Cardiology Newsletter Volume 6 No 1February 2015

Sponsored in the interests of continuing medical education by:

CPD Accredited

• The enigma of heart rate in heart failure• Matters of the heart at end of life, Organ and Tissue donation in

South Africa• Choosing a heart safe eating pattern• Congress Reportback: European Society of Cardiology

Page 3 Volume 6 No 1 February 2015

Editorial

This newsletter is proudly sponsored by

If you have any suggestions or topics you would like to see published or have articles and/or

case studies for publishing, please email us at: lakeann@mweb.co.za.

Dr Mike BennettCardiologist

Wilgers Hospital, Pretoria

Production Editors: Ann Lake, Helen Gonçalves Design: Jane Gouveia

Enquiries: Ann Lake Publications 011 802 8847 Email: lakeann@mweb.co.za

Website: www.annlakepublications.co.za

Editorial board Dr M. Bennett (Editor)CardiologistWilgers Hospital, Pretoriabennett@uitweb.co.za

Dr D. BlomConsultant PhysicianLipid Clinic, Groote Schuur HospitalHealth Sciences FacultyUniversity of Cape TownCape Town

Dr A.J. DalbyCardiologistMyocardial Ischaemia and InfarctionMilpark Hospital, Johannesburg

Dr J. HarrisbergPaediatric CardiologistSunninghill HospitalJohannesburg

Prof B. JacobsonHaematologistThrombosis and Haemostasis University of WitwatersrandJohannesburg

Dr R. JardineCardiologistArrhythmiasGlynwood HospitalBenoni

Prof J.A. KerCardiologistDepartment of Internal Medicine,University of PretoriaPretoria

Prof. K. Sliwa-HanhleCardiovascular ResearchHatter Cardiovascular Research Institute and Institute of Infectious Disease and Molecular Medicine, University of Cape TownHeart Failure/Translational Research

Dr A. ThorntonCardiologistElectrophysiologySunninghill Hospital, Johannesburg

The views expressed by the authors in this newsletter do not necessarily reflect those of

the sponsor and editorial board.

he New Year lies ahead with all of its own challenges. I recently read an excellent review by Mayosi and Benatar reflecting on the major health

challenges facing South Africa.i It is a pity that it was published in an international journal which will not be read by the majority of the local South African medical community.

Too much expectation for narrowing disparities in the new South Africa was embedded in the reversal of legislated racial discrimination, and possibly too little emphasis on the social determinants of health. Extreme poverty which affects a large proportion of the South African population (10 million people live on less than $1 per day) leads to lack of access to basic requirements - clean water, adequate nutrition, effective sanitation, good education and access to vaccinations. These conditions are associated with diseases of poverty which include HIV/AIDS, Tuberculosis, interpersonal violence and diarrhoeal diseases, to mention only a few.

The number of medical students enrolled annually increased by 34% between 2000 and 2012, but the number of doctors graduating increased by only 18% (almost a 50% dropout rate). Despite this, the ratio of physicians/1000 population remained essentially unchanged from 2004 (0.07) and 2011 (0.76) compared to countries like Brazil (1.76 in 2008); China (1.46 in 2010) and India (0.65 in 2009). Furthermore, we have lost (and are still losing) a large proportion of doctors emigrating to Western countries.

On a more positive note, the total number of nurses in all categories on the Nursing Register has increased by 40% between 2003 and 2012 and the growth rate has exceeded the population growth. All of us

are still aware that there is still a shortage of qualified nurses in certain categories.One of the biggest positive developments that contributed to better medical care, was the implementation of obligatory continuing medical education. Many of older doctors will remember the lack of keeping up with modern developments in the “old days”. In many instances practitioners were largely dependant, and quite happy, with the information provided by the “rep” of the day. Today doctors can pick and choose which topics they want to know more about and there is an abundance of reliable sources to obtain it from. We, at Heart Matters, are proud to be one of those sources. We strive to cover topical issues that will hopefully improve your decision-making pertaining to cardiovascular medicine.

This issue has a number of informative articles written by cardiologists who are clinically orientated and cover issues that each of you regularly encounter. I am sure that the articles will be of help to many of you.

Organ donation remains a ray of hope to many desperate patients with end-stage disease. Too many organs are not harvested. I know that many clinicians find it difficult or embarrassing to raise this topic under these emotional circumstances, but we should do better than that. The lives of many people can be dramatically changed by your contribution in getting an organ.

Enjoy the reading and let me know if there are topics that you would like to be discussed. I appreciate the feedback. Remember to complete the CPD questionnaire on the website.

i. Mayosi BM and Benatar SR. Health and Health Care in South Africa – 20 Years after Mandela. N Engl J Med 2014;371:1344-51.

Volume 6 No 1 February 2015 Page 4

Professor James KerCardiologist

Department of Internal Medicine, University of Pretoria, Pretoria

The enigma of Heart Rate in Heart Failure

he number of heart beats in a lifetime is believed to be relatively constant across many animal species, including man, with an

inverse semi-logarithmic relationship between heart rate and life expectancy.1 In various cardiovascular diseases, it was shown over the last 2 decades or more that a high resting heart rate is a marker of an adverse outcome. It seems that among the different clinical conditions, the threshold of heart rate from which the risk of adverse events is increased, is different.

There is evidence that increased heart rate increases the risk of mortality in the general population. There are a number of large prospective cohort studies that have shown this increased mortality risk. Some of these studies from all over the world include: Chicago People Gas Company Study (USA), Paris Prospective Study (France), the CASTELL study (Italy), and the CORDIS study (Israel).2 There has been estimated that an increase in heart rate of 10 beats per minute increases the risk of cardiac disease by 20% (the same increase in risk as a 10 mmHg blood pressure increase).

In heart failure the association of an elevated heart rate and cardiovascular risk is closer and the pathophysiology of this risk is plausible: in heart failure the force-frequency relationship is reversed, shortening of diastole (in tachycardia) reduces oxygen supply to the myocardium, high heart rate is associated with atherosclerosis and all of this reduces energy supply to the failing myocardium which is already in a state of energy starvation. In addition, high heart rate is a sign of the neuro-hormonal activation in heart failure, a state which is associated with the increased mortality in heart failure.

Kjekshus and co-authors analysed the relation of treatment of heart rate and outcome in heart failure and found a relationship between reduction of heart rate and mortality and they also

observed that drugs that increased heart rate tended to increase mortality.3

Guideline suggestionThe European Society of Cardiology states that heart rate should be controlled to less than 70 beats per minute in patients with heart failure with reduced systolic ejection fractions.4

Role of Beta-BlockersIn the CIBIS trial (Cardiac Insufficiency Bisoprolol Study), reduction of heart rate of 15 beats per minute was achieved by the beta-blocker and in multivariate analysis this reduction in heart rate was the most powerful predictor of survival.5 Over the past decade there appeared several clinical trials that confirmed the mortality and morbidity benefits of beta-blockers in the treatment of heart failure. A reduction of heart rate by beta-blockers in heart failure is not the only mechanism by which beta-blockers reduce mortality in heart failure. A meta-analysis aimed to determine whether this benefit of beta-blockers was related to the magnitude of heart rate reduction or to the maximum dose of beta-blockers achieved in the treatment.6 This is seen as an important question as the side-effects of beta-blockers are dose-related. There were 23 trials of beta-blockers in heart failure with reduced systolic ejection fraction in 19209 patients.

The summary Relative Risk Reduction of mortality for all 23 trials was 24% (95% CI: 16-32%) with a moderate heterogeneity of I² 30%. The results were shown for Bisoprolol, Carvedilol and Metropolol but were inconclusive for Atenolol and Nebivolol. In trials with heart rate reduction of 15 beats per minute the risk reduction of mortality was 36% (95%CI: 14-52%) and in those with a heart rate reduction of 8 beats per minute the risk reduction was 9% (95% CI: 1-27%).

Meta-regression confirmed that treatment-related heart rate reduction was statistically associated with the magnitude of the beta-blocker survival benefit. For every 5 beats per minute reduction in heart rate with beta-blocker treatment the relative risk reduction is 18% (95%CI: 6-29%).

What is also important from this meta-analysis is that the dose of beta-blockers was not important in reduction in mortality but only the magnitude of the reduction of heart rate.

Role of IvabradineIvabradine works on the sinus node to reduce the heart rate without any other known cardiovascular effect. Two large randomized clinical trials evaluated the effect of Ivabradine on cardiovascular outcomes, the BEAUTIFUL trial (morbidity–mortality evaluation of Ivabradine in patients with coronary disease and left-ventricular dysfunction) and the SHIFT trial (systolic heart failure treatment with Ivabradine). The results of BEAUTIFUL suggested that Ivabradine reduced the incidence of coronary outcomes provided that the baseline heart rate was above 70 beats per minute.7 In SHIFT the patients had heart failure with reduced ejection fraction and heart rate above 70 beats per minute.8 Ivabradine reduced the incidence of heart failure outcomes significantly.

All the patients in these two trials had reduced ejection fractions (impaired

In various cardiovascular diseases, it was shown

over the last 2 decades or more that a high resting

heart rate is a marker of an adverse outcome.

It seems that among the different clinical

conditions, the threshold of heart rate from which

the risk of adverse events is increased, is different.

Page 5 Volume 6 No 1 February 2015

left ventricular function) and therefore a pooled analysis was published of the two trials and individual patient data used to evaluate the effect of Ivabradine on outcomes in a broad population of patients with left ventricular dysfunction and a baseline heart rate of above 70 beats per minute.9 This population consisted of 11897 patients with a mean age of 62 years and baseline heart rate of 79.6 (± 9.2) beats per minute.

The primary endpoint of cardiovascular mortality and hospitalization for heart failure was reduced by 13% (95%CI: 6-20%) p<0.001. This meant that treating patients with left-ventricular dysfunction for 21 months with Ivabradine 6.5 mg twice daily resulted in 207 deaths per 1000 treated as compared to 232 deaths per 1000 treated with a placebo. In other words Ivabradine saved 25 of the 232 patients out of 1000 that would have died by not taking Ivabradine. Cardiovascular mortality, hospitalisation for heart failure or for myocardial infarction was reduced by 15% (95%CI: 9-21%). Cardiovascular death or non-fatal myocardial infarction was reduced by 10% (95% CI: 2-19%). Total mortality was not reduced significantly. In a group of these pooled patients with heart rates above 75 beats per minute the results were even more impressive and the effect greater and here the total mortality was also reduced by the use of Ivabradine: mortality reduced by 11% (95%CI: 0-10%).

The pooled analysis showed that Ivabradine reduces the risk for major outcomes in a broad group of patients with impaired left ventricular dysfunction. When heart rate remains elevated in these patients despite guideline treatment, the addition of Ivabradine seems to be an alternative in the management.

The effect of Ivabradine in patients with heart rate of above 75 beats per minute was evaluated in the SHIFT trial.10 There were 4150 patients with heart rate

above 75 beats per minute and 2351 with heart rates below 75. The primary endpoint was cardiovascular mortality and hospitalization for worsening heart failure. In the group with heart rate above 75 beats per minute, Ivabradine reduced the endpoint by 24% (95%CI: 15-32%), p<0.0001. All-cause mortality was reduced by 17% (95%CI: 4-28%) and cardiovascular mortality by 17% (3-29%).The risk of hospitalization for heart failure was reduced by 30% (95%CI: 20-39%).The results demonstrated the importance of identifying high-risk patients with heart failure who have high heart rates (above 75 per minute) and may benefit by heart rate lowering drugs such as Ivabradine.

Role of Digitalis and other DrugsIt was presumed that digoxin can also reduce heart failure hospitalizations in a secondary analysis of the Digitalis Investigation Group although heart rate was not directly captured.11 This is an interesting suggestion, but unfortunately no real data are available.

Other rate lowering drugs such as non-dehidropridine calcium channel blockers (e.g. verapamil) cannot be used in heart failure due to their negatively reducing cardiac contraction.

ConclusionHeart rate lowering has emerged as a possible target for treatment in heart failure. A heart rate above 70 beats per minute despite treatment with beta-blockers has been accepted as an indication for additional treatment and Ivabradine has been shown to reduce cardiovascular events in such patients and should be considered as part of the management plan for heart failure. References1. Levine HJ et.al. Rest heart rate and

life expectancy. J Am Coll Cardiol 1997; 30: 1104-1106.

2. Perret-Guillaume C et al. Heart rate as a risk factor for cardiovascular

disease. Progress in Cardiovascular Diseases 2009; 52: 6-10.

3. Kjekshus et.al. Heart rate as a therapeutic target in heart failure. European Heart J 1999; Suppl 1: H64-H69

4. McMurray JJ et.al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012. Europ J Heart Failure 2012; 14: 803-869.

5. Lechat P et.al. Prognostic value of Bisoprolol-induced hemodynamic effects in heart failure during the CIBIS trial. Circulation 1997; 96: 2197-21205.

6. McAlister FA et.al. Meta-analysis: Beta-Blocker dose, heart rate reduction and death in patients with heart failure. Ann Intern Med 2009; 150: 784-794.

7. Fox K et.al. Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomized double-blind placebo-controlled trial. Lancet 2008; 372: 807-816.

8. Swedberg K et.al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomized placebo-controlled trial. Lancet 2010; 376: 875-885.

9. Fox K et.al. Effect of Ivabradine in patients with left-ventricular systolic dysfunction: a pooled analysis of individual patient data from the BEATIFUL and SHIFT trials. Europ Heart Journal 2013;doi;10: 1093

10. Bὂhm M et.al. Heart rate at baseline influences the effect of Ivabradine on cardiovascular outcomes in chronic heart failure: analysis from the SHIFT study. Clin Res Cardiol 2013; 102:11-22.

11. The Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 1997;336:525-533.

Volume 6 No 1 February 2015 Page 6

Matters of the heart at end of life, organ and tissue donation in South Africa

ugust in South Africa is organ donor awareness month and as health professionals many of us are unaware of the national

critical need for organs and tissue. An organ donor is a member of the community who in life or death chooses to share a gift with others as an altruistic act of care to the community. We know well that the circle of life ends in death and that many lives are lost as organs for the many who suffer from end stage organ failure are simply not available.

For end stage cardiac disease like many other end stage failures there are very few options of care. Heart transplantation was pioneered in South Africa in 1967 when Professor Christiaan Barnard performed the first heart transplant in the world. This pioneering transplant took place in Cape Town. South Africa is not just rich in natural resources and beautiful landscapes but we are very privileged to have amongst the best in the world as far as health professionals who dedicate their lives to making a major contribution to enriching and enhancing the lives of those in desperate need of life saving and life enhancing transplants.

South Africa has also pioneered transplants for the HIV positive community who develop end stage kidney failure by offering not only hope but longevity of life with the HIV to HIV kidney transplant programme in Cape Town.

In 2013, only 25 patients across South Africa received a lifesaving heart transplant and the total of all transplants, which includes heart, lungs, liver, kidneys, pancreas alone as well as combined kidney and pancreas numbered only 304. Tissue transplants of corneas nationally was 231 in total (National transplant stats ODF 2013). The total number of organ donors in a per million population is estimated at approximately 1.2 donors per million population yet according to the recently

released renal registry South Africa has 154 per million requiring dialysis. At any time there are at least 50 patients with end stage heart disease of which 5 are on a priority list as life expectancy is limited.

The need for organs far outweighs the availability and loss of life occurs. Limited resources within the state sector limit the care offered to many patients as there are simply not sufficient facilities that can care for these patients and dialysis slots are simply only available if a transplant occurs or should a patient die.

There are transplant coordinators in the main cities of South Africa and should there be no resident coordinator then one will be sent to the region and hospital to assist with all aspects of organ donor care and family support.

Few organ donors are identified and this is not that deaths do not occur but rather that medical professionals often do not think further than the life which is ebbing away while that patient is in their care. Some professionals view organ donation as something best left for others to deal with and end of life care is not planned nor openly discussed with families. Advanced directives are often the “let’s not escalate treatment and just allow nature to take its course.”

Society may also not be keen participants in the sharing of life as an end of life decision. It is often cited that cultural, religious and all sorts of other reasons are given that consent is not achieved.

It is with wonder that I have been told on numerous occasions that there is nothing for “Mahala” in Africa and should I be prepared to gift a sum of money then donation can occur. It is also with regret that I am asked at least 4 times a month so “where is my kidney?” My usual response is: “your diseased, non-functioning organs are still where God placed them and your new organ has yet to be graciously donated to you”.

Organ donation and transplantation is governed by chapter 8 of the National Health Act, Act number 61 of 2003.

Who are suitable donors?Any person who has been declared brain dead may be a medical cause of death. Cerebral bleed after a cerebral vascular accident or stroke, hypoxic brain injuries, encapsulated brain tumours are possible causes.

Traumatic cause of brain death include traumatic head injuries as a result of trauma car accidents, assaults or other non-natural causes, for example stabbed head or neck.

There are currently no lower or upper age limits as each case referred as a potential organ donor is evaluated and organs accepted or rejected on their function rather than age.

HIV as previously mentioned is not a contraindication to donation as these donors, but these organs are only allocated to the HIV positive recipients in the Cape based HIV to HIV kidney programme.

Who performs the brain death tests?Two doctors are required to test and they should test independently but there are no specific qualifications requirements. For example two physicians can test and it is not stipulated that any of the persons who perform the brain death tests need to be a neurosurgeon or a neurologist.

The Harvard Criteria is the standard test for brain death testing and documentations and pre testing parameters are available from every transplant coordinator.

No sedation should have been administered for at least 4 hours. If an infusion had been utilized then there needs to be 24 hour period of no sedation prior to testing. No muscle relaxants should have been administered within 4 hours of testing.

Kim CrymbleTransplant Co-ordinator

Wits Donald Gordon Medical Centre Transplant Clinic, Johannesburg

Page 7 Volume 6 No 1 February 2015

It is a privilege not a right to receive a lifesaving transplant in South Africa. We all need to be mindful that without a donor no transplant would ever happen. Donors are either living donors such as a father who donates a kidney to his son, a mother who donates a portion of her liver to her child or the community identified brain stem dead donor who donates organs and or tissue to assist many as a final gesture of goodwill.

Ethics, compassionate care and a dignified end of life is nonnegotiable we need always to be “nice”.

Make organ donation a priority and discuss organ donation with all who will listen as the more we talk about donation the more our community will listen and take action. Live life but when it’s over, give life, reduce, reuse and recycle this circle of life.

The contact details for Wits Donald Gordon Medical Centre Transplant Clinic are: Tel - 0113569488 or email - kcrymble@dgmc.co.za

Become an organ donor and save 7 lives www.odf.org.za

The relevant transplant teams can be contacted on the following numbers in their home region:

The patient should have a core temperature above 35.5oC, a normal blood glucose level, not be hyponatraemic and have a normal PH on arterial blood gas.

Haemodynamics: Blood Pressure must be normal but a mean of at least a 100, a pulse rate below 120 and above 50 bpm and Sats of 99% plus.

Alternative methods of testing such as EEG’s evoked potentials and cerebral angiograms showing perfusion or non-perfusion can also be used to confirm brain death but they have to be supported with Harvard Criteria testing.

Who should approach the family at end of lifeIt is usually advisable that the attending doctor be the person who has the frank discussion with families about end of life and the current health care status, but many doctors are not comfortable to do this so then the coordinator will on invitation chat to the family and offer end of life care and support and at an appropriate time introduce organ donation as an end of life commitment to society. Nursing staff often plant a “seed” of organ donation with family and then call a coordinator to manage the case till theatre.

Trauma counsellors (psychologists, social workers, ministers of religion) also play an important role in the organ donor approach.

If consent is obtained and declaration of death has been performed then a call is placed to the relevant teams, commencing with what’s on the urgent list and then proceeding. If the organs are declined for the urgent recipients, kidneys generally remain in the home region but other organs may travel to the most urgent recipient or to a region who accepts them for their patients who wait.

The general rule is once offered then there is an acceptance period of 30 minutes. Should the organ not be formally accepted, then we move on to the next region.

Transplant coordinators are well skilled in approaching organ donation as an end of life option of care and will gladly become a member of the care team to care for the family and their loved ones

at end of life. I am always humbled when families embrace and consent to organ donation as they place the needs of others above their own heart ache and pain and grant many deserving people the gift of life.

The coordinator will ensure all the legal requirement are met by contacting and discussing the case with the state pathologists and all other relevant consenters to the organ donor process.

There are costs involved as no private clinic views the organ donor as a case not to be charged. These costs are never for the family of the donor but rather the hospital group who employs the coordinators who manage the donor and who assist with the allocation of these organs. The original file on the patient is closed and an organ donor file is opened. A reclaim to the recipients is performed as each recipients medical aid usually will support some organ retrieval fees. Within the state sector there is no reclaim possible so these fees are written off by the private sector as community responsibility. Should any donor family receive accounts that they believe are related to the donation they should contact their coordinator immediately to clarify or, if necessary, to rectify immediately. It is against the law to trade in organs so we cannot buy nor sell so no family may be gifted in any manner and no recipient pays for an organ their medical aid may be billed for their organs portion of the retrieval process.

Region Sector/facility Contact person Contact numbers

Johannesburg Potchestroom Klerksdorp

Mediclinic, State Sector and Life Group Sister Kim Crymble 0849270693

Netcare (Johannesburg)

Sister Angela Van Heerden 0828215453

Pretoria and Bloemfontein All referrals Siser Anette Otto 0828206229

Western CapeState Facilities Sister Fiona McCurdie 0824582343

Netcare Sister Alexia Michaelides 082 455 8024

Eastern Cape All health care facilities Sister Sally Brooks 082 334 7267

KwaZulu-NatalNetcare Vanessa Wentnik 031 268 5000Ethekwini Cindy Goldie 083 301 1743State Sister Shannon Naidoo 083 775 7623

Volume 6 No 1 February 2015 Page 8

Dr AJ Dalby, Cardiologist, Milpark HospitalProf FD Raal, Endocrinologist, Charlotte Maxeke Hospital, University of the Witwatersrand

Johannesburg

Choosing a heart safe eating pattern

therosclerotic cardiovas-cular disease (ASCVD) is responsible for the great majority of myocardial infarctions, strokes and

peripheral arterial disease and is the most frequent cause of morbidity and premature death. Its emergence throughout the developed and devel-oping world is a crisis that engages the medical profession and national gov-ernments in measures devised to pre-vent its development.

In this context, Prof Tim Noakes’ advocacy of the Banting diet in his bestselling book “The Real Meal Revolution,” as well as in a dedicated magazine “Lose It”, in the press and popular magazines, on radio and in television appearances, and in his public lectures, deserves comment. He recommends eliminating virtually all carbohydrate from the diet and replacing it with saturated fat as the prime source of energy. While significant weight loss and an increased feeling of wellbeing are reported by many persons following this diet, potentially adverse effects on serum cholesterol are being observed. In addition, the Banting diet lacks outcome studies that demonstrate its long-term safety and benefits.

The Nature of ASCVDAny physician familiar with the nature of ASCVD finds it impossible to accept that it is caused by a single dietary component and that the risk can be reduced by eliminating carbohydrate and consuming saturated fat instead. Our understanding is that the aetiology of ASCVD is multifactorial.

Firstly, numerous environmental factors are operative. These are as varied as air pollution, our built environment, and the emotional stresses to which we are subjected. Secondly, there are personal characteristics such as smoking habit, the amount of physical activity, excessive body weight and eating pattern which alter the risk. Lastly,

often arising from these lifestyle factors, hypertension, diabetes and hypercholesterolaemia may develop which increase the risk of ASCVD and, ultimately, its dire consequences. Yet even this is not the whole story. All of these factors are underpinned by age, gender and as yet largely undefined genetic predispositions. Given this understanding, it is clear that ASCVD needs to be combated by a multipronged approach to reducing patients’ risk, not simply by dietary modification alone.

The Lipid HypothesisThe lipid hypothesis of atherosclerosis has been central to physicians’ understanding of ASCVD for decades. In 1858 the German pathologist Rudolph Virchow described the accumulation of lipid in atherosclerotic plaques in the arteries. Later experiments found that rabbits fed on a high cholesterol diet developed atherosclerosis. Patients with familial hypercholesterolaemia or FH develop ASCVD prematurely. Those with homozygous FH develop ASCVD in their teens; those with heterozygous FH are generally affected by their fifties.

In 1963 Ancel Keys reported that communities consuming high-fat diets had a higher incidence of ASCVD. More recent research has demonstrated that when low density lipoprotein cholesterol (LDL-c) enters beneath the arterial intima it provokes inflammation that facilitates the development of plaque. This inflammatory response

is augmented by oxidised LDL-c. Meticulously conducted intravascular ultrasound studies have demonstrated that reducing LDL-c reduces plaque growth in coronary arteries.

The case for the lipid hypothesis was advanced further when statins were introduced into medical therapy from the late 1980’s following the publication of 4S trial results. Simvastatin, in common with the other statins that were developed later, reduces the hepatic production of LDL-c. 4S found that simvastatin reduced cholesterol levels by up to 47% in patients. This fall in cholesterol was associated with a 30% reduction in the risk of dying when compared to those on placebo treatment. 4S was followed by a large number of trials involving different statins that were used in conditions as varied as asymptomatic subjects, high risk patients with hypertension or diabetes, and patients who had already suffered an acute coronary or cerebrovascular event.

To date, almost 200 000 patients have been involved in these trials, typically for a 4-5 year period. Combining all these results, the Cholesterol Trialists’ Collaboration confirmed the benefits of statin treatment in a broad spectrum of patients across age ranges and including both primary and secondary prevention. One remarkable aspect of these trials is that they demonstrate a continuous relationship between the extent of cholesterol reduction and the reduction in the frequency of clinical events. This hypothesis is strengthened by the demonstration that lowering LDL-c further by adding a non-statin agent, ezetimibe, to a statin provides a greater improvement in outcome.

Even after all these trials we still do not know how low the cholesterol should be reduced to obtain the maximum benefit. In the STENO-2 study, by combining statin treatment with good control of other risk factors, it has been shown that risk can be reduced by 50% in patients with diabetes in

Any physician familiar with the nature of ASCVD

finds it impossible to accept that it is caused

by a single dietary component and that the

risk can be reduced by eliminating carbohydrate and consuming saturated

fat instead.

Page 9 Volume 6 No 1 February 2015

the long term. In developed countries, the risk of ASCVD has declined in the last 2 decades by managing these risks effectively.

The lipid hypothesis has not been “discredited” as Noakes alleges. Indeed it remains one of the mainstays of our understanding of how to combat ASCVD and is the subject of active, ongoing research. Dietary Research and International GuidelinesIn his public utterances Noakes has criticised the pharmaceutical industry for exerting undue influence upon guideline development and the bias that he perceives amongst the authors of guidelines. He then proceeds to discount the value of guidelines in clinical practice, a view that is hard to support given the number of instances in which improved clinical outcomes have been recorded when the guidelines are followed.

Broadly, two methods are used in dietary research. Either the short-term effect of adding, removing or substituting a single component of the diet is measured, or a population-based observational study is performed on a large number of patients who have a reasonably uniform diet. Dietary research is beset by the difficulties inherent in maintaining fixed eating patterns amongst trial subjects especially when a study is set to run over a number of years. Recognising that there are deficiencies in our knowledge about the ideal eating pattern, the 16 member expert committee of the American Heart Association and the American College of Cardiology issued guidelines on life style and diet at the end of 2013. They had weighed the strength of the all the scientific evidence and based

their advice on the best information available. Ultimately they favoured either the Mediterranean diet or the DASH diet which share a number of similarities.

The authors found that the evidence pointed to LDL-c and blood pressure

being reduced by substituting saturated fat with, in order of preference, polyunsaturated fat, monounsaturated fat or carbohydrate. Transfats were noted to be disadvantageous.

In summary, the 2013 AHA/ACC rec-ommendations encourage consump-tion of vegetables and fruit, whole grains and legumes, low fat dairy prod-ucts, poultry and fish, and non-tropical oils and nuts. The consumption of salt, sweets and sugar-containing bever-ages, and red meat should be limited (Table 1).

Support for the benefit of the Mediterranean diet came recently from the Spanish Predimed diet study. The Mediterranean diet, supplemented by either extra virgin olive oil or nuts, was shown to be associated with 30%

fewer deaths, heart attacks and strokes than the usual diet. Around the same time another trial found that eating nuts may be preferable to using extra virgin olive oil.

The Predimed study is particularly interesting because it provides information on the eventual clinical outcomes in the population that was being evaluated. Many previous studies had employed surrogate endpoints. These surrogates were often simply the biochemical changes or weight changes brought about by an intervention and which could be measured within a short time. Although such changes might appear to be beneficial in theory, they might not result in a better outcome for the patient.

This lesson was starkly illustrated by the Cardiac Arrhythmia Suppression Trial (CAST). Patients were entered into the trial after experiencing a myocardial infarct. Such patients who have ventricular ectopy have a worse prognosis. The CAST investigators had found the ectopy could be suppressed by flecainide and surmised that by reducing the ectopy, patients’ lives would be saved. Unfortunately this did not prove to be true and more patients died taking flecainide than those who were given placebo. Another illustration of this point was in the LIFE study which compared two drug strategies to control blood pressure. Even though both strategies resulted in an identical fall in blood pressure, the outcome was better with one than with other. We learn from these experiences that it is not enough to modify a surrogate endpoint and expect a better outcome. We need to know that on balance a particular strategy prolongs life while also being free of adverse side-effects.

Banting DietAlthough the Banting diet results in significant weight loss, accompanied by a reduction in the emergence of new diabetes and a modest fall in blood pressure, many medical practitioners have observed that their patients’ blood cholesterol levels rose sharply on the Banting diet. In one recorded instance a patient’s cholesterol rose 77% to an alarming 12.9 mmol/L. Worse still, patients who have established

Table 1. The 2013 dietary recommendations of the ACC/AHA Guidelines

Committee on Lifestyle Management to Reduce Cardiovascular RiskEncouraging consumption of: Limiting consumption of:

• vegetables and fruits• whole grains and legumes • low fat dairy products• poultry and fish • non-tropical vegetable oils and nuts

• sodium (salt)• sweets and sugar-containing beverages• red meat

The Mediterranean diet, supplemented by

either extra virgin olive oil or nuts, was shown

to be associated with 30% fewer deaths, heart attacks and strokes than

the usual diet. Around the same time another trial

found that eating nuts may be preferable to using

extra virgin olive oil.

Volume 6 No 1 February 2015 Page 10

ASCVD have inferred from Noakes’ pronouncements that they could safely stop taking their statin treatment.

Noakes defends his position by labelling the rise in blood cholesterol as unimportant. He supports the theory of insulin resistance and atherogenic dyslipidaemia as the only causative factor in ASCVD, stating that LDL-c is not implicated in the generation of ASCVD. He holds that the Banting diet will benefit all the known risk factors for atherosclerotic vascular disease. In his words “high fat diets have the unique ability to reverse all known coronary risk factors.” However, ASCVD is not a disease of carbohydrate metabolism. There is no evidence to support the measurement of insulin resistance to estimate the ASCVD risk.

There is very little evidence that low carbohydrate diets prevent ASCVD. Marathon runners, having a low

percentage of body fat and being in peak physical condition, generally consume large quantities of refined and complex carbohydrates and do not exhibit insulin resistance. Indeed they are exquisitely sensitive to insulin. If insulin resistance were the cause of ASCVD, patients with FH would manifest it to a marked degree, which they do not. The small dense LDL-c particles, typically found in patients with metabolic syndrome or diabetes, are thought to be more atherogenic. However, FH patients tend to have large LDL-c particles and are at much higher risk.

Insulin resistance, the metabolic syn-drome and atherogenic dyslipidaemia are neither new concepts nor can they be summarily dismissed as not con-tributing to ASCVD, but as yet we have sparse evidence about the best means of managing these problems and none that indicates what the clinical out-

come of intervention may be. Noakes is well aware that a clinical trial needs to be performed to prove the safety and benefit of what he is proposing. Until such time his theories must re-main just theories, his results merely surrogate results.

ConclusionIn deciding on the best eating pattern, we may need to keep an open mind but not so open that our brains fall out! We already have reassuring evidence that the Mediterranean diet reduces the risk of heart attack and stroke. We do not have comparable evidence for the Banting diet. Potentially, we place ourselves, our families and our patients at risk by adopting a diet that has not been proved to produce a long-term benefit and is known to be associated with a rise in cholesterol. Until more is known about its long-term effects, the Banting diet should not be promoted to the South African public.

10 Points to remember about: Ectopic fat in Insulin Resistance. Dyslipidemia and Cardiovascular Disease

Authors: Shulman GICitation: N Engl J Med 2014;371;1131-1141

Perspective:

1. Type 2 diabetes currently affects more than a third of a billion people worldwide and is the leading cause of end-stage renal disease, non-traumatic loss of limb, and blindness in working adults, with estimated annual worldwide healthcare costs exceeding half a trillion dollars.

2. Although impaired beta-cell function is ultimately responsible for the progression from normoglycemia to hyperglycemia, insulin resistance predates beta-cell dysfunction and plays a major role in the pathogenesis of type 2 diabetes.

3. The association between excess lipid storage in the form of obesity and insulin resistance has long been recognised and proton (H) MRS studies have shown an even stronger relationship between intramyocellular lipid content and insulin resistance in muscle.

4. Accumulation of an intracellular lipid metabolite mediates insulin resistance associated with obesity and type 2 diabetes by causing defects in insulin signalling and reduced insulin-stimulated glucose-transport activity.

5. The most common cause of ectopic lipid deposition in skeletal muscle and the liver is a level of energy intake that exceeds the level of energy expenditure, resulting in spill over of energy storage from adipose tissue to the liver and skeletal muscle.

6. Studies show that ectopic accumulation of intracellular lipid leads to insulin resistance in muscle and the liver even in the absence of peripheral and visceral adiposity and the myocellular diacylglycerol (DAG)s are the lipid-derived metabolites responsible for triggering insulin resistance through activation of protein kinase C (PKC)s in the liver and PKDB in muscle

7. Acquired mitochondrial dysfunction has been shown to be an important predisposing factor for ectopic lipid accumulation and insulin resistance in the elderly.

8. Preserving mitochondrial function by reducing mitochondrial oxidative damage may be a therapeutic target for preventing age-associated reduction in muscle mitochondrial function, insulin resistance in muscle, and type 2 diabetes in the elderly.

9. Macrophage-induce lipolysis, as opposed to alteration in circulating cytokines and hepatic gluconeogenic protein transcription, may be the major culprit in the transition from insulin resistance to impaired glucose tolerance and type 2 diabetes.

10. Increasing hepatic energy expenditure by promoting mitochondrial uncoupling should be a novel approach for treating the related epidemics of non-alcoholic fatty liver disease, the metabolic syndrome, and type 2 diabetes.

Debabrata Mukherjee, M.D., F.A.C.C.Republished here with courtesy from the American College of Cardiology,

www.cardiosource.org/Science-And-Quality/Journal-Scan.aspx

Page 11 Volume 6 No 1 February 2015

Effect of High-Intensity Statin Therapy on Atherosclerosis in Non-Infarct-Related Coronary Arteries (IBIS-4): a Serial Intravascular Ultrasonography Study

Raber L, Taniwaki M, Zaugg S, et al., on behalf o the IBIS-4 (integrated Biomarkers and Imaging Study-4) Trial InvestigationsEur Heart J 2014; Sep 2: (Epub ahead of print)

Study question What is the impact of high-intensity statin therapy on plaque burden, composition, and phenotype in non-infarct-related arteries of ST-segment elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PCI)?

MethodsBetween September 2009 and January 2011, 103 STEMI patients underwent intravascular ultrasonography (IVUS) and radiofrequency ultrasonography (RF-UVUS) of the two non-infarct-related epicardial coronary arteries (non-IRA) after successful primary PCI. Patients with either non-IRA with > 50% stenosis were excluded. Patients were treated with rosuvastatin 40 mg/day throughout 13 months, and serial intracoronary imaging with the analysis of matched segments was available for 82 patients with 146 non-IRAs. The primary IVUS endpoint was the change in percent atheroma volume (PAV).

ResultsAfter 13 months, low-density lipoprotein cholesterol (LDL-C) had decreased from a median of 127 to 73 mg/dl (p <0.001), and high

density lipoprotein cholesterol (HDL-C) levels had increased from 42.6 to 46.4 mg/dl (p<0.0001). PAV of the non-IRA decreased by 20.9% (95% confidence interval (CI), 21.56-20.25; p = 0.007). Patients with regression in at least one non-IRA were more common (74%) than those without (26%). Percent necrotic core remained unchanged (20.05%; 95% CI, 21.05-0.96%; p = 0.93), as did the number of RF-IVUS defined thin-cap fibroatheromas (124 vs. 116, p = 0.15).

ConclusionsHigh-intensity rosuvastatin therapy over 13 months is associated with regression of coronary atherosclerosis in non-IRAs without changes in RF-IVUS defined necrotic core or plaque phenotype among STEMI patients.

PerspectiveInterestingly, the greater reduction in LDL-C and increase in HDL-C over 13 months resulted in larger PAV reduction, which was not the case for baseline LDL-C and HDL-C. The failure to reduce the size of the necrotic core and fibroatheroma characteristics was a surprise that may be related to the relatively short follow-up. As in other statin studies, there was an increase in calcium content, which may be a signal of healing and formation of more stable plaques.

Reviewed by Melvyn Rubenfire, MD, F.A.C.C. Republished here with courtesy from the American College of Cardiology,

www.cardiosource.org/Science-And-Quality/Journal-Scan.aspx

Effect of Self-Monitoring and Medication Self-Titration on Systolic Blood Pressure in Hypertensive Patients at High Risk of Cardiovascular Disease: The TASMIN-SR Randomized Clinical TrialMcManus RJ, Mant J, Haque S, et al.JAMA 2014; 312: 799-808

Study question What is the impact of self-monitoring of blood pressure with self-titration of anti-hypertensive medication (i.e., self-management), compared with usual care, on systolic blood pressure among high-risk patients with existing cardiovascular disease, diabetes mellitus, or chronic kidney disease?

MethodsTASMIN-SR (The Targets and Self- Management for the Control of Blood Pressure in Stroke and at Risk Groups) was an unblended, randomized trial. Eligible patients had at least one “high-risk” condition (defined as cardiovascular disease, diabetes mellitus, stage 3 chronic kidney disease or coronary heart disease ) with a blood pressure reading during the baseline examination of at least 130/80 mm Hg; participants were not required to have been prescribed antihypertensive medication. Those randomized to self-management were trained to use a validated monitor and follow a predetermined plan (taught in 2-3 approximately 1-hour sessions) to self-titrate medications. Target blood pressure was <120/75 mm Hg. The primary prespecified outcome was the difference between intervention and control groups in systolic blood pressure at 12 months.

ResultsThe analytic sample included 450 patients (81% of 555 patients randomized). Mean baseline blood pressure was 143.1/80.5 mm Hg and 143.6/79.5 mm Hg in the intervention and control groups, respectively. The mean blood pressure decreased to 128.2/73.8 mm Hg (95%)

confidence interval [Cl], 5.7-12.7 in systolic and 3.4 mm Hg (95% CI, 1.8-5.0) in diastolic blood pressure between groups. With multiple imputation for missing value, the difference in diastolic blood pressure did not meet statistical significance.

ConclusionsThe authors concluded that self-management of blood pressure in patients with or at high risk of cardiovascular disease resulted in lower systolic blood pressure at 12 months.

PerspectiveThis is an important study that suggests the merits of a strategy of self-monitoring of blood pressure with self-titration of antihypertensives in select patients. Any strategies to mitigate the substantial and global burden of hypertension are welcome. It should be noted that the blood pressure target of 120/75 mm Hg (based on recommendations by the British Hypertension Society and the Joint British Society Guidelines) is significantly lower than the 150/90 mm Hg threshold recommended by the Eighth National Committee (JNC 8) panel members in adults older than 60 years of age (in TASMIN-SR, mean age in randomized patients in the usual care and intervention groups was 69.6 and 69.3, respectively). Furthermore, the mean baseline blood pressure in both groups was below this threshold. Although the thresholds defined by JNC 8 are not without controversy, it would be valuable to test such a strategy of self-monitoring in patients with significantly worse hypertension at baseline.

Prashant Vaishnava, M.D.Republished here with courtesy from the American College of Cardiology,

www.cardiosource.org/Science-And-Quality/Journal-Scan.aspx

Volume 6 No 1 February 2015 Page 12

Konstantinides S, Torbicki A, Agnelli G, et al.Eur Heart J 2014;Aug 29:[Epub ahead of print].

PerspectiveThis guideline statement from the European Society of Cardiology discusses the appropriate diagnosis and management strategies for acute pulmonary embolism (PE). The following are eleven key points from the guideline statement:

2014 ESC Guidelines on the Diagnosis and Management of Acute Pulmonary Embolism: The Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC)

day) are alternatives to the combination of parenteral and warfarin anticoagulation (Class I for both).

• In place of warfarin, dabigatran (150 mg twice a day, 110 mg twice a day for patients ≥80 or taking verapamil) is recommended following the acute phase of parenteral anticoagulation (Class I).

• New oral anticoagulants (dabigatran, rivaroxaban and apixaban) are not recommended in patients with severe renal impairment (Class III).

7. Routine use of systemic thrombolytic therapy is not recommended in low- and intermediate-risk acute PE patients (Class III). Thrombolytic therapy can be considered in patients with intermediate- to high-risk acute PE with clinical signs of hemodynamic decompensation (Class IIa).

8. Patients with low-risk acute PE should be considered for early discharge and continuation of treatment at home if proper outpatient care and anticoagulation therapy can be arranged (Class IIa).

9. Routine use of inferior vena cava (IVC) filters in patients with acute PE is not recommended (Class III). IVC filters can be considered in patients with a contraindication to anticoagulation (Class IIa) or with recurrence of PE despite therapeutic anticoagulation (Class IIa).

10. Anticoagulation should be given for 3 months in all patients (Class I). Indefinite treatment is recommended for patients with a recurrent unprovoked PE (Class I), and considered for patients with a first unprovoked PE and low risk of bleeding (Class IIa). In patients with acute PE and cancer, consider administering weight-adjusted LMWH for the first 3-6 months (Class IIa).

11. All patients with chronic thromboembolic pulmonary hypertension (CTEPH) should be assessed for potential operability by a multidisciplinary team (Class I), and should receive life-long anticoagulation (Class I). Riociguat is recommended for symptomatic CTEPH patients who are inoperable (Class I).

Revuewed by Geoffrey D. Barnes, MD Republished here with courtesy from the American College of Cardiology,

www.cardiosource.org/Science-And-Quality/Journal-Scan.aspx

1. In suspected high-risk acute PE (presence of shock or hypotension), emergent computed tomography (CT) angiography or bedside transthoracic echocardiography is recommended for diagnostic purposes (Class I). Pulmonary angiography may be considered in unstable patients referred directly to a catheterization laboratory to exclude acute coronary syndromes (Class IIb).

2. In suspected acute PE without shock or hypotension, use of a validated risk stratification scheme (e.g., Modified Well’s or Revised Geneva scores) should be employed (Class I). If pretest probability is low or intermediate, D-dimer test should be used in outpatient and emergency department settings (Class I). Low pretest probability and a negative D-dimer test excludes acute PE (Class I). D-dimer testing is not recommended in patients with a high pretest probability for acute PE (Class III).

3. Normal CT angiography excludes PE in patients with low or intermediate pretest probability (Class I). Normal perfusion lung scintigram (V/Q scan) excludes acute PE (Class I). Lower limb compression ultrasound with a proximal deep venous thrombosis (DVT) in a patient with a clinically suspected PE confirms the diagnosis of acute PE (Class I).

4. In acute PE patients without shock or hypotension, use of the PESI or sPESI score can be considered to distinguish between low- and intermediate-risk PE (Class IIa). Similarly, assessment of the right ventricle with echocardiography or CT, along with assessment of myocardial injury (usually troponin testing), can be considered for further risk stratification (Class IIa).

5. In patients with high-risk acute PE (shock or hypotension), initial therapy should include intravenous anticoagulation with unfractionated heparin (Class I) and thrombolytic therapy (Class I). Surgical pulmonary embolectomy is recommended in patients with a contraindication to thrombolysis or when thrombolytic therapy has failed (Class I).

6. In patients with intermediate- or low-risk acute PE, initiation of parenteral anticoagulation is recommended (Class I). Use of low molecular weight heparin (LMWH) or fondaparinux is recommended for most patients (Class I). In parallel to parenteral anticoagulation, treatment with warfarin (international normalized ratio [INR] goal 2-3) is recommended (Class I).

• Rivaroxaban (15 mg twice a day for 3 weeks, then 20 mg daily) or apixaban (10 mg twice a day for 7 days, then 5 mg twice a

Page 13 Volume 6 No 1 February 2015

Dr Mike BennettCardiologist

Wilgers Hospital, Pretoria

European Society of Cardiology 2014

he recently held ESC meet-ing held in Barcelona once again did not disappoint and a wealth of information was disseminated to the

medical community. The amount of in-formation from such a meeting is sim-ply too overwhelming to absorb. I will try and briefly cover the most impor-tant and new studies that should influ-ence our clinical practice in the future.

LipidsThe pivotal role of LDL-Cholesterol in the formation and progression of atherosclerosis is firmly established. Although the pleiotropic effects of statins are important, their main mechanism by which they limit atherosclerosis is by reducing LDL-C. Many studies have confirmed that lower, is better. However, even with the newer potent statins, a large number of patients do not reach their target levels.

In the IBIS-4 study the burden and composition of atherosclerotic plaque in non-infarct related arteries was imaged by intravascular sonography (IVUS) at the time of PCI for acute STEMI, was compared to with follow-up IVUS 13 months later. Patients were started on 20 mg/d of rosuvastatin for 2 weeks and the dose was then increased to 40 mg/d for the remainder of the study. LDL-C decreased from a median of 3.29 to 1.89 mmol/l (p<0.001). Atheroma volume decreased significantly from 43.95% to 43.02% (p=0.007), there was no significant change in the percent necrotic core. Of interest was that the more pronounced changes in LDL-C decrease and HDL-C increase over 13 months resulted in larger decreases in per cent atheroma volume, which was not the case for baseline LDL-C. These results are supported by other studies which showed a decrease in cardiovascular events associated with high-intensity statin therapy, even in patients with mildly elevated LDL-C levels. Lower is still better.

AlirocumabDespite statins being the drugs of choice, even at maximal tolerated doses in patients with heterozygous familial hypercholesterolemia (HeFH), approximately 80% of adult patients with HeFH fail to reach the target of <2.5 mmol/l with monotherapy. The efficacy of alirocumab in lowering LDL-C in patients with HeFH not controlled by statin and other lipid-lowering therapy was investigated in the ODYSSEY FH I and FH II trials.

Patients with HeFH; a history of CVD, LDL-C >1.81 mmol/l or no history of CVD and LDL-C≥2.59 mmol/l and on maximally tolerated statin, were randomized for 78 weeks to alirocumab 75 to 150 mg 2/w, or a matching placebo, in addition to current therapy.

At week 24, alirocumab reduced LDL-C levels compared with placebo in both FH1 (-48.8% vs 9.1%) FHII (48.7% vs 2.8%), both p<0001. By week 24 more high risk patients on alirocumab compared with placebo reached the prespecified target of <2.59 mmol/l or <1.81 mmol/L in the very high-risk group (72.2% vs 2.4% in FH1 and 81.4% vs 11.3% in FH II) and maintained their reduction to 52 weeks.

Treatment related adverse events occurred in similar proportion of alirocumab and placebo patients (74.8% and 75.4%) and treatment had to be discontinued in 3.1% and 3.7% of patients, respectively.

With the lack of adverse events compared to placebo, and the large number of patients achieving their target LDL-C levels, alirocumab may become a promising treatment in this high-risk group of patients.

ODYSSEY COMBO II: Alirocumab versus Ezetimibe In this trial of 720 patients conducted over 104 weeks, the safety and efficacy of alirocumab was compared with ezetimibe in hypercholesterolemic patients with either no history of CVD

and LDL-C <2.59mmol/L or a history of CVD and LDL-C ≥1.81 mmol/L. All patients were already on maximally tolerated doses of a statin. At 24 weeks alirocumab significantly reduced LDL-C levels as compared with ezetimibe (-50.6% vs -20.7%; p<.0001). At this point, 77% of patients on alirocumab and 45.6% of patients on ezetimibe were able to achieve a prespecified target of 1.81mmol/L (p.0001).

Adverse events occurred in 72.2% of the alirocumab arm and 67.2% in the ezetimibe arm but discontinuation occurred in only 7.5% (alirocumab) and 5, 4% (ezetimibe) of the 2 arms.

In conclusion, alirocumab appears to be a potent and promising treatment for the large numbers of patients who are not sufficiently controlled with statins. They will not replace statins, but will certainly help many high-risk and very high-risk patients to achieve their target LDL-C levels.

Heart failure: PARADIGM-HFAngiotensin enzyme converting inhibitors (ACE) represent the gold standard treatment for heart failure (HF) and have been shown to reduce cardiovascular (CV) mortality in patients with systolic dysfunction on top of optimal medical therapy.

LCZ696 combines a neprilysin inhibitor and the angiotensin receptor blocker (ARB) valsartan, to simultaneously counteract maladaptive mechanisms caused by degradation of vasoactive peptides by neprilysin. ARB’s interfere with the action of angiotensin II receptor at its type 1 receptor, resulting in vasodilatation. Neprilysin is a neutral endopeptidase involved in metabolism of a number of vasoactive peptides. Blocking the action of neprilysin results in higher levels of peptides such as natriuretic peptides which have vasodilating properties, facilitate sodium excretion, and may have an effect on remodelling.

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The PARDIGM-HF study enrolled almost 9,000 patients (age 63.8 years, 22% women, 60% with ischemic cardiomyopathy, LVEF 30%) with clinically stable NYHA II to III HF. Patients were randomized to standard therapy and either enalapril or LCZ696, and followed-up for a mean of 27 months.

LCZ696 was more effective than enalapril in reducing the endpoints of CV death, HF hospitalization and all-cause mortality. Quality of life at 8 months was significantly improved by LCZ696 versus enalapril (p=.001). The reduction in CV mortality over enalapril was similar to that achieved when an ACE inhibitor is compared with placebo, indicating that LCZ696 doubles the effect of ACE inhibitors on CV death.

More patients in the enalapril group discontinued treatment because of hypotension, hyperkalaemia and worsening renal function, and angioedema was similar in the 2 groups.

The positive result on outcomes combined with less adverse effects requiring discontinuation of the drug, is very exciting and promising for a group of patients with a poor outcome.

Resistant hypertension

DefinitionTreatment-resistant hypertension can be defined as the failure of drugs and lifestyle modifications to lower blood pressure (BP) to appropriate levels. A working definition of resistant hyper-tension is an office systolic/diastolic BP ≥140/90 mm Hg on adequate doses of at 3 classes of drugs, 1 of which is a diu-retic. This means that a patient could have treatment-resistant hypertension even though his BP is controlled.

Secondary Causes of Resistant HypertensionThe commonest causes resistant hy-pertension included: obstructive sleep apnoeal (60-70%), primary hyperaldo-steronism (7-20%), renal artery steno-sis (1-24%), renal parenchymal disease (1-2%), drug-induced or heavy alcohol abuse (2-4%) and thyroid disorders (<1%).

Pseudo-resistance due to noncompli-ance with BP-lowering medications (one-quarter of patients) must always be considered in all patients.

Renal denervation (RD)The results of the SYMPLICITY HTN-3 indicated no reduction in BP after

RD in 535 patients 6 months after the procedure and caused havoc in the interventionist community. This study was dissected and scrutinized, and the results, design and execution was discussed in several sessions. It was emphasized that the procedure is not easy, is often incomplete and the experience of the operator is critical. The interventionists performing the procedure in the SYMPLICITY trial had little experience in RD and there was no way to determine if RD actually occurred. It is possible that the trial failed because of the execution of the procedure, and not necessarily because the RD does not work for resistant hypertension.

The development of a reliable way to confirm adequate RD is crucial to be able to objectively judge the functional result of this procedure. Newer catheters are also more user-friendly and may lead to improved outcomes.

ConclusionThe above is just a sliver of the enormous amount of information made available at this prestigious meeting. Those of you interested in an overview of the 2014 Guidelines and clinical trial highlights, should visit the ESC website at www.escardio.org for more.

CPD AccreditationDoctors can acquire CPD points with this newsletter by visiting www.mpconsulting.co.za and completing an online MCQ consisting of 15 questions. Should you have any queries regarding the completion of the online MCQ, please contact Inge Erasmus at 0861 111 335 or email inge@mpconsulting.co.za.

Congress Calendar 2015Event/Congress Date Venue Contact

Cardio Rhythm 201530 January - 1 February

2015

Honk Kong Convention and Exhibition Centre,

Hong Kong, Chinawww.cardiorhythm.com/

Biomarkers, Therapy and Devices in Heart Failure

18 February 2015

Table Bay Hotel, Cape Town http://hf-ce.org/

Arica PCR 2015 26-28 March 2015

The Forum, Bryanston, Johannesburg

http://eoafrica.co.za/africa-pcr-march-2015/

SA Heart Annual Congress 2015 25 - 28 October 2015 Sun City, South Africa sue@eoafrica.co.za