can lead to hypotension. Reducing severely elevated blood pressure below the autoregulatory zone too quickly can result in markedly decreased perfusion to the brain and eventually ischemia or infarction. An early trial including 143 patients with a diastolic blood pressure between 115 and 129 mmHg compared hydrochlorothiazide, reserpine, and hydralazine therapy with no treatment.20 No adverse events occurred in the untreated group within the first three months. Another study evaluated the benefit of initiating a loading dose of oral medication before discharge in patients with severely elevated blood pressure.9 There was no significant difference among groups in the degree of blood pressure improvement at 24 hours and one week.

Rapidly lowering blood pressure in the emergency department is usually unnecessary in asymptomatic

The VALUE (Valsartan Antihypertensive Long-term Use Evaluation) trial compared valsartan with amlodipine

Asian Journal of Clinical Cardiology, Volume 17, Number 3, January-March 2015

19

Review article to determine their effects on cardiovascular outcome in high-risk patients with hypertension.21 Many of the cardiovascular events occurred within the first six months of treatment, when the blood pressure difference between the two treatment groups was greatest. Of note, the difference in adverse cardiovascular events between the two groups decreased as blood pressure control became more similar.

Although there is no evidence that treating poorly controlled hypertension within hours or days is beneficial, the VALUE findings suggest that blood pressure goals should be reached within a relatively short time (certainly within six months), at least in patients at high cardiovascular risk. Thus, a loading dose of an antihypertensive in the physician’s office or emergency department is generally not warranted, and most patients only need a maintenance dose with follow-up after a few days. True hypertensive emergencies require admission to an intensive care unit and immediate treatment within one to two hours. Even in the emergent setting, blood pressure should not be acutely lowered because of the risk of hypoperfusion.

Follow-up and Monitoring Recommendations for treatment and follow-up of patients with severe asymptomatic hypertension are shown in Table 3.8,12,15,22,23 Outpatient treatment is generally

acceptable, with appropriate follow-up. If it is unclear whether the patient will comply with follow-up, a short hospital stay may be needed. Initiating treatment for asymptomatic hypertension is optional with appropriate follow-up. Previously treated patients usually need adjustments in their long-term oral antihypertensive therapy, particularly the use of combination drugs, or reinstitution of medications if they have been nonadherent.6 If the patient has no history of hypertension, elevated blood pressure should be confirmed at a follow-up visit. However, a patient with severe asymptomatic hypertension can be expected to have some degree of hypertension at follow-up. In one study, more than one half of emergency department patients with two increased blood pressure readings and no history of hypertension met the definition of hypertension the following week based on home blood pressure monitoring.24 If a maintenance dose of an oral antihypertensive is initiated, the patient may be sent home without waiting for normalization of blood pressure. However, it is imperative to educate patients about the importance of compliance with antihypertensive medications and multiple follow-ups, as well as the risks of uncontrolled hypertension. Over weeks to months, the dosage and selection of medications may be modified to achieve desired goals.

Table 3. Treatment Recommendations for Severe Asymptomatic Hypertension Type of severe asymptomatic hypertension

Recommendations

Hypertensive urgency*

Initiate treatment and follow-up within 24 to 48 hours of presentation.

Initiate a maintenance dose of an oral medication before discharge in patients with SBP of 200 mm Hg or greater, or DBP of 120 mm Hg or greater; this is optional for patients with lower blood pressure.

Consider a short observation period, depending on the patient’s risk factors.

Safely discharge the patient, emphasizing the importance of close follow-up.

If follow-up is uncertain and the patient has many risk factors, consider hospitalization for initial therapy.

Severe uncontrolled hypertension†

Initiate treatment and follow-up within one to seven days of presentation.

Initiate a maintenance dose of an oral medication before discharge in patients with SBP of 200 mm Hg or greater, or DBP of 120 mm Hg or greater; this is optional for patients with lower blood pressure.

Safely discharge the patient, emphasizing the importance of close follow-up.

Note: Severe asymptomatic hypertension is defined as SBP of 180 mm Hg or greater, or DBP of 110 mm Hg or greater in a patient without signs or symptoms of end-organ damage.

DBP = Diastolic blood pressure; SBP = Systolic blood pressure. *Presence of risk factors for progressive end-organ damage. †Absence of risk factors for progressive end-organ damage.

Information from references 8, 12, 15, 22, and 23.

20

Asian Journal of Clinical Cardiology, Volume 17, Number 3, January-March 2015

Review article For complete article visit: www.aafp.org/afp.

REFERENCES

12. Marik PE, Varon J. Hypertensive crises: challenges and management [published correction appears in Chest.

2007;132(5):1721]. Chest. 2007;131(6):1949-1962.

1. Thaker D, Frech F, Suh D, Aranda J, Shin H, Rocha R. Prevalence of hypertension and ethnic differences in sociodemographic and cardiovascular health characteristics of U.S. hypertensives. Am J Hypertens. 2005;18 (suppl 4):117A.

14. Flanigan JS, Vitberg D. Hypertensive emergency and severe hypertension: what to treat, who to treat, and how to treat.

Med Clin North Am. 2006;90(3):439-451.

2. Hajjar I, Kotchen JM, Kotchen TA. Hypertension: trends in prevalence, incidence, and control. Annu Rev Public Health. 2006;27:465-490.

3. Ong KL, Cheung BM, Man YB, Lau CP, Lam KS. Prevalence, awareness, treatment, and control of hypertension among United States adults 1999-2004. Hypertension. 2007;49(1): 69-75.

4. Karras DJ, Wald DA, Harrigan RA, et al. 2001 SAEM annual meeting abstracts. Elevated blood pressure in an urban emergency department: prevalence and patient characteristics. Acad Emerg Med. 2001;8(5):559.

5. Zampaglione B, Pascale C, Marchisio M, Cavallo-Perin P. Hypertensive urgencies and emergencies. Prevalence and clinical presentation. Hypertension. 1996;27(1):144-147.

6. Chobanian AV, Bakris GL, Black HR, et al., for the National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National High Blood Pressure Education Program Coordinating Committee. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report [published correction appears in JAMA. 2003;290(2):197]. JAMA. 2003;289(19):2560-2572.

7. Cherney D, Straus S. Management of patients with hypertensive urgencies and emergencies: a systematic review of the literature. J Gen Intern Med. 2002;17(12): 937-945.

8. Shayne PH, Pitts SR. Severely increased blood pressure in the emergency department. Ann Emerg Med. 2003;41(4): 513-529.

9. Zeller KR, Von Kuhnert L, Matthews C. Rapid reduction of severe asymptomatic hypertension. A prospective, controlled trial. Arch Intern Med. 1989;149(10):2186-2189.

13. Varon J, Marik PE. The diagnosis and management of hypertensive crises. Chest. 2000;118(1):214-227.

15. Varon J, Marik PE. Clinical review: the management of hypertensive crises. Crit Care. 2003;7(5):374-384.

16. Mancia G, De Backer G, Dominiczak A, et al. 2007 ESH-ESC practice guidelines for the management of arterial hypertension: ESH-ESC Task Force on the Management of Arterial Hypertension [published correction appears in J Hypertens. 2007;25(10):2184]. J Hypertens. 2007;25(9): 1751-1762.

17. Decker WW, Godwin SA, Hess EP, Lenamond CC, Jagoda AS, for the American College of Emergency Physicians Clinical Policies Subcommittee (Writing Committee) on Asymptomatic Hypertension in the ED. Clinical policy: critical issues in the evaluation and management of adult patients with asymptomatic hypertension in the emergency department. Ann Emerg Med. 2006;47(3):237-249.

18. Karras DJ, Kruus LK, Cienki JJ, et al. Evaluation and treatment of patients with severely elevated blood pressure in academic emergency departments: a multicenter study.

Ann Emerg Med. 2006;47(3):230-236.

19. Karras DJ, Heilpern KL, Riley LJ, Hughes L, Gaughan JP. Urine dipstick as a screening test for serum creatinine elevation in emergency department patients with severe hypertension. Acad Emerg Med. 2002;9(1):27-34.

20. Effects of treatment on morbidity in hypertension. Results in patients with diastolic blood pressures averaging 115 through 129 mm Hg. JAMA. 1967;202(11):1028-1034.

21. Julius S, Kjeldsen SE, Weber M, et al., for the VALUE trial group. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet.

2004;363(9426):2022-2031.

22. Vidt DG. Hypertensive crises: emergencies and urgencies.

J Clin Hypertens (Greenwich). 2004;6(9):520-525.

10. Handler J. Hypertensive urgency. J Clin Hypertens (Greenwich). 2006;8(1):61-64.

23. Slovis CM, Reddi AS. Increased blood pressure without evidence of acute end organ damage. Ann Emerg Med. 2008;51(3 suppl):S7-S9.

11. Karras DJ, Kruus LK, Cienki JJ, et al. Utility of routine testing for patients with asymptomatic severe blood pressure elevation in the emergency department. Ann Emerg Med. 2008;51(3):231-239.

24. Tanabe P, Persell SD, Adams JG, McCormick JC, Martinovich Z, Baker DW. Increased blood pressure in the emergency department: pain, anxiety, or undiagnosed hypertension? Ann Emerg Med. 2008;51(3):221-229.

■■■■

Asian Journal of Clinical Cardiology, Volume 17, Number 3, January-March 2015

21

review article

TURP Syndrome: A Quick Review and Update PARINITA C HAZARIKA

Abstract Transurethral resection of the prostate syndrome (TURP-S) is one of the commonest and dreaded complications of urological endoscopic surgery. It is characterized by cardiocirculatory and neurological changes consequent to acute changes in intravascular volume and plasma solute concentrations occurring as a result of excess absorption of irrigating fluid. Even in best of hands, incidence of TURP-S is up to 20% and carries a significant mortality rate- 0.5-5% die perioperatively. It may occur at any time perioperatively and has been observed as early as few minutes after surgery has started and as late as several hours after surgery has been completed. Symptoms and signs are varied and unpredictable, and result from fluid overload and disturbed electrolyte balance and hyponatremia. Treatment is largely supportive and relies on removal of the underlying cause, and organ and physiological support. Preoperative prevention strategies are extremely important.

Keywords: TURP syndrome, constant vigilance, prevention, early diagnosis, treatment

T

ransurethral resection of the prostate syndrome (TURP-S), first described by Creevy in 1947 is defined as a clinical condition characterized by cardiocirculatory and neurological changes consequent to acute changes in intravascular volume and plasma solute concentrations occurring as a result of excess absorption of irrigating fluid. It is one of the commonest and dreaded complications of urological endoscopic surgery. Even in best of hands, incidence of TURP-S is up to 20% and carries a significant mortality rate- 0.5-5% die perioperatively. It may occur at any time perioperatively and has been observed as early as few minutes after surgery has started and as late as several hours after surgery has been completed. TURP-S like syndrome may occur during endoscopic procedures such as ureterorenoscopy (URS), hysteroscopic submucosal fibroid resection, transcervical resection of endometrium (TCRE), percutaneous nephrolithotomy (PCNL), etc.

Pathophysiology TURP-S affects many systems and the pathophysiology can be summarized under the following heads: ÂÂ

Hypervolemia Increased fluid absorption

Antidiuretic response to stress

ÂÂ

Alteration in concentration of plasma solutes

Hyponatremia (dilutional)

Dept. of Anesthesiology Rajan Babu Institute of Pulmonary Medicine and Tuberculosis Kingsway Camp, Delhi

22

Hypo-osmolality

Hyperglycinemia

Hyperammonemia

Hypocalcemia

Hypoproteinemia (Hypoalbuminemia)

Decreased hematocrit

ÂÂ

Role of anesthesia and drugs

ÂÂ

Hemolysis

ÂÂ

Role of bacterial endotoxins

Important considerations

Hemolysis When hypotonic irrigants such as distilled water is used, there is acute hypo-osmolality with massive hemolysis.

Bleeding and red cell destruction are additional sources of volume and oxygen carrying capacity losses. The hemoglobinemia and hemoglobinuria coupled with hypotension can cause acute renal failure and death.

Again, hyperkalemia occurring due to cell breakdown may cause cardiac arrest.

Hyponatremia Dilutional hyponatremia (serum Na+ <130 mmol/L) is the hallmark of TURP-S. Hyponatremia causes lowering of cell membrane potential. Thus, there is disturbance of nerve conduction and muscle contraction. Also, hyponatremia leads to a reduction in plasma osmolality.

Hence, water enters the intracellular space causing cell edema, hemolysis, pulmonary edema, kidney failure and in severe cases cerebral edema.

Asian Journal of Clinical Cardiology, Volume 17, Number 3, January-March 2015

Review article Hypo-osmolality The real cause of neuronal disturbance is the rapidly established hypo-osmolality and not hyponatremia. The effective pore size of blood brain barrier is such that it makes the barriers essentially impermeable to sodium but freely permeable to water. Physiologically, the neurons react to serum hypo-osmolality with a mechanism called ‘idiogenic osmoles’. When there is acute change of serum osmolality (within minutes-to-hours), this compensatory mechanism may not be triggered fast enough to prevent neuronal expansion, cerebral edema and increased intracranial pressure, which in term cause bradycardia and hypertension by cushing’s reflex.

A volume of more than 2 liters, gained in 1 hour can lead to TURP-S; >3.5 liters precipitates shock and multiple system dysfunction.

Hyperglycinemia Although glycine is accepted as the most likely cause of ‘visual disturbance’ following TURP, it may also result in 'glycine-induced encephalopathy and seizure’ and ’toxic renal effects’. The glycine absorbed with the irrigating fluid is metabolized at the hepatic and kidney level with the synthesis of ammonia, glyoxylic acid, glycolic acid, serine and elastase, which are accumulated both in blood and cerebrospinal fluid (CSF). Glycine is the major inhibitory neurotransmitter at the levels of retina, whereas glyoxylic acid and glycolic acid are neurotoxic. Its link with the receptor of γ-aminobutyric acid (GABA) opens channels for the chloride located at the neurone surface with consequent hyperpolarization of ganglion cells (retina) thus inhibiting the neuronal impulses. Normal plasma glycine levels are 13-17 mg/L, whereas levels as high as 1,029 mg/L (up to 65 times normal) can be reached leading to transient blindness.

Glycine may also lead to encephalopathy and seizure via NMDA (N-methyl-d-aspartate), an excitatory neurotransmitter. Renal toxic effects of glycine may occasionally occur from hyperoxaluria (glycine metabolites-oxalate and glycolate).

Hyperammonemia Ammonia is a major by-product of glycine metabolism.

High ammonia concentration suppresses norepinephrine and dopamine release in the brain. This causes the encephalopathy of TURP-S. Fortunately ammonia toxicity is rare in man. Characteristically the toxicity oc­curs within 1 hour after surgery. The patient develops nausea and vomiting and then lapses into coma. Blood ammonia rises above 500 µmol/L (normal value is

11-35 µmol/L). Hyperammonemia lasts for over 10 hours postoperatively, probably because glycine contin­ues to be absorbed from the periprostatic space.

It is not clear why hyperammonemia does not develop in all TURP patients. Hyperammonemia implies that the body cannot fully metabolize glycine through the glycine cleavage system, citric acid cycle and conversion to glycolic acid and glyoxylic acid. Another possible ex­planation is arginine deficiency. Ammonia is normally con­verted to urea in the liver via the ornithine cycle.

Arginine is one of the intermediary products necessary for this cy­cle. When a patient has arginine deficiency, ornithine cycle is not fueled and thus ammonia accumulates.

SIGNS OF SYMPTOMS OF TURP-S The first sign of significant fluid absorption is a gradual or sudden rise of blood pressure (BP) (generally between 20 and 60 mmHg) accompanied by a bradycardia (10-25 beats/min). Retrosternal chest pain is another early symptom.

Cardiopulmonary Hypertension Tachycardia Dysrhythmia Respiratory distress

Hypotension Bradycardia Cyanosis Shock-death

Hemolytic and Renal ÂÂ

Hyponatremia

ÂÂ

Hemolysis/Anemia

ÂÂ

Hyperglycinemia

ÂÂ

Acute renal failure-death

Central Nervous System ÂÂ

Nausea and vomiting

ÂÂ

Visual disturbance- Temporary total blindness

ÂÂ

Confusion, restlessness

ÂÂ

Twitches - seizures Lethargy - Paralysis Dilated, nonreactive pupils Coma - death

Prevention of TURP-S This has two aspects: Surgical and anesthetic, but no method ensures that TURP-S will be avoided. Surgical preventive aspects are all designed to limit the absorption of excess irrigant during TURP.

Asian Journal of Clinical Cardiology, Volume 17, Number 3, January-March 2015

23

Review article Surgical Aspects of Prevention ÂÂ

Avoidance of early capsular perforation and opening of various sinuses during TURP.

ÂÂ

Limiting the intravesical pressure by:

Adjusting the height of the irrigation bag

Use of continuous flow systems or suprapubic trocar.

ÂÂ

Limiting the resection time to 1 hour and proper selection of gland size.

ÂÂ

Selection of proper irrigation fluid.

ÂÂ

Use of bipolar saline TURP (using sodium chloride irrigation).

ÂÂ

Selecting alternative intervention in high-risk cases.

ÂÂ

Novel and experimental approaches:

Intraoperative intraprostatic vasopressin

Use of 5a-reductase inhibitors.

Although TURP is still considered the gold standard, there are other attractive techniques such as Ho: YAG and potassium-titanyl-phosphate lasers, microwave ablation and cryosurgery. Their main advantages over conventional TURP include minimal blood loss, low morbidity and minimal fluid absorption.

Anesthetic Aspects of Prevention ÂÂ

ÂÂ

Preoperative screening

Recognizing high-risk patients for TURP-S.

Assigning proper ASA grade.

Optimization of cardiopulmonary system.

Intra- and postoperative aspects

Proper choice of anesthetic technique

Intense monitoring of vitals:

zz

SpO2

zz

ECG

zz

Noninvasive BP

zz

Heart rate/Pulse rate

zz

End tidal CO2 (EtCO2)

zz

Respiration.

zz

Adjusting OT temperature

zz

Use of warm blankets, mattresses

zz

Intravenous (IV) fluids and irrigating fluids pre-warming to 37˚C.

Plasma sodium

zz

Plasma glycine concentration.

(The above blood samples should be monitored just before surgery, every 15 minutes during surgery and 30 minutes after termination of operation).

Other relevant measurements are: zz

Breath ethanol content

zz

Plasma magnesium level susceptibility to seizures)

zz

Serum acid phosphates

zz

Arterial blood gases (ABG) (may herald metabolic acidosis)

zz

Plasma concentration of fluorescein

zz

Plasma concentration of potassium

zz

Use of load cell transducers.

(indicates

Ethanol Monitoring Highly specific and inexpensive method. This simple and safe method clearly requires a 1% ethanol marker in the irrigating fluids. It is measured by instrument called Alcomed. Cut-off level is 0.2 mg/L. TREATMENT ÂÂ

In the early phase:

Intraoperatively as soon as the signs and symptoms of TURP-S appear, the following measures should be taken.

Alert the operating surgeon.

Try to minimize fluid absorption (adjusting reservoir height or putting a suprapubic trocar) and sometimes it is advisable to terminate surgery as soon as possible after proper hemostasis.

IV furosemide (40-100 mg) to induce diuresis.

Draw arterial blood sample for ABG and serum electrolytes. ÂÂ

Prevention of hypothermia:

Blood sample measurements: zz

24

zz

Osmolality

Asian Journal of Clinical Cardiology, Volume 17, Number 3, January-March 2015

In the late intraoperative or early postoperative phase:

Mannitol is useful in promoting diuresis and eliminating IV volume overload.

Ascertain normal gaseous exchange between lungs and blood.

Packed RBC

O2 by mask

Calcium and magnesium ions to give positive inotropic effects, when needed.

If required, support respiration by endotracheal intubation and intermittent positive pressure ventilation.

Review article

Correct hyponatremia by using hypertonic saline (3%).

responses are preserved, but pupillary responses to light and accommodation are lost in TURP blindness.

When there is hypotension, vasoconstrictors are useful.

Summary

In case of convulsion, short-acting anticonvulsants (diazepam or midazolam IV) and in resistant cases, phenytoin or barbiturates can be given.

Packed RBC rather than whole blood is indicated in case of significant blood loss.

Restricted and cautious administration of IV fluid is necessary as these patients are very prone to pulmonary edema.

For temporary total blindness, reassurance that unimpaired vision is expected to return within 24 hours is the best treatment as half-life of glycine is only 85 minutes.

peripheral

Clinical Relevance Circulatory overload occurs when weight of prostate is >45 g. Ideal height of irrigating fluid is 60 cm, so that approximately 300 mL of fluid is obtained per minute for good vision. Symptoms of water intoxication appear when serum sodium level falls 15-20 mEq/L below normal levels. Clonus and positive Babinski responses are seen.

Papilledema with dilated, sluggishly reacting pupils and low voltage EEG can occur. When serum sodium level is below 120 mEq/L there is, hypotension due to reduced myocardial contractility. Below 115 mEq/L, bradycardia, widening of QRS complexes, ventricular ectopics and T-wave inversion are seen. At levels below 100 mEq/L generalized seizures, coma, respiratory arrest, ventricular tachycardia, ventricular fibrillation and finally cardiac arrest occurs. Sodium deficit = Normal serum sodium-estimated serum sodium × volume of body water (body water is usually 60% of body weight).

The most feared complication of correcting hyponatremia is central pontine myelinolysis (CPM), also referred to as ‘osmotic demyelination syndrome’ as demyelination can occur in extrapontine areas. Also, CPM is most commonly seen in women, probably due to sex differences in cellular ion pump capacity. It has been reported after rapid as well as slow correction of serum sodium concentration in TURP patients. About 1.5-2 mmol/L/hr correction in the serum sodium levels has been suggested to be safe. Visual disturbances: Transient blindness, foggy vision and patients see halos around objects. Pupils may be dilated and unresponsive.

Optic disc appears normal. Perception to light and blink

TURP is a procedure carried out on predominantly elderly population with a higher incidence of co-existing disease. Consequently anesthetizing for the procedure may present a challenge. Early detection and prompt treatment of the syndrome are vital for a favorable outcome. Newer techniques of TURP promise a reduced risk of TURP-S. Suggested Reading 1. Creevy CD. Hemolytic reactions during transurethral prostatic resection. J Urol 1947;58(2):125-31.

2. Ghanem AN, Ward JP. Osmotic and metabolic sequelae of volumetric overload in relation to the TUR syndrome. Br J Urol 1990;66(1):71-8.

3. Gravenstein D. Transurethral resection of the prostate (TURP) syndrome: a review of the pathophysiology and management. Anesth Analg 1997;84(2):438-46.

4. Malhotra V. Transurethral resection of the prostate.

Anesthesiol Clin North America 2000;18(4):883-97, x.

5. Bakan N, Gedik E, Ersoy O. Early detection of the TURP syndrome. Anesth Analg 2000;91(1):250-1.

6. Moorthy HK, Philip S. Serum electrolytes in TURP syndrome: is the role of potassium underestimated? Indian J Anaesth 2002;46(6):441-4.

7. Norris HT, Aasheim GM, Sherrard DJ, Tremann JA. Symptomatology, pathophysiology and treatment of the transurethral resection of the prostate syndrome. Br J Urol 1973;45(4):420-7.

8. Hoekstra PT, Kahnoski R, McCamish MA, Bergen W, Heetderks DR. Transurethral prostatic resection syndrome: a new perspective: encephalopathy with associated hyperammonemia. J Urol 1983;130(4):704-7.

9. Olsson J, Hahn RG. Ethanol monitoring of irrigating fluid absorption in transcervical resection of the endometrium.

Acta Anaesthesiol Scand 1995;39(2):252-8.

10. Hahn RG. Ethanol monitoring of irrigating fluid absorption.

Eur J Anaesthesiol 1996;13(2):102-15.

11. Olsson J, Nilsson A, Hahn RG. Symptoms of the transurethral resection syndrome using glycine as the irrigant. J Urol 1995;154(1):123-8.

12. Hahn RG, Ekengren JC. Patterns of irrigating fluid absorption during transurethral resection of the prostate as indicated by ethanol. J Urol 1993;149(3):502-6.

13. Mebust WK. Transurethral surgery. In: Campbell’s Urology.

Walsh PC, Retik AB, Stamey TA, Vaughan ED (Eds.), Saunders: Philadel­phia 1992:p.2900-19.

14. Henderson DJ, Middleton RG. Coma from hyponatremia following transurethral resection of prostate. Urology 1980;15(3):267-71.

15. Bernstein GT, Loughlin KR, Gittes RF. The physiologic basis of the TUR syndrome. J Surg Res 1989;46(2):135-41.

Asian Journal of Clinical Cardiology, Volume 17, Number 3, January-March 2015

25

Review article 16. Zhang W, Andersson BS, Hahn RG. Effect of irrigating fluids and prostate tissue extracts on isolated cardiomyocytes.

Urology 1995;46(6):821-4.

17. Hahn RG, Essén P. ECG and cardiac enzymes after glycine absorption in transurethral prostatic resection. Acta Anaesthesiol Scand 1994;38(6):550-6.

18. Evans JW, Singer M, Coppinger SW, Macartney N, Walker JM, Milroy EJ. Cardiovascular performance and core temperature during transurethral prostatectomy. J Urol 1994;152(6 Pt 1):2025-9.

19. Ashton CM, Lahart CJ, Wray NP. The incidence of perioperative myocardial infarction with transurethral resection of the prostate. J Am Geriatr Soc 1989;37(7):614-8.

20. Krohn JS. Dilutional hypocalcemia in association with dilutional hyponatremia. Anesthesiology 1993;79(5):1136-8.

21. Roesch RP, Stoelting RK, Lingeman JE, Kahnoski RJ, Backes DJ, Gephardt SA. Ammonia toxicity resulting from glycine absorption during a transurethral resection of the prostate.

Anesthesiology 1983;58(6):577-9.

22. Hahn RG, Stalberg HP, Ekengren J, Rundgren M. Effects of 1.5% glycine solution with and without 1% ethanol on the fluid balance in elderly men. Acta Anaesthesiol Scand 1991;35(8):725-30.

23. Périer C, Mahul P, Molliex S, Auboyer C, Frey J. Progressive changes in glycine and glycine derivatives in plasma and cerebrospinal fluid after transurethral prostatic resection.

Clin Chem 1990;36(12):2152-3.

24. Harrison RH 3rd, Boren JS, Robison JR. Dilutional hyponatremic shock: another concept of the transurethral prostatic resection reaction. J Urol 1956;75(1):95-110.

25. Hahn RG. Fluid and electrolyte dynamics during development of the TURP syndrome. Br J Urol 1990;66(1): 79-84.

26. Hahn RG. Acid phosphatase levels in serum during transurethral prostatectomy. Br J Urol 1989;64(5):500-3.

27. Sohn MH, Vogt C, Heinen G, Erkens M, Nordmeyer N, Jakse G. Fluid absorption and circulating endotoxins during transurethral resection of the prostate. Br J Urol 1993;72(5 Pt 1): 605-10.

28. Ovassapian A, Joshi CW, Brunner EA. Visual disturbances: an unusual symptom of transurethral prostatic resection reaction. Anesthesiology 1982;57(4):332-4.

29. Hahn RG. Irrigating fluids in endoscopic surgery. Br J Urol 1997;79(5):669-80.

30. Hahn RG. Transurethral resection syndrome from extravascular absorption of irrigating fluid. Scand J Urol Nephrol 1993;27(3):387-94.

31. Weber S, Acuff JH, Mazloomdoost M, Kirimli BI. Transurethral prostatectomy complicated by intraperitoneal extravasation of irrigating fluid. Can J Anaesth 1987;34(2):193-5.

32. Hahn RG. Transurethral resection syndrome after transurethral resection of bladder tumours. Can J Anaesth 1995;42(1):69-72.

33. Stjernström H, Henneberg S, Eklund A, Tabow F, Arturson G, Wiklund L. Thermal balance during transurethral resection of the prostate. A comparison of general anaesthesia and epidural analgesia. Acta Anaesthesiol Scand 1985;29(7): 743-9.

34. Ekengren J, Zhang W, Hahn RG. Effects of bladder capacity and height of fluid bag on intravesical pressure during transurethral resection of the prostate. Eur Urol 1995;27(1):26-30.

35. Madsen PO, Frimodt-Møller PC. Transurethral prostatic resection with suprapubic trocar technique. J Urol 1984;132(2):277-9.

36. Ekengren J, Hahn RG. Continuous versus intermittent flow irrigation in transurethral resection of the prostate. Urology 1994;43(3):328-32.

37. Singer M, Patel M, Webb AR, Bullen C. Management of the transurethral prostate resection syndrome: time for reappraisal? Crit Care Med 1990;18(12):1479-80.

38. Hahn RG, Nilsson A, Hjelmqvist H, Zhang W, Rundgren M. Renal function during intravenous infusion of urological irrigating fluids in the sheep. Acta Anaesthesiol Scand 1996;40(6):671-8.

39. Hoffman RM, MacDonald R, Wilt TJ. Laser prostatectomy for benign prostatic obstruction. Cochrane Database Syst Rev 2004;(1):CD001987.

40. O’Donnell AM, Foo IT. Anaesthesia for transurethral resection of the prostate. Contin Educ Anaesth Crit Care Pain 2009;9(3):92-6.

41. Jennifer Heisler, RN, About.Com. Guide May 27, 2010.

Available at: http://surgery.about.com/bio/Jennifer-HeislerRN-41438.htm 42. Rocco B, Albo G, Ferreira RC, Spinelli M, Cozzi G, Dell’orto P, et al. Recent advances in the surgical treatment of benign prostatic hyperplasia. Ther Adv Urol 2011;3(6):263-72.

■■■■

26

Asian Journal of Clinical Cardiology, Volume 17, Number 3, January-March 2015

Clinical Study

Prevalence of Metabolic Syndrome in Patients with Essential Hypertension D Makwana, S Bagga, M Nandal

Abstract The objective of this study was to study the prevalence of metabolic syndrome among patients with essential hypertension and to correlate metabolic parameters. It was a noninterventional, observational study in which 172 patients having essential hypertension who fulfilled the inclusion criteria were included and all were subjected to a uniform questionnaire, medical examination and investigations. Prevalence of metabolic syndrome was 55.23% in patients with essential hypertension in this study, more common in females and most common in age group between 40 and 50 years (39.60%). Low high-density lipoprotein cholesterol (HDL-C) level was the most common metabolic abnormality detected in patients with metabolic syndrome followed by an abnormal fasting blood sugar (FBS), abnormal waist circumference and abnormal triglyceride (TG) level. The females had an abnormal HDL-C levels in 92.06% (z = 16.19, p < 0.05) followed by an abnormal waist circumference in 61.90% (z = 6.85, p < 0.05). The FBS and TG were abnormal in 60.3% (z = 3.34, p < 0.05) and 50.7% (z = 2.57, p < 0.05), of female patients, respectively, while in males, the most common abnormality was low HDL-C in 87.5% (z = 12.54, p < 0.05) followed by abnormal TG levels in 65.62% (z = 3.71, p < 0.05), abnormal FBS 62.5%, (z = 2.92, p < 0.05) and abnormal waist circumference 40.62% (z = 2.14, p < 0.05). TG/HDL-C ratio of ≥3 was the variable that had the best correlation (p = 0.534) with the presence of metabolic syndrome.

Keywords: Metabolic syndrome, essential hypertension, metabolic parameters, high-density lipoprotein, waist circumference, triglycerides

T

he definition of metabolic syndrome refers to a cluster of metabolic abnormalities that are thought to occur due to insulin resistance and are associated with the presence of abdominal obesity. This cluster of metabolic abnormalities is known to increase the risk of coronary heart disease (CHD) and type 2 diabetes. Various abnormalities have been associated with metabolic syndrome. Here is a list of these abnormalities and the various metabolic derangements that are associated with each one of them.

ÂÂ

Abdominal obesity

ÂÂ

Atherogenic dyslipidemia

Increase in triglycerides (TGs)

Decrease in high-density lipoprotein cholesterol (HDL-C)

Increase in low-density lipoprotein (LDL) particle

Postprandial lipidemia

ÂÂ

Hypertension

ÂÂ

Insulin resistance

Dept. of Medicine, BJ Medical College, Ahmedabad, Gujarat Address for correspondence Dr D Makwana Dept. of Medicine BJ Medical College, Ahmedabad, Gujarat

Impaired fasting glucose

Impaired glucose intolerance

ÂÂ

Prothrombotic effect

ÂÂ

Increased fibrinogen proinflammatory effect

ÂÂ

Abnormal uric acid metabolism

ÂÂ

Endothelial dysfunction

ÂÂ

Reproductive

Polycystic ovarian syndrome.

There is an increasing evidence that nonalcoholic steatohepatitis and several forms of cancer are more likely to occur in insulin-resistant individuals.

It is important to note that not all insulin-resistant individuals will develop the entire cluster of abnormalities listed above and the number of manifestations present in an insulin-resistant individual will vary with the cut point used to separate normal from abnormal. Thus, detection of presence of insulin resistance along with other risk factor is more important. Indians living in urban areas of the Indian subcontinent as well as those who have migrated to western countries have a high prevalence of CHD as compared to Caucasians.

Asian Journal of Clinical Cardiology, Volume 17, Number 3, January-March 2015

27

Clinical Study Material and Methods To achieve the above-mentioned aims and objectives, we carried out a noninterventional observational study in 172 patients having essential hypertension attending the medicine outdoor patients department (OPD) of the tertiary care center from May 2010 to April 2011.

The study subjects were examined and their laboratory investigations were carried out in a fasting state.

Inclusion Criteria The study included patients between the age group of 25 and 70 years attending the medicine OPD having essential hypertension, that is, blood pressure (BP) >140/90 mmHg or on antihypertensive treatment.

Exclusion Criteria ÂÂ

Age >70 years

ÂÂ

Age <25 years

ÂÂ

Patient on medications like steroid treatment for any cause, decongestants, appetite suppressants, cyclosporine, tricyclic antidepressants, monoamine oxidase inhibitors, erythropoietin, nonsteroidal antiinflammatory agents and cocaine.

total cholesterol raised was also measured. The various variables of the metabolic syndrome were also correlated.

The information thus obtained was analyzed using percentages; chi-square test and the variables correlated using Spearman’s correlation coefficient.

Observation and Analysis Overall prevalence of metabolic syndrome in our study population was 55.23%, out of which 31.97% patients were females (Table 1). The prevalence was found to be highest in the middle age group of 40-50 years and the prevalence of metabolic syndrome did not increase with age (Table 2). The association of metabolic syndrome

Table 1. Distribution of Metabolic Syndrome Among the Cases Metabolic syndrome Yes Male

Number

%

40

23.26

55

31.97

43

25

Female No Male

Renal failure

Female

34

19.76

ÂÂ

Obstructive sleep apnea

Total

172

100

ÂÂ

Hypothyroidism, hyperthyroidism, hypercalcemia and acromegaly

ÂÂ

Pre-eclampsia/eclampsia

ÂÂ

The metabolic syndrome in these patients was defined by the Adult Treatment Panel III (ATP III) criteria as the presence of any three or more of the following parameters: ÂÂ

Fasting blood glucose of ≥100 mg/dL

ÂÂ

Serum TGs ≥ 150 mg/dL

ÂÂ

Serum HDL-C <40 mg/dL (men) and 50 mg/dL (women)

ÂÂ

BP of ≥130/85 mmHg (or on antihypertensive treatment)

ÂÂ

Waist circumference of >102 cm (men) and 88 cm (women)

Outcomes Measured The final outcome measured was prevalence of metabolic syndrome in patients with essential hypertension, using the above-mentioned criteria, attending the medicine OPD. The predisposing factors like the age and the sex of the patient, lifestyle and the family history and their correlation with the metabolic syndrome were studied.

The percentage of patients having only LDL-C and the

28

Table 2. Prevalence of Metabolic Syndrome Among Various Age Groups Age groups (years)

<30

30-40

40-50

50-60

60-70

>70

Syndrome present

1.10

4.40

39.60

36.30

16.50

2.20

Syndrome absent

4.10

11.00

31.60

28.80

15.10

9.60

Table 3. Association of Waist Circumference (cm) with Metabolic Syndrome Waist circumference (cm) Abnormal Normal Total Chi-square test applied Pearson chi-square

Asian Journal of Clinical Cardiology, Volume 17, Number 3, January-March 2015

Metabolic syndrome Yes Number % 57 60.0 38 40.0 95 55.23 Value df 34.92

1

No Number 12 65 77 p value

% 15.58 84.41 44.77 Significance

<0.000001 Significance

Clinical Study Discussion

Table 4. Association of FBS (mg/dL) with Metabolic Syndrome FBS (mg/dL)

The findings of our study carried out in 172 patients with essential hypertension attending the Medicine OPD of tertiary care center indicate that the prevalence of metabolic syndrome among hypertensive patients is around 55.23%, out of which 31.97% patients were females. Thus, we concluded that the prevalence of metabolic syndrome is higher in patients with essential hypertension as compared to the normotensive patients. Overall, metabolic syndrome in patients with essential hypertension was more prevalent among women than in men. The prevalence of metabolic syndrome in our study did not increase with age and the prevalence was found to be highest in the middle age group of 40-50 years.

Metabolic syndrome Yes

No

Number

%

Number

%

Abnormal

51

53.68

3

3.89

Normal

44

46.32

74

96.10

Total

95

55.23

77

44.77

Chi-square test applied

Value

df

p value

Significance

Pearson chi-square

48.94

1

2.27E-11

Significance

The most common abnormal metabolic parameter detected was HDL-C (91.57%) among subjects with metabolic syndrome. This was also the most common abnormal parameter in males as well as in females. Another parameter TG/HDL-C ratio has been shown to be a good surrogate marker for hyperinsulinemia as is FBS and it also provides an independent risk estimate for coronary artery disease. Our study showed that patient with TG/HDL-C ratio >3.0 have higher chances of associated metabolic syndrome. Patients with the syndrome had an almost double cardiovascular event rate than those without (3.23 vs 1.76/100 patient-years, p < 0.001). The ATP III too underlines this fact and recognizes the primary endpoint of metabolic syndrome as an increased risk of cardiovascular disease (CVD) and emphasizes the need of targeting metabolic syndrome and its individual components in preventing the CVD after targeting LDL-C.

FBS = Fasting blood sugar.

Table 5. Association of TG with Metabolic Syndrome Triglyceride

Metabolic syndrome Yes

No

Number

%

Number

%

Abnormal

54

56.84

9

14.29

Normal

41

43.16

68

62.39

Total

95

55.23

77

44.77

Chi-square test applied

Value

df

p value

Significance

Pearson chi-square

37.35

1

1.04E-09

Significant

Conclusion Table 6. Association of HDL-C with Metabolic Syndrome HDL-C

Metabolic syndrome Yes

No

It has been demonstrated in our study that all patients of essential hypertension should be screened for various parameters of metabolic syndrome, as it was found that this population is at a higher risk of developing metabolic syndrome and its associated complications.

As the prevalence is more in younger age group, screening should start at an early age and further studies should be carried out in Indian population to support the same evidence.

Number

%

Number

%

Abnormal

87

82.07

27

17.93

Normal

8

13.79

50

86.21

Total

95

55.23

77

44.77

Chi-square test applied

Value

df

p value

Significance

Suggested Reading

Pearson chi-square

60.77

1

1.90E-15

Significant

1. McKeigue PM, Miller GJ, Marmot MG. Coronary heart disease in south Asians overseas: a review. J Clin Epidemiol 1989;42(7):597-609.

with waist circumference, fasting blood sugar (FBS), TGs, HDL-C is shown in Tables 3-6 respectively.

2. Chadha SL, Radhakrishnan S, Ramachandran K, Kaul U, Gopinath N. Epidemiological study of coronary heart disease in urban population of Delhi. Indian J Med Res 1990;92:424-30.

Contâ&#x20AC;&#x2122;d on page 35...

Asian Journal of Clinical Cardiology, Volume 17, Number 3, January-March 2015

29

Case Report

A Rare Case of Cor Triloculare Biventriculare Detected in a Postpartum Female Parneet Kaur*, Khushpreet Kaur†, Rama Garg‡, Isha Gupta#

Abstract Maternal heart disease complicates at least 1% of pregnancies and is one of the most important cause of maternal death. This is a case report of postpartum female incidentally diagnosed with cor triloculare biventriculare. Recognizing heart disease during pregnancy is challenging as physiological changes during pregnancy can cause signs and symptoms mimicking cardiac disease, e.g., fatigue, shortness of breath, edema and systolic ejection murmur. Early diagnosis, prompt and effective management is important in decreasing maternal and fetal mortality and morbidity.

Keywords: Cor triloculare biventriculare, pregnancy, congenital heart disease

M

aternal heart disease complicates at least 1% of pregnancies and is one of the most important cause of maternal death.1 In developing countries, rheumatic heart disease remain the major cause, while in developed countries congenital heart diseases (CHD) are more prevalent due to improved survival of children with CHDs. Hemodynamic burden of pregnancy can unmask previously asymptomatic heart disease. Women with pre-existing but yet undiagnosed heart diseases are likely to present primarily to obstetrician and not to cardiologist. The prevalence of heart disease in pregnant women and its potentially lifethreatening consequences justify a careful cardiac history, family history and physical examination in all pregnant women. Recognizing heart disease during pregnancy is challenging as physiological changes during pregnancy can cause signs and symptoms mimicking cardiac disease, e.g., fatigue, shortness of breath, edema and systolic ejection murmur.

Case Report

A 19-year-old G2P1L0 female, married for 3 years with 7-month period of amenorrhea reported in labor

*Associate Professor †Professor ‡Assistant Professor #Junior Resident Dept. of Obstetrics and Gynecology Government Medical College and Rajindra Hospital, Patiala, Punjab Address for correspondence Dr Parneet Kaur House No.: 151, Punjabi Bagh Near Klair Orthopedic Centre, Patiala - 147 001, Punjab E-mail: parneetkd@yahoo.co.in

30

room of Government Medical College and Rajindra Hospital, Patiala on 18/4/2014 (vide CR No. 3325) with complaints of pain abdomen and slight bleeding per vaginum (BPV) for the last 12 hours with no proper antinatal care. Ultrasonography (USG) already done on 1/4/14 showed single live intrauterine fetus with 20-21 weeks of gestation with intrauterine growth restriction (IUGR) and oligohydramnios, amniotic fluid index (AFI) 0.6 cm, placenta posterior showing 13 × 6.0 cm heterogeneous mass suggestive of retroplacental hemorrhage. Patient did not consult any doctor after this USG. Her first pregnancy was home conducted preterm delivery at 7½ months of gestation and baby died after 22 days (1 year back).

On admission, her vitals were: pulse rate 99/min, blood pressure (BP) 100/60 mmHg, respiratory rate 20/min, afebrile, chest was clear on auscultation. On per abdomen, height of uterus was 28 weeks, abdomen was tense and uterine contractions were present. Fetal heart sound could not be localized. On per vaginum examination, cervix was 3 cm dilated, fully effaced.

Her routine investigations were within normal limits.

She delivered a dead male baby (macerated) with birth weight of 500 g after 3 hours of admission.

After about 1 hour of delivery patient had palpitations.

On examination, uterus was well-retracted and BPV was within normal limits. Vitals at that time were pulse rate 130/min irregularly irregular, BP 110/70 mmHg; tachypnea was present. Her O2 saturation was 85%, cyanosis and clubbing were present. But no pallor, icterus, enema or lymphadenopathy (LAP) was present. Jugular venous pressure (JVP) was normal. On auscultation, chest was clear with bilateral air entry equal. On cardiovascular

Asian Journal of Clinical Cardiology, Volume 17, Number 3, January-March 2015

case report examination, apex beat was present in left 5th intercostal space in midclavicular line, parasternal heave present, P2 palpable, S1 loud, ejection systolic murmur was present in pulmonary area. Central nervous system examination was normal. Provisional diagnosis of atrial fibrillation with cyanotic heart disease was made.

Patient was shifted to intensive coronary care unit (ICCU) and put on treatment in form of O2 inhalation, injection furosemide, tablet metoprolol 25 mg along with antibiotics. Her fluids intake was restricted and she was put on cardiac monitoring. Electrocardiography (ECG), chest radiography and echocardiogram was done. Chest X-ray was normal. ECG depicted RSR’ pattern in lead V1 suggestive of right bundle branch block (RBBB).

Echocardiogram revealed congenital cyanotic heart disease with single common atrium (intra-atrial septum deficient), large perimembranous VSD (ventricular septal defect 22 mm), moderate pulmonary arterial hypertension (PAH), moderate mitral regurgitation and moderate tricuspid regurgitation. She was managed conservatively and responded well to the treatment.

Patient was discharged on 7th postpartum day with stable vitals and advised to continue tablet metoprolol 25 mg b.i.d. and regular follow-up in Cardiology Department.

Cunningham in 1948, reported a case of a man with cor triloculare biventriculare, pulmonary dilatation and membranous VSD who lived till 51 years of age.5 Ellis et al, Dubost and Blondaeu described similar patients who were between ages 3 and 31 years.6 Ellis-van Creveld syndrome is a rare combination of cor triloculare biventriculare, chordra and ectodermal dysplasia, polydactyly and most patients die in infancy.7 Baron also reported another case from Spain in 1962.8 Peachey and Robertson reported a case of cor triloculare biventriculare with hypoplasia of the tricuspid valve surviving to the age of 65 years in United Kingdom.9 Sangam et al recently reported a case of a stillborn male fetus of 35 weeks gestation with cor triloculare biventriculare and persistent left superior vena cava in India.10 Akintunde et al reported a similar case of cor triloculare biventriculare and pulmonary stenosis in Nigerian primigravid woman.11 Contraindications of pregnancy in cardiac diseases are: ÂÂ

Severe hypertension of any etiology

ÂÂ

Severe fixed obstructive cardiac lesion

ÂÂ

New York Heart Association (NYHA) Class III and IV heart failure

ÂÂ

Left ventricular ejection fraction <40%

Discussion

ÂÂ

Prior peripartum cardiomyopathy (PPCM)

Cor triloculare biventriculare (single common atrium) is a very rare congenital disorder in adults with very few reports among adults.2 It is similar to a very large septal defect. This defect occurs as a result of lack of septum primum and septum secundum formation.

Clinical presentation includes mild tachypnea, cyanosis and clubbing of fingers and toes. Our patient was incidentally diagnosed because of the thrill discovered on routine physical examination. The patient presented here was essentially asymptomatic until the second stage of labor. Hemodynamic changes of labor had altered the hemodynamic balance with resultant decompensation.

ÂÂ

Dilated unstable aorta of 40-45 mm or above or severe cyanosis.

Major hemodynamic changes occur during late pregnancy, labor, delivery and postpartum period.

In patients with pre-existing cardiovascular disease (CVD), cardiac decompensation often coincides with this peak. Few cases have been reported among the whites, since the early 20th century. The few reported cases of cor triloculare biventriculare include Abott’s in 1936, who reported five cases in her analysis of 1,000 CHD cases in United State.3 Brown et al also reported isolated case series with few surviving beyond middle age.4

Cardiac diseases in pregnancy score (CARPREG) risk score has been shown to predict the adverse cardiac complications during pregnancy (Table 1): ÂÂ

It is composed of four clinical features

ÂÂ

Each risk factor is associated with 1 point

ÂÂ

Maternal cardiac event rate associated with 0, 1, >1 points is 5%, 27% and 75%, respectively.

Maternal mortality in women with this syndrome ranges from 30% to 50% with a 50% risk to fetus if mother survives.

Mortality is frequently caused by thromboembolic events. Fetal risk due to maternal hypoxemia is substantial with a high incidence of fetal loss, premature delivery, IUGR and perinatal death.

Because of considerable risk to fetus and mother, pregnancy is contraindicated. If pregnancy occurs, therapeutic abortion is recommended. Studies show that a low maternal oxygen saturation (<85%) is associated with a very low rate of live born infants (12%).

Women who choose to continue pregnancy are advised to restrict physical activity, use continuous oxygen at

Asian Journal of Clinical Cardiology, Volume 17, Number 3, January-March 2015

31

case report References

Table 1. CARPREG Risk Score Criteria

Examples

Prior cardiac events

Heart failure, TIA, stroke before pregnancy, arrhythmia

1. Weiss BM, von Segesser LK, Alon E, Seifert B, Turina MI. Outcome of cardiovascular surgery and pregnancy: a systematic review of the period 1984-1996. Am J Obstet Gynecol 1998;179(6 Pt 1):1643-53.

Point

NYHA III or IV or cyanosis

1 1

2. Shaher RM, Johnson AM. The haemodynamics of common atrium. Guys Hosp Rep 1963;112:166-70.

3. Abbott ME. Atlas of congenital cardiac diseases. American Heart Association, New York, 1936.

Valvular and outflow tract obstruction

Aortic valve <1.5 cm2, mitral valve <2 cm2

1

Myocardial dysfunction

LVEF <40% or restrictive or obstructive cardiomyopathy

1

4. Brown JW. Congenital Heart Disease. 2nd edition, Staples Press: London, 1950.

5. Dexter L. Atrial septal defect. Br Heart J 1956;18(2): 209-25.

TIA = Transient ischemic attacks; NYHA = New York Heart Association; LVEF = Left ventricular ejection fraction.

6. Ellis FH Jr, Kirklin JW, Swan HJ, Dushane JW, Edwards JE. Diagnosis and surgical treatment of common atrium (cor triloculare-biventriculare). Surgery 1959;45(1):160-72.

least for third trimester and consider use of pulmonary vasodilating drugs such as iloprost and prostacyclin.

Anticoagulation is recommended during the third trimester and for 4 weeks after delivery.

7. Giknis FL. Single atrium and the Ellis-van Creveld syndrome. J Pediatr 1963;62:558-64.

The most vulnerable period for mother is labor, delivery and first week postpartum. Vaginal delivery, facilitated by vacuum or low forceps extraction is the method of choice. Cesarean delivery is associated with substantially higher mortality than the vaginal route.

Anesthetic management includes central venous and arterial pressure monitoring, with maintenance of adequate systemic vascular resistance and intravenous volume and prevention of sudden increasing pulmonary vascular resistance.

9. Peachey RD, Robertson PG. Cor trilocularebiventriculare with hypoplasia of the tricuspid valve: survival to the age of 65 years. Br Heart J 1965;27(5): 786-90.

8. Baron Lis De Vijnovich E. Congenital heart defect; cor triloculare biventriculare. Rev Assoc Med Argent 1962;76:313-6.

10. Sangam MR, Devi SS, Krupadanam K, Anasuya K. Cor triloculare biventriculare with left superior vena cava.

Folia Morphol (Warsz) 2011;70(2):135-8.

11. Akintunde AA, Aremu AA, Akinboro AO, Akinlade MA. Cor triloculare biventriculare and pulmonary stenosis in a Nigerian primigravid woman: a case report. Int J Cardiovasc Res 2013;2:3.

■■■■

32

Asian Journal of Clinical Cardiology, Volume 17, Number 3, January-March 2015

Case Report

A Rare Case of Diencephalic Seizures Secondary to Hemorrhagic Stroke Muhammed Zohaib Ghatala*, Swamikannu Murugan†, Shriraam Mahadevan‡, Booma Soundarajan#

Abstract Diencephalic seizure or sympathetic storm is a rare condition characterized by paroxysmal episodes of acute increase in heart rate, blood pressure, respiratory rate, temperature and diaphoresis with extensor posturing that can occur following brain injury. Here we report a case of a 45-year-old male with hemorrhagic stroke who had symptoms of diencephalic seizure during his hospital stay.

Keywords: Diencephalic seizure, paroxysmal episodes, extensor posturing, brain injury, hemorrhagic stroke

D

iencephalic seizure was first described by Penfield in 1929 in a patient with a cerebral disorder who had paroxysmal episodes of acute increases in blood pressure (BP), heart rate and respiratory rate with lacrimation and extensor posturing. Since then, there have been several reports of similar cases and the suggestion that these seizures were associated with cerebral autonomic dysfunction secondarily because no evidence of seizure activity was detected by electroencephalography (EEG).

We report on a patient with an intracerebral hemorrhage who developed characteristics of diencephalic seizures.

The patient responded well to sodium valproate and adrenergic blockers.

Case Report A 45-year-old male presented with acute onset left hemiplegia, progressive decrease in the level of consciousness and one episode of generalized tonicclonic seizure. His past medical history was significant for hypertension and residual right upper and lower limb weakness from a hemorrhagic stroke at the age of 31 years. He was also an alcoholic but no history suggesting substance abuse. He was on regular antihypertensive medication with long-acting calcium channel blockers. *Senior House Officer †Consultant Physician Dept. of Internal Medicine ‡Consultant Endocrinologist Sundaram Medical Foundation, Shanthi Colony, Anna Nagar, Chennai, Tamil Nadu #Senior Registrar Dept. of General Medicine St. Marthas Hospital, Bengaluru, Karnataka Address for correspondence Dr Muhammed Zohaib Ghatala Address: #67 AJ Block, 3rd Street Anna Nagar, Chennai - 600 040, Tamil Nadu E-mail: zghatala@gmail.com

On examination, the patient had a BP of 150/90 mm Hg, heart rate of 88/min, normal body temperature and as he was not able to maintain airway, he was intubated.

The patient was in postictal with a GCS of 6/15, he had paucity of movements of the left upper and lower limb and his left pupil was 2 mm in diameter but reactive to light.

Given the patient’s history and clinical exam, an urgent computed tomography (CT) scan of the brain was done, which showed hemorrhage in the right lentiform nucleus (2.5 × 5.6 × 3.9 cm) with intraventricular extension, moderate midline shift, contralateral obstructive hydrocephalus, ipsilateral edema.

There was also evidence of left middle cerebral artery (MCA) gliosis and encephalomalacia. The patient was admitted in the intensive care unit and he was managed with labetalol for his BP, loading dose and then maintenance dose of phenytoin for seizure prophylaxis which was later changed to sodium valproate, antiedema measures were taken with hypertonic fluids and nasogastric tube feeding was started.

On Day 3, his sensorium improved, and he was opening eyes to painful stimulus with paucity of movements of limbs.

On Day 4, tracheostomy was done and he was weaned off the ventilatory support.

On Day 11, BP of percentage the patient dropped, because of which labetalol was discontinued. However, later on during his hospital course, his BP was high again and was managed with short-acting metoprolol and amlodipine.

On Day 39, the hypertonic fluid infusion was discontinued.

From Day 51, the patient was reported to have repeated episodes of sudden onset tachypnea (RR-24-42/min), tachycardia (90-146/min), increased BP (180/100-200/130), diaphoresis with extensor posturing.

Asian Journal of Clinical Cardiology, Volume 17, Number 3, January-March 2015

33

case report Table 1. Vital Parameters Recorded on Day 54.

Time

BP

PR

T

RR

12 am

190/100

138

100.2

34

02 am

120/80

60

98.6

20

04 am

110/80

62

98.6

20

06 am

110/70

60

98.6

20

08 am

130/80

76

98.6

22

10 am

120/80

70

98.6

20

12 pm

120/80

61

98.6

22

02 pm

120/80

72

98.4

22

04 pm

130/90

76

98.4

18

06 pm

130/70

86

98.6

22

08 pm

186/110

126

99.4

32

10 pm

130/80

68

99

20

11 pm

160/90

104

99

38

BP = Blood pressure in mmHg; PR = Pulse rate per minute; T = Temperature in degree Fahrenheit; RR = Respiratory rate per minute.

These episodes occurred at an average of 3-4 times/day and lasted for 10-150 minutes. These episodes did not respond to conventional antiepileptic benzodiazepines.

Table 1 shows vitals on a randomly selected day (Day 54), for a better understanding of the episodic of sympathetic surge.

Diagnostic investigations for paroxysmal hypertension, arrhythmias and seizure activity were negative. Twentyfour hour urine for metanephrines was within normal limits. CT scan of the abdomen showed no evidence of an adrenal gland mass. EEG showed diffuse bilateral slow wave dysfunction with mild accentuation to right side. Dexamethasone suppression test ruled out hypercortisolism. Holter recording was unyielding.

His thyroid profile was within normal limits. With this background, the patient was diagnosed with diencephalic seizure secondary to cerebral hemorrhage.

These episodes of diencephalic dysautonomia responded moderately to α1-blocker, but had a significant response when we replaced the short-acting β1-blocker that the patient was already getting with a long acting β1-blocker.

Discussion Diencephalic seizures is a rare condition. It presents with autonomic dysregulation. Symptoms include intermittent hyperthermia, hypertension, tachypnea, tachycardia, diaphoresis and extensor posturing.

34

In the literature, various terms have been used in reference to this condition like paroxysmal sympathetic storms, midbrain dysregulatory syndrome and paroxysmal autonomic instability with dystonia.1 This condition results from traumatic brain injury, intracranial hemorrhage, brain tumors, hydrocephalus and hypoxic brain injury. However, in our extensive literature search we found that traumatic brain injury was by far the most common cause of diencephalic seizure.

It is still unclear what causes the sympathetic storm in these patients. Some of the possible causes include dysfunction of autonomic centers in the diencephalon (thalamus or hypothalamus) or their connection to cortical, subcortical and brainstem loci that control autonomic function and loss of parasympathetic inhibitory response to sympathetic surge produced under stress.2,3 It is primarily a diagnosis of exclusion. With our patient, we checked his thyroid profile, did an EEG, dexamethasone suppression test, 24 hours urine metanephrines and Holter monitoring before concluding that the sympathetic surge was because of diencephalic seizures. In one study of 814 patients with diencephalic seizures, the EEG findings were consistent with paroxysmal slow waves and 6 or 14 c/sec positive spikes.4 This condition can be managed with bromocriptine, clonidine, dantrolene, lorazepam, morphine sulfate, and nonselective β-blockers such as propranolol.5 Usually a combination of these drugs is used. Authors of various published studies in the past have stated that selective β1-blockers are not as effective as nonselective β-blockers or combined α1 and β-blockers but, interestingly, our patient responded well to a longacting selective β1-blocker (metoprolol) in combination with sodium valproate.

Conclusion Diencephalic seizures is a relatively rare condition characterized by sympathetic surge. As many physicians rarely see this condition during their medical practice, this is an often misdiagnosed condition. It is very important to recognize the symptoms and start the appropriate treatment. We suggest that these patients be treated with long-acting β-blockers in combination with an antiepileptic medication. In our case, the patient responded well to long-acting metoprolol and sodium valproate.

Asian Journal of Clinical Cardiology, Volume 17, Number 3, January-March 2015

case report References 1. Blackman JA, Patrick PD, Buck ML, Rust RS Jr. Paroxysmal autonomic instability with dystonia after brain injury. Arch Neurol 2004;61(3):321-8.

2. Ramdhani NA, Sikma MA, Witkamp TD, Slooter AJ, de Lange DW. Paroxysmal autonomic instability with dystonia in a patient with tuberculous meningitis: a case report. J Med Case Rep 2010;4:304.

3. Lemke DM. Riding out the storm: sympathetic storming after traumatic brain injury. J Neurosci Nurs 2004;36(1):4-9.

4. Shimoda Y. The clinical and electroencephalographic study of the primary diencephalic epilepsy or epilepsy of brain stem. Acta Neuroveg (Wien) 1961;23:181-91.

5. Levy ER, McVeigh U, Ramsay AM. Paroxysmal sympathetic hyperactivity (sympathetic storm) in a patient with permanent vegetative state. J Palliat Med 2011;14(12): 1355-7.

■■■■

...Cont’d from page 29 3. Balarajan R. Ethnic differences in mortality from ischaemic heart disease and cerebrovascular disease in England and Wales. BMJ 1991;302(6776):560-4.

4. Beckles GL, Miller GJ, Kirkwood BR, Alexis SD, Carson DC, Byam NT. High total and cardiovascular disease mortality in adults of Indian descent in Trinidad, unexplained by major coronary risk factors. Lancet 1986;1(8493):1298-301.

5. McKeigue PM, Shah B, Marmot MG. Relation of central obesity and insulin resistance with high diabetes prevalence and cardiovascular risk in South Asians. Lancet 1991;337(8738):382-6.

6. Ramachandran A, Jali MV, Mohan V, Snehalatha C, Viswanathan M. High prevalence of diabetes in an urban population in south India. BMJ 1988;297(6648):587-90.

7. Ramachandran A, Snehalatha C, Dharmaraj D, Viswanathan M. Prevalence of glucose intolerance in Asian Indians.

Urban-rural difference and significance of upper body adiposity. Diabetes Care 1992;15(10):1348-55.

8. McKeigue PM, Pierpoint T, Ferrie JE, Marmot MG. Relationship of glucose intolerance and hyperinsulinaemia to body fat pattern in south Asians and Europeans.

Diabetologia 1992;35(8):785-91.

9. Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 1988;37(12):1595-607.

10. Meigs JB. Epidemiology of the metabolic syndrome, 2002.

Am J Manag Care 2002;8(11 Suppl):S283-92; quiz S293-6.

11. Chan JM, Rimm EB, Colditz GA, Stampfer MJ, Willett WC. Obesity, fat distribution, and weight gain as risk factors for clinical diabetes in men. Diabetes Care 1994;17(9):961-9.

■■■■

Asian Journal of Clinical Cardiology, Volume 17, Number 3, January-March 2015

35

ArounD the Globe

News and Views ÂÂ

Results from the AUGMENT HF trial, presented at the American Heart Association (AHA) 2014 Scientific Sessions, have stated that an injection of the novel hydrogel Algisyl-LVR hydrogel into the left ventricular myocardium of patients with advanced heart failure was safe and improved functional and clinical endpoints over 6 months.

ÂÂ

Emerging research is shedding new light on the possible involvement of cardiac factors in sudden unexpected death in epilepsy (SUDEP). Increasing evidence suggests that cardiac arrhythmia precedes SUDEP. The findings were presented at the American Epilepsy Society (AES) 68th Annual Meeting.

ÂÂ

New research has pointed that differences in gene expression suggest that defective maturation of the endometrium during the secretory phase and early pregnancy precedes the development of pre-eclampsia. The findings are published online in Hypertension.

ÂÂ

Three new studies have reported that a chemical called nitrate, found in green vegetables including spinach, lettuce and celery, may aid heart health and reduce the risk of obesity and diabetes. The studies are published in The FASEB Journal, The Journal of Physiology and Diabetes.

ÂÂ

Screening asymptomatic persons with diabetes using coronary computed tomographic angiography (CTA) may improve their cardiovascular risk profile by guiding them toward more aggressive therapy, but this may have little effect on mortality or nonfatal CV events over 4 years, reports a randomized trial presented at the American Heart Association (AHA) 2014 Scientific Sessions.

ÂÂ

Chronic kidney disease (CKD) increases the risk of stroke and systemic thromboembolism in patients with atrial fibrillation (AF) independently of other stroke risk factors, especially in those needing renal replacement therapy (RRT), suggests an observational cohort study published in the December 16 issue of the Journal of the American College of Cardiology.

ÂÂ

Statin therapy significantly increases the risk of developing cataracts severe enough to warrant surgery, suggest analyses of two distinct cohorts.

The report is published in the December issue of the Canadian Journal of Cardiology.

ÂÂ

The time to transfer a patient with ST-segmentelevation MI (STEMI) from a community hospital to a hospital with around-the-clock PCI seems to be a major obstruction to providing optimal care for MI patients, reports a new analysis conducted in the US, published online December 8 in JAMA Internal Medicine.

ÂÂ

A new review article suggests that sugar, not salt, appears to contribute to the majority of the hypertension risk associated with processed food.

The review is published in Open Heart.

ÂÂ

A new analysis based on a randomized trial suggests that all healthy middle-aged and older women should not take low-dose aspirin for primary prevention of CVD or colorectal cancer, since the risk of major gastrointestinal (GI) bleeding outweighs the prevention benefits. The study is published online in Heart.

ÂÂ

Routine measures of obesity are significantly associated with an increased risk of sudden cardiac death (SCD) among middle-aged citizens who do not smoke, findings from the atherosclerosis risk in communities (ARIC) study indicate. However, only the waist-to-hip ratio, an index of reflecting both subcutaneous and intra-abdominal fat, was directly associated with SCD, while measures of body-mass index (BMI) and waist circumference were indirectly associated with SCD, apparently via effects on traditional CVD risk factors. The study was published online November 19, 2014 in Heart.

ÂÂ

In compliant patients with true-resistant hypertension, renal denervation does not appear to reduce blood pressure more than intensified drug treatment and it is not ready to be used routinely yet, suggests new research from the Czech Republic published online in Hypertension.

■■■■

36

Asian Journal of Clinical Cardiology, Volume 17, Number 3, January-March 2015

Asian

Journal of

CLINICAL CARDIOLOGY

Information for Authors

Manuscripts should be prepared in accordance with the ‘Uniform requirements for manuscripts submitted to biomedical journals’ compiled by the International Committee of Medical Journal Editors (Ann. Intern. Med. 1992;96: 766-767).

Asian Journal of Clinical Cardiology strongly disapproves of the submission of the same articles simultaneously to different journals for consideration as well as duplicate publication and will decline to accept fresh manuscripts submitted by authors who have done so.

The boxed checklist will help authors in preparing their manuscript according to our requirements. Improperly prepared manuscripts may be returned to the author without review.

The checklist should accompany each manuscript.

Authors may provide on the checklist, the names and addresses of experts from Asia and from other parts of the World who, in the authors’ opinion, are best qualified to review the paper.

Covering letter -

- -

The covering letter should explain if there is any deviation from the standard IMRAD format (Introduction, Methods, Results and Discussion) and should outline the importance of the paper.

Principal/Senior author must sign the covering letter indicating full responsibility for the paper submitted, preferably with signatures of all the authors.

Articles must be accompanied by a declaration by all authors stating that the article has not been published in any other Journal/Book. Authors should mentioned complete designation and departments, etc. on the manuscript.

Manuscript - Three complete sets of the manuscript should be submitted and preferably with a CD; typed double spaced throughout (including references, tables and legends to figures).

- The manuscript should be arranged as follow: Covering letter, Checklist, Title page, Abstract, Keywords (for indexing, if required), Introduction, Methods, Results, Discussion, References, Tables, Legends to Figures and Figures.

- All pages should be numbered consecutively beginning with the title page.

Note: Please keep a copy of your manuscript as we are not responsible for its loss in the mail. Manuscripts will not be returned to authors.

Title page Should contain the title, short title, names of all the authors (without degrees or diplomas), names and full location of the departments and institutions where the work was performed, name of the corresponding authors, acknowledgment of financial support and abbreviations used.

-

The title should be of no more than 80 characters and should represent the major theme of the manuscript.

A subtitle can be added if necessary.

-

A short title of not more than 50 characters (including inter-word spaces) for use as a running head should be included.

-

The name, telephone and fax numbers, e-mail and postal addresses of the author to whom communications are to be sent should be typed in the lower right corner of the title page.

- A list of abbreviations used in the paper should be included. In general, the use of abbreviations is discouraged unless they are essential for improving the readability of the text.

Summary - The summary of not more than 200 words. It must convey the essential features of the paper.

- It should not contain abbreviations, footnotes or references.

Introduction - The introduction should state why the study was carried out and what were its specific aims/objectives.

Methods - These should be described in sufficient detail to permit evaluation and duplication of the work by others.

- Ethical guidelines followed by the investigations should be described.

Statistics The following information should be given: - The statistical universe i.e., the population from which the sample for the study is selected.

-

Method of selecting the sample (cases, subjects, etc. from the statistical universe).

-

Method of allocating the subjects into different groups.

-

Statistical methods used for presentation and analysis of data i.e., in terms of mean and standard deviation values or percentages and statistical tests such as Student’s ‘t’ test, Chi-square test and analysis of variance or non-parametric tests and multivariate techniques.

-

Confidence intervals for the measurements should be provided wherever appropriate.

Results -

These should be concise and include only the tables and figures necessary to enhance the understanding of the text.

Asian Journal of Clinical Cardiology, Volume 17, Number 3, January-March 2015

37

Discussion -

This should consist of a review of the literature and relate the major findings of the article to other publications on the subject. The particular relevance of the results to healthcare in India should be stressed, e.g. practicality and cost.

References These should conform to the Vancouver style. References should be numbered in the order in which they appear in the texts and these numbers should be inserted above the lines on each occasion the author is cited (Sinha12 confirmed other reports13,14...). References cited only in tables or in legends to figures should be numbered in the text of the particular table or illustration. Include among the references papers accepted but not yet published; designate the journal and add ‘in press’ (in parentheses). Information from manuscripts submitted but not yet accepted should be cited in the text as ‘unpublished observations’ (in parentheses). At the end of the article the full list of references should include the names of all authors if there are fewer than seven or if there are more, the first six followed by et al., the full title of the journal article or book chapters; the title of journals abbreviated according to the style of the Index Medicus and the first and final page numbers of the article or chapter. The authors should check that the references are accurate. If they are not this may result in the rejection of an otherwise adequate contribution.

Examples of common forms of references are:

Figures - Two complete sets of glossy prints of high quality should be submitted. The labelling must be clear and neat.

- All photomicrographs should indicate the magnification of the print.

- Special features should be indicated by arrows or letters which contrast with the background.

- The back of each illustration should bear the first author’s last name, figure number and an arrow indicating the top. This should be written lightly in pencil only. Please do not use a hard pencil, ball point or felt pen.

- Color illustrations will be accepted if they make a contribution to the understanding of the article.

-

Do not use clips/staples on photographs and artwork.

-

Illustrations must be drawn neatly by an artist and photographs must be sent on glossy paper. No captions should be written directly on the photographs or illustration. Legends to all photographs and illustrations should be typed on a separate sheet of paper. All illustrations and figures must be referred to in the text and abbreviated as ‘Fig.’.

Articles Paintal AS. Impulses in vagal afferent fibres from specific pulmonary deflation receptors. The response of those receptors to phenylguanide, potato S-hydroxytryptamine and their role in respiratory and cardiovascular reflexes.

Q. J. Expt. Physiol. 1955;40:89-111.

Books Stansfield AG. Lymph Node Biopsy Interpretation Churchill Livingstone, New York 1985.

Articles in Books Strong MS. Recurrent respiratory papillomatosis. In: Scott Brown’s Otolaryngology. Paediatric Otolaryngology Evans JNG (Ed.), Butterworths, London 1987;6:466-470.

Tables -

These should be typed double spaced on separate sheets with the table number (in Roman Arabic numerals) and title above the table and explanatory notes below the table.

Legends - These should be typed double spaces on a separate sheet and figure numbers (in Arabic numerals) corresponding with the order in which the figures are presented in the text.

-

38

The legend must include enough information to permit interpretation of the figure without reference to the text.

Asian Journal of Clinical Cardiology, Volume 17, Number 3, January-March 2015

Please complete the following checklist and attach to the manuscript: 1. Classification (e.g. original article, review, selected summary, etc.)_______________________________ 2. Total number of pages ________________________ 3. Number of tables ____________________________ 4. Number of figures ___________________________ 5. Special requests _____________________________ 6. Suggestions for reviewers (name and postal address) Indian 1.____________Foreign 1.________________

2.____________ 2.________________

3.____________ 3.________________

4.____________ 4.________________

7. All authors’ signatures________________________ 8.

Corresponding author’s name, current postal and e-mail address and telephone and fax numbers __________________________________________

Online Submission Also e-issue @ www.ijcpgroup.com For Editorial Correspondence

Dr KK Aggarwal

Group Editor-in-Chief Asian Journal of Clinical Cardiology E - 219, Greater Kailash, Part - 1, New Delhi - 110 048. Phone: 011-40587513 E-mail: editorial@ijcp.com, Website: www.ijcpgroup.com

R.N.I. No. 71217/98 Date of Publishing 25 of Same Month Date of Posting 25-26 Same Month

REGISTRATION NO. DL (S)-01/3288/2013-2015 POSTED IN NDPSO NEW DELHI