PracticeUpdate: Cardiology | Vol1 - No.2 - 2016

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VOL. 1 • No. 2 • 2016 ISSN 2206-4672

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Implantable cardioverter- defibrillator does not improve overall survival in nonischaemic heart failure

OPINION

App-based technology for diagnosing AF is definitely cool; however, chasing AF in a low-risk patient in the absence of an integrated program to

manage false– positive results may send us chasing the elusive Pokemon! 14

Placement of an implantable cardioverter-defibrillator in patients with nonischaemic systolic heart failure did not improve overall survival compared with usual clinical care. Risk of sudden cardiac death, however, was halved, reports the DANISH trial.

CONFERENCE COVERAGE 2016 ESC Congress CPAP is shown to improve wellbeing but not cardiovascular outcomes 5 Lipoprotein(a) apheresis proves beneficial in refractory angina 8 CORONARY HEART DISEASE Benefits of omega-3 fatty acids from fish oil after acute MI: an off and on affair? 9 MYOCARDIAL DISEASE The pivotal position of IL-6 in the pathogenesis of ischaemic heart disease, and a lot of new questions 12 ARRHYTHMIAS/ HEARTRHYTHM DISORDERS My approach to atrial fibrillation: rate vs rhythm control 15

Comparison of inhospital mortality and frequency of coronary angiography on weekend versus weekday admissions in patients with non-ST-segment elevation acute myocardial infarction American Journal of Cardiology Admission on a weekend was associated with higher inhospital mortality compared with admission on a weekday.

Hypochloraemia, diuretic resistance,

Diagnostic performance of a smartphone-based

Development and validation of a sudden cardiac death prediction model for the general population Circulation This new risk equation provides slightly better predictive ability for SCD than the ACC/AHA model and

and outcome in patients with acute heart failure Circulation: Heart Failure Data indicated that chloride

photoplethysmographic application for atrial fibrillation screening in a primary care setting Journal of the American Heart Association

The smartphone PPG application Cardiio Rhythm detected AF in

measurement in acute HF patients at admission and at 14 days could be used as a marker for response to therapy and outcome. 11

patients at risk of developing AF and could be used to enable population- based screening for AF. 14

is generalisable to the US population without cardiovascular disease.

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EXPERT OPINION

ESC 2016: Highlights from Professor Garry Jennings

EDITORIAL Managing Editor Anne Neilson anne.neilson@elsevier.com Editor Carolyn Ng carolyn.ng@elsevier.com Designer Jana Sokolovskaja j.sokolovskaja@elsevier.com SALES Commercial Manager Fleur Gill fleur.gill@elsevier.com Account manager Linnea Mitchell-Taverner l.mitchell@elsevier.com

By Garry Jennings, AM, MBBS, MD, FRCP, FRACP Professor Jennings, Chief Medical Adviser of the Heart Foundation of Australia, attended the recent 2016 ESC Congress. Here are his highlights from the meeting. Clinical trial updates:

in the New England Journal of Medicine with a supplementary editorial, the study showed that CPAP improves symptoms of sleep apnoea but not outcomes. • The DANISH trial casts doubts on previously accepted guide- lines for the use of ICDs in peo- ple with nonischaemic heart failure. • NORSTENT showed no differ- ence in outcomes in a com- parison of drug-eluting and bare metal stents. However, revascu- larisation rates over the next 2 years were less with the former. PRAGUE-18 did not detect a dif- ference between prasugrel and ticagrelor but, like a number of studies where no differences

were seen, recruitment failed to meet targets and the study was underpowered. • ENSURE-AF found that edoxa- ban was equivalent to warfarin in the prevention of stroke around the time of electrical cardioversion. • A study was presented showing that the CHADS-DS2-Vasc score for defining risk in people with atrial fibrillation overestimates the number of people with low risk. GARFIELD-AF, a new score was proposed. There was also much interest in some new drug classes including PCSK9 inhibitors, powerful LDL- cholesterol lowering agents, dual angiotension receptor blocker/

neprilysin inhibitors for heart failure, new oral anticoagulants (NOACs) and their inhibitors, and SGLT2 inhibitors for diabetes. The meeting also saw the release of important new ESC guidelines that will no doubt influ- ence Australian experts as our own guidelines are revised: re- vised atrial fibrillation guidelines recommended NOACs over war- farin; heart failure guidelines were updated; dyslipidaemia guidelines took a different line to the US in recommending statins, lifestyle for everyone with dyslipidaemia but not providing targets based on risk level; and the CVD prevention guidelines put great emphasis on the Mediterranean diet, amongst other lifestyle measures.

• The SAVE study was presented by Doug McEvoy from Flinders University in Adelaide and coor- dinated from the George Insti- tute in Sydney. This international study, with over 2000 people with moderately severe sleep apnoea, examined whether CPAP reduced cardiovascu- lar endpoints that have been shown to be associated with sleep apnoea in observational studies. The result was that CPAP reduced snoring and im- proved quality of life but had no effect on the combined cardio- vascular endpoints or on mor- tality. Blood pressure was also similar in CPAP and control sub- jects. Published simultaneously

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ESC 2016: Highlights from Professor TomMarwick

Interview with Tom Marwick, MBBS, PhD, MPH Professor Marwick, Director and Chief Executive of BakerIDI Heart and Diabetes Institute, attended the 2016 ESC Congress. He shares his highlights from the meeting. 1. DANISH: ICDs in nonischaemic heart failure

I think it’s an interesting juxtaposition that one study says “do a non-invasive CT test before an angiogram so that you can avoid doing angiography” while the other says “do a non-invasive stress test instead of using current guidelines” because, again, you can save a bunch of angiograms. It also demonstrates how we’re still really uncertain about how to use non-invasive test- ing in people with chest pain. There is still a lot of work to be done in this area and I think the emphasis here is that MRI perfusion imaging is an interesting strategy that we should probably think more about in Australia. 4. NACIAM: N-acetylcysteine with glyceryl trinitrate on infarct size This is an important Australian trial investigat- ing the free radical scavenger N-acetylcysteine. The hypothesis was that, in people having myo- cardial infarction, some of the damage from the infarct is related to free radicals. And so if you could scavenge the free radicals, either that would be of direct benefit or it would enable nitrates to be effective. The investigators found a 38% reduction in infarct size with the use of the N-acetylcysteine with glyceryl trinitrate versus glyceryl trinitrate alone. What we’ve been doing with MI has really been focused on early revascularisation for a long time, but not so much on other things we can do to try to salvage tissue. This is a nice example of such a strategy. Second, this group in Adelaide has been really imaginative about selecting agents for that purpose. It’s nice to see one of these come in with a really impactful result.

with HF requires more than monitoring – we can get huge amounts of data but there needs to be some kind of interventional strategy that arises from the interpretation of the data. These results are a reality check on what telemoni- toring has to offer – I don’t think they signal the end of telemonitoring but it needs to be thought through more carefully. 3. CE-MARC 2 and CONSERVE: diagnostic trials on imaging technologies for recognition of coronary disease Both of these were diagnostic trials on the use of new imaging technologies for the recog- nition of coronary disease, comparing combina- tions of functional testing with CT and invasive angiography. In CE-MARC-2, the authors looked at MRI or SPECT imaging for perfusion versus the current NICE guidelines (which use a probability-based approach for test selec- tion). They found that the use of a functional test reduced the need for angiography and reduced interventions. In fact, in the group that had the functional test, 8% of the subsequent angiography was unnecessary compared with 28% in the group that was guided by the NICE guidelines. So that one was a win for doing stress testing. The CONSERVE trial was a comparison between coronary CT angiography versus invasive angiography in symptomatic patients to reduce the number of negative angiograms. The study showed that if CT angiogram was performed before catheterisation, there was an 85% reduction of invasive angiography, with similar outcomes. That one was a win for CT angiography.

For me, this was the top trial presented at this year’s meeting. The DANISH study looked at primary prevention with ICDs for patients with nonischaemic heart failure. Most cardiologists have, at some stage, had some disquiet about the impact of primary prevention ICDs, espe- cially in the elderly. Many ICDs are implanted and never discharge. This Danish group, in a pragmatic clinical trial, looked at whether there was a benefit of implanting an ICD in nonis- chaemic HF with an impaired ejection fraction. The investigators reported no difference in all-cause mortality with ICD versus medical care in nonischaemic HF. This is despite the fact that ICDs reduce sudden cardiac death. The results point to the role of multi-morbidity – HF patients are very likely to have multiple diseases. The message from this study is that ICDs do not benefit older patients – the study did a subgroup analysis of patients older than 68 years – whereas it might benefit younger patients. This is contrary to current guidelines and an incredibly important observation. 2. REM-HF and MORE CARE: remote telemonitoring in heart failure The REM-HF and MORE CARE were two studies of remote telemonitoring in HF pre- sented at the ESC. The conclusions were pretty much the same: telemonitoring did not change HF outcomes. We know that telemonitoring is inexpensive, and some private insurers in the US are considering it as a means of controlling costs. Clearly, the long-term care of patients

VOL. 1 • No. 2 • 2016

CONFERENCE COVERAGE

European Society of Cardiology Congress 2016 27–31 AUGUST 2016 • ROME, ITALY

One of the largest and most influential cardiovascular meetings globally, this year’s European Society of Cardiology (ESC) Congress saw the release of exciting clinical trial data, some of which were contrary to current clinical practice guidelines. The PracticeUpdate Editorial Team attended the Congress and we bring you coverage of the key clinical trials presented, including two from Australian researchers: the SAVE and NACIAM studies. Implantable cardioverter- defibrillator does not improve overall survival in nonischaemic heart failure Placement of an implantable cardioverter- defibrillator in patients with nonischaemic systolic heart failure did not improve overall survival compared with usual clinical care. Risk of sudden cardiac death, however, was halved, reports the DANISH trial. L ars Kober, MD, of Copenhagen University Hospital, Den- mark, explained that the results suggest a caveat to both European and American Heart Association guidelines that recommend implantable cardioverter-defibrillators for all heart failure. DANISH stands for DANish randomised, controlled, multi- centre study to assess the efficacy of Implantable cardioverter defibrillator in patients with nonischaemic Systolic Heart failure on mortality. Dr Kober said, “Prophylactic cardioverter-defibrillator im- plantation is a class 1 recommendation in patients with heart failure and reduced left ventricular systolic function in both European and American guidelines. The evidence is much weaker, however, for patients with non-ischaemic aetiology. Limited data supports the devices in this population. The DANISH trial filled that gap by suggesting the cardioverter- defibrillators should not be routinely implanted in all patients with systolic heart failure.” A total of 1116 stable patients with chronic, nonischae- mic, symptomatic heart failure were randomised to usual care including guideline-recommended medications such as including beta blockers, renin-angiotensin inhibitors, and mineralocorticoid-receptor antagonists (n = 560); or an im- plantable cardioverter-defibrillator (n = 556). An equal proportion of patients (58%) in both groups also needed cardiac resynchronisation therapy, which was delivered via biventricular pacemaker in the control arm, and a device

that younger patients may experience a survival benefit with implantation of the device.” Fifty-eight percent of controls had received a biventricular pacemaker and device-related infections occurred in both groups. Patients not receiving cardiac resynchronisation therapy in the implantable cardioverter-defibrillator group, however, were at excess risk of device infection (5.1% vs 0.8% in controls; HR 6.35; 95% CI 1.38 to 58.87; P = 0.006). Inappropriate shocks, another risk associated with implantable cardioverter- defibrillators, occurred in 5.9% of the implantable cardioverter- defibrillator group. American Heart Association guidelines include implantable cardioverter defibrillator implantation as a class 1A recommen- dation for primary prevention of all-cause mortality in patients with symptomatic systolic heart failure, with no differentiation between patients with ischaemic and nonischaemic aetiology. European guidelines carry a class IB recommendation specifi- cally for patients with nonischaemic heart failure. Dr Kober concluded, “Guidelines are based on multiple stud- ies. Implantable cardioverter-defibrillator treatment should still carry a class 1A recommendation for prevention of sudden cardiac death in nonischaemic heart failure also. Patients at high risk of non-sudden death, however, may not benefit, and age should be an important factor in the decision to implant the device, along with comorbidities.”

Patients at high risk of non-sudden death ... may not benefit, and age should be an important factor in the decision to implant the device, along with comorbidities.

combining cardiac resynchronisation therapy and implantable cardioverter-defibrillator in the implantable cardioverter- defibrillator arm. After a median of 67.6 months, the primary outcome of death from all causes occurred in 21.6% of implantable cardioverter- defibrillator patients and 23.4% of controls, a nonsignificant difference. Sudden death, a secondary outcome, occurred in 4.3% of implantable cardioverter-defibrillator patients and was almost doubled (8.2%) in the control group (hazard ratio 0.50; 95% confidence interval 0.31 to 0.82; P = 0.01). Results were independent of whether or not a patient received a cardiac resynchronisation device, but an important interaction with age was observed. Dr Kober said, “Patients younger than 68 years of age had a significant reduction in all-cause mortality if they received an implantable cardioverter-defibrillator (hazard ratio 0.64; 95% confidence interval 0.45 to 0.90, P = 0.01), suggesting

PRACTICEUPDATE CARDIOLOGY

ESC 2016

Given the level of risk of cardiovascular disease attributed to obstructive sleep apnoea in previous observational studies, wewere surprised not to find a benefit fromCPAP treatment. >5

Any intervention that reduces myocardial infarct size by approximately a thirdmight reasonably be expected to substantially improve long-term outcomes. >6

Findings suggest that lipoprotein apheresis provides significant clinical benefit to patients with refractory angina in the context of raised lipoprotein(a). The outcome represents amuch needed novel treatment option for this therapeutically challenging patient cohort. >8

Direct catheter-based thrombectomy is as effective as bridging thrombolysis in ischaemic stroke

Direct catheter-based thrombectomy is equally effective as thrombolysis in the treatment of acute ischaemic stroke, according to results from the prospective, observational, pilot PRAGUE-16 registry study. P etr Widimsky, MD, of Charles University, Prague, Czech Republic, explained, “If left untreated, acute ischaemic stroke caused by a major artery occlusion results in death PRAGUE-16 included 103 patients who presented within 6 h from the onset of moderate to severe acute ischaemic stroke. Patients had an occluded major cerebral artery but no large ischaemia yet on a CT scan. The attending neurologist decided whether patients received direct catheter-based thrombectomy or bridging thrombolysis + catheter-based thrombectomy based on the clinical picture and CT scan. The intervention was performed within 60 minutes of the CT scan.

for up to half of patients and an additional 40% to 50% are left permanently disabled. In other words, without treatment, only a few patients with major ischaemic stroke survive without severe sequelae.” Functionally independent survival (defined as a modified Rankin Scale score of 0–2) after these major strokes increases to approximately 20% to 30% with thrombolytic treatment in specialised stroke units. The majority of patients, however, still die or remain permanently disabled. In 2015 several randomised trials demonstrated that 45% to 50% of patients can survive and be functionally independent with catheter-based (endovascular) mechanical thrombectomy. If the intervention is performed very early (within 3 h of stroke onset), results are even better – up to 70% of patients may return to normal daily life. Thus, catheter-based mechanical thrombectomy is now recommended for all patients with acute ischaemic stroke caused by a major artery occlusion. Many questions remain, however. Dr Widimsky and col- leagues investigated two of them. First, they set out to deter- mine whether direct (without thrombolysis) cathether-based thrombectomy can achieve comparable results to thrombec- tomy performed after intravenous (“bridging”) thrombolysis. Second, they determined whether catheter-based thrombec- tomy performed in interventional cardiology departments (when no interventional neuroradiology department is available) can achieve results comparable to neuroradiology settings. Dr Widimsky said, “The study aim was to evaluate the feasibility and safety of direct catheter-based thrombectomy performed in close cooperation between cardiologists, neurolo- gists, and radiologists – a true interdisciplinary approach.”

Approximately 73 patients received direct catheter-based thrombectomy and 30, bridging thrombolysis + catheter-based thrombectomy. Good functional outcome (defined as a modi- fied Rankin Scale score of 0–2 after 90 days) was achieved in 41% patients overall with similar results between the two groups. “In our study, 41% of patients who received direct catheter- based thrombectomy had good functional recovery. This compares to 48% of patients given this intervention in seven randomised trials performed in expert neuroradiology units. Our outcomes, however, were significantly better than trials in which patients received medical therapy (intravenous throm- bolysis) alone, of whom only 30% recovered,” Dr Widimsky said. “Our findings suggest that direct catheter-based thrombec- tomy performed in a timely manner may be an alternative to thrombectomy after bridging thrombolysis. Furthermore, in regions with no (or limited) interventional neuroradiology services, modern stroke treatment might be offered via inter- ventional cardiology services in close cooperation with neurolo- gists and radiologists. Both of these preliminary conclusions, however, should be confirmed by larger multicentre studies or large international registries.”

CPAP is shown to improve wellbeing but not cardiovascular outcomes More than 3 years of nightly treatment with a continuous positive airway pressure (CPAP) machine did not reduce cardiovascular risk more than usual care among patients with cardiovascular disease and obstructive sleep apnoea, reports the Sleep Apnea Cardiovascular Endpoints (SAVE) study. D oug McEvoy, MD, of Flinders University, Adelaide, Australia, explained, “Given the level of risk of cardio- vascular disease attributed to obstructive sleep apnoea in previous observational studies, we were surprised not to find a benefit from CPAP treatment.” apnoea. A total of 2717 individuals were randomised to receive usual care alone or usual care plus CPAP. hypothesised level of effect on cardiovascular outcomes.” Importantly, however, CPAP did improve participant well- being, defined by symptoms of daytime sleepiness, health- related quality of life, mood (particularly depressive symptoms), and attendance at work.

Forty-two percent of patients assigned to CPAP achieved good adherence (an average of 4 or more hours per night). Mean apnoea–hypopnoea index (a measure of obstructive sleep apnoea severity) decreased from 29.0 to 3.7 events per hour when patients used CPAP, indicating good control of their obstructive sleep apnoea. After a mean of 3.7 years for 1341 usual care and 1346 CPAP patients included in the final analysis, however, no dif- ference between groups was observed in the primary outcome, a composite of death from any cardiovascular cause, myocardial infarction or stroke, and hospitalisation for heart failure, acute coronary syndrome, or transient ischaemic attack. Specifically, 17.0% of patients in the CPAP group and 15.4% in usual care experienced a serious cardiovascular event. Dr McEvoy said, “It’s not clear why CPAP treatment did not improve cardiovascular outcomes. It is possible that, even though the average CPAP adherence of approximately 3.3 h per night was as expected, and more than we estimated in our power calculations, it was still insufficient to show the

Dr McEvoy said, “While it is disappointing not to find a reduction in cardiovascular events with CPAP, our results showed that treatment of obstructive sleep apnoea in patients with cardiovascular disease is nevertheless worthwhile. They were much less sleepy and depressed, and their productivity and quality of life was enhanced.” He added, “More research is needed on how to reduce the significant risk of cardiovascular events in people who suffer from sleep apnoea. Given our finding of a possible reduction in cerebrovascular events in patients who were able to use CPAP for more than 4 h per night, and prior studies showing a stronger association between obstructive sleep apnoea and stroke than between obstructive sleep apnoea and coronary artery disease, future trials should consider targeting patients with obstructive sleep apnoea and stroke who can achieve a high level of CPAP compliance.”

The SAVE study recruited sleep apnoea patients with moderate-to- severe disease from 89 clinical centres in seven countries. Participants were predominantly elderly (approxi- mately 61 years), overweight, habitually snoring males, and all had coronary artery or cerebrovascular disease. Participants had to achieve a minimum 3 h of sham-CPAP adherence per night in a 1-week run-in before the study started. Usual care included concomitant cardiovascular risk manage- ment, based on national guidelines, as well as advice on healthy sleep habits and lifestyle changes to minimise obstructive sleep Future trials should consider targeting patients with obstructive sleep apnoea and stroke who can achieve a high level of CPAP compliance.

VOL. 1 • No. 2 • 2016

CONFERENCE COVERAGE

ESC 2016

Two trials of stem cells fail to meet primary endpoints but improve health status Two trials of regenerative therapy for heart failure failed to meet their primary endpoints but brought clinically relevant benefits.

N-acetylcysteine reduces post-MI infarct size by a third

Trial 1: A phase 2, randomised, single-blind, placebo-controlled, crossover, multicentre study Javed Butler MD, of The State Univer- sity of New York at Stony Brook, reported on the first trial. He and a colleague de- livered a single dose of mesenchymal stem cells intravenously to patients with chronic nonischaemic cardiomyopathy. Significant cardiac structural or functional improvement did not occur but several clinically relevant benefits were observed. Dr Butler said the trial “demonstrated that a more convenient and less invasive infusion strategy is safe, well-tolerated and shows improvements in multiple measurements of patient health status.” Previous work in this field has focused almost exclusively on the more invasive approach of injecting stem cells directly into the heart. Dr Butler and his colleague used “is- chaemia tolerant” mesenchymal stem grown under chronic hypoxic conditions, with the aim of enhancing their potential benefits. He explained, “The premise was that stem cells may exert immune modulatory properties, which are enhanced when grown under hypoxic conditions.” This potential immune modulation and anti- inflammatory effect also opens the door to new methods of delivery. “Virtually all studies of stem cell therapy for heart failure have centred on the con- cept that the cells must be injected di- rectly into the heart to trigger new growth, but if stem cells yield anti-inflammatory benefits, direct cardiac delivery may not be necessary to repair and stimulate the dysfunctional viable myocardium.” Patients with nonischaemic cardiomyo- pathy and left ventricular ejection fraction ≤ 40% were randomised to intravenous ischaemia-tolerant mesenchymal stem cell therapy (n=10) or placebo (n=12) for 90 days and then crossed over to the other treatment. Stem cells were donated

(clinical summary score +5.22, P = 0.02, and functional status scores +5.65, P = 0.06) at 90-days post infusion. Additionally, ischaemia-tolerant mes- enchymal stem cell infusion resulted in significant alterations in several inflamma- tory cells, “supporting the immunomodu- latory and anti-inflammatory mechanisms of ischaemia-tolerant mesenchymal stem cells,” noted Dr Butler. Dr Butler concluded, “To our knowl- edge, this trial represents the first expe- rience with intravenously administered ischaemia-tolerant mesenchymal stem cells in patients with any type of chronic cardiomyopathy. Further studies should explore the efficacy of serial dosing to produce more sustained immunomodula- tory effects and thereby perhaps facilitate improvement in left ventricular structure and function, and in clinical outcomes.” Trial 2: CHART-1, the largest cardiac regenerative therapy trial to date Jozef Bartunek, MD, PhD, of OLV Hos- pital, Aalst, Belgium, presented results of the Congestive Heart failure cardiopoi- etic Regenerative Therapy (CHART-1). This trial used bone-marrow stem cells to promote heart repair. The cells did not significantly improve the primary outcome over a sham procedure among patients with congestive heart failure, but results revealed critical new insights. Dr Bartunek explained that thought results were neutral in the overall patient population, an exploratory analysis iden- tified a subgroup of patients who may benefit from cardiopoietic cell therapy. “Within a well-defined patient population, based on baseline heart failure severity, this therapy showed benefit,” he said. “Lessons learned from CHART-1 will now provide the foundation for the design of the ensu- ing CHART-2 trial, which will target these patients.” Cardiopoietic cell therapy involves the isolation of mesenchymal stem cells from

a patient’s own bone marrow. Exposing these cells to a “cardiogenic cocktail” turns them into cardiopoietic cells, which are then injected into damaged heart tissue. The CHART-1 study randomised pa- tients with symptomatic ischaemic heart failure from 39 hospital centres in Europe and Israel. Patients received either a sham procedure (n=151) or cardiopoietic cells (n=120). At 39 weeks, no significant difference between groups was observed for the primary efficacy endpoint, a composite of all-cause mortality, worsening heart failure events, Minnesota Living withHeart Failure Questionnaire total score, 6-minute walk distance, and left ventricular end-systolic volume and ejection fraction. A subgroup analysis of patients with se- vere heart enlargement at baseline (left ven- tricular end-diastolic volumes between 200 and 370 mL), however, suggested a positive effect of the cell treatment over sham. Dr Bartunek concluded, “Outcomes for all components of the composite endpoint, including mortality and worsening heart failure, were ‘directionally consistent.’” He, added that “the effect was also related to clinically meaningful improved quality of life, greater 6-minute walk distance, and reduced left ventricular end-systolic volume for cell treatment vs sham.” “We observed a modifying effect of treatment intensity, with suggestion of a greater benefit with a lower number of injections. Overall safety was demon- strated across the study cohort, with no difference in adverse clinical outcomes observed between groups.” Ongoing analyses will evaluate 12-month clinical outcomes. Dr Bartunek said, “Insights from the CHART-1 trial carry implications for targeting the patient population that should be considered for cardiopoietic cell therapy in future clini- cal trials or for broader clinical consid- erations. More generally, indexes of heart failure severity and optimised therapeutic intensity should be considered.”

The addition of intravenous N-acetyl- cysteine to intravenous glyceryl trinitrate reduced infarct size by approximately one third in patients undergoing percutaneous coronary intervention after ST-segment el- evation acute myocardial infarction. This outcome of N-AcetylCysteine In Acute Myocardial infarction (NACIAM), a placebo- controlled, double-blind trial, was reported at the 2016 ESC Congress. S ivabaskari Pasupathy, BS, of the University of Ad- elaide, Australia, explained, “Timely and effective myocardial reperfusion by percutaneous coronary intervention is the treatment of choice for limiting my- ocardial infarct size and improving clinical outcomes in patients presenting with ST-segment elevation acute myocardial infarction, additional pharmacological in- terventions may help reduce infarct size further. Any intervention that reduces myocardial infarct size by approximately a third might reasonably be expected to substantially improve long-term outcomes.” NACIAM included 112 patients with ST-segment elevation acute myocardial infarction (mean age 64 years) from three Australian hospitals. All underwent emergency percutaneous coronary intervention and received low dose intravenous glyceryl trinitrate. They were randomised before the percutaneous coronary intervention to receive either high-dose (15 g/24 h) N-acetylcysteine or placebo, both deliv- ered intravenously over 48 h, “the hypothesis being that N-acetylcysteine might reduce infarct size, ei- ther by potentiating the effects of glyceryl trinitrate or via ‘scavenging’ of reactive oxygen species,” said Ms Pasupathy. Cardiac magnetic resonance imaging performed within 1 week (early) and again 3 months post myo- cardial infarction (late) showed that patients who received N-acetylcysteine experienced reductions in infarct size of 33% and 50%, respectively, compared to placebo (P = 0.02 for both). A similar but not signifi- cant trend toward reduction in creatine kinase release was observed. Additionally, myocardial salvage, measured at 1 week, approximately doubled in patients who re-

by a health volunteer and grown under hypoxic conditions from the moment of extraction. At 90-days post infusion, no major differences in primary safety endpoints of all-cause mortality, all-cause hospitalisa- tion, and adverse events were observed. Secondary endpoints of car- diac remodelling (left ventricular ejection fraction and ventricular volumes), assessed by cardiac magnetic resonance imaging, did not differ between groups at 90-days. Ischaemia-tolerant mesenchymal stem cell adminis- tration did result in the second- ary endpoints of better health status and functional capacity, however. Specifically, compared with placebo, ischaemia-tolerant mesenchymal stem cell therapy resulted in statistically signifi- cant improvements in 6-min- ute walk test (an estimated 36 m more than placebo, P = 0.02) and Kansas City Cardio- myopathy Questionnaire scores

ceived N-acetylcysteine (60% vs 27%, P < 0.001). Evidence of ac- celerated tissue reperfusion and hypochlorous acid “scavenging” was also observed. Over 2 years of follow-up, the combination of car- diac readmissions and deaths was less frequent in N-acetylcysteine- treated (three vs 16 patients, P < 0.01). Safety endpoints including hy- potension, bleeding, and contrast- induced nephropathy were similar in both groups. Ms Pasupathy concluded, “In- travenous N-acetylcysteine ad- ministration was associated with more rapid chest pain resolution, improved myocardial salvage, a fa- vourable in-hospital safety profile, sustained infarct size reduction at 3 months post ST-segment eleva- tion acute myocardial infarction, and promising clinical outcomes at 2 years. While the results were encouraging, NACIAM should be regarded as the precursor to a follow-up study sufficiently sized to meet clinical endpoints.”

PRACTICEUPDATE CARDIOLOGY

CONFERENCE COVERAGE

ESC 2016

Lipoprotein(a) apheresis proves beneficial in refractory angina Lipoprotein apheresis, a therapy normally used to fil- ter excess cholesterol from the blood of patients with fa- milial hypercholesterolemia, may play a role in patients with refractory angina, reports a prospective, ran- domised, sham-controlled, blinded, crossover study. T ina Khan, MRCP, of Impe- rial College, London, UK, explained that the extracorpor- eal treatment resulted in significant improvement over sham therapy in patients with refractory angina and raised levels of lipoprotein(a). Lipoprotein(a) is similar in structure to low density lipoprotein cholesterol, except for an additional, attached protein-apolipoprotein(a). Raised lipoprotein(a) is a strong risk factor for coronary heart disease and may be prevalent in patients with refractory angina. with cardiac magnetic resonance imaging, was myocardial perfusion reserve, which is the ratio of myocar- dial blood flow at stress vs rest after 3 months of lipoprotein apheresis, compared to baseline.

• Angina frequency score (mean change of 35.0 vs –5.0) • Quality of life score (mean change of 25.8 vs 4.6) In the fifth domain, SeattleAngina Questionnaire treatment satisfac- tion score improved slightly, by 6.25, during apheresis vs 0.0 or no change during sham administration. Simi- larly, physical component scores of quality of life assessed by the Short Form-36 Questionnaire also im- proved significantly after apheresis but not sham administration. Dr Khan concluded, “Our study was the first randomised controlled trial to assess the impact of lipopro- tein apheresis in patients with refrac- tory angina and raised lipoprotein(a), in the absence of significantly raised low density lipoprotein cholesterol. “Findings suggest that lipopro- tein apheresis provides significant clinical benefit to patients with refractory angina in the context of raised lipoprotein(a). The outcome represents a much needed novel treatment option for this therapeu- tically challenging patient cohort.”

A significant increase of 0.63 in myocardial perfusion reserve was observed after apheresis treatment vs sham (P < 0.001). Specifically, myocardial perfusion reserve in- creased from 1.45 to 1.93 with apheresis, and did not change sig- nificantly after sham. Secondary endpoints of carotid wall volume and distensibility also improved after apheresis, as did exercise capacity, symptoms of angina, and quality of life scores. These parameters did not improve after sham. Significant symptom improve- ment was observed after apheresis but not after sham in four of five domains in the SeattleAngina Ques- tionnaire, including: • Physical limitation score (median change of 27.8 vs –4.2) • Angina stability score (mean change of 17.5 vs –3.75)

“Angina refractory to both medical therapy and revascularisation is a de- bilitating condition that is increasing in frequency, and there is a pressing need for novel treatments for these patients. Such patients continue to suffer with troublesome angina despite optimal medical therapy, as well as surgical and/or percutaneous coronary revascularisation. Treat- ment options are limited,” she said. “Our trial provided the first evidence that lipoprotein apheresis leads to improvement among these patients in the primary endpoint of myocardial blood flow, as measured by myocardial perfusion reserve, as well as the secondary endpoints of exercise capacity, angina symptoms, quality of life, and atheroma burden. This treatment approach could im- prove the cardiac health and lives of such patients.”

Studies suggest that elevated lipoprotein(a) may promote ath- erosclerosis and reduce myocardial perfusion, but no effective pharma- cologic treatment is yet approved to treat elevated lipoprotein(a). Elevat- ed lipoprotein(a) is essentially resist- ant to conventional lipid-lowering treatment with statins. Dr Khan and colleagues have now shown that lipoprotein(a) can effectively be lowered with lipoprotein apheresis. The apheresis study included 20 patients with refractory angina and elevated lipoprotein(a) levels above 500 mg/L. Patients were randomised to weekly lipoprotein apheresis or a sham procedure for 3 months, then crossed over for another 3 months, with a 1-month washout period be- tween the two. The primary outcome, measured

Functional imaging for suspected CHD can help avoid angiography Initial investigation of patients with suspected coronary heart disease using functional imaging rather than guideline-directed care resulted in significantly less unnecessary angiography, outcome of the Clinical Evaluation of MAgnetic Resonance imaging in Coronary heart disease 2 (CE-MARC 2) study shows.

J ohn Greenwood, PhD, of the University of Leeds, UK, said that the findings could exert an important impact on referral rates for invasive coronary angiography, and potentially healthcare costs. “Rates of invasive angiography are considered too high among patients with suspected coronary heart disease,” he said. “Our findings show that both cardiovascular magnetic resonance and myocardial perfusion scintigraphy significantly reduced rates of unnecessary angiography compared to guideline-directed care, with no penalty in terms of major adverse cardiovascular events. This suggests that functional imaging should be adopted on a wider basis, even in high-risk patient subgroups.” CE-MARC 2 included 1202 patients with suspected coronary heart disease from six UK centres. Patients were randomised to functional imaging-based investigation with

coronary angiography, with secondary endpoints of major ad- verse cardiovascular events, and positive angiography within this same time period. Twenty-two percent of the study population underwent coronary angiography within 12 months, with unnecessary angiography performed in 28.8% of the NICE guidelines group, 7.5% of the cardiovascular magnetic resonance group, and 7.1% of the myocardial perfusion scintigraphy group. The adjusted odds ratio of unnecessary angiography for the cardiovascular magnetic resonance group vs the NICE guide- lines group was 0.21 (95% confidence interval 0.12–0.34; P < 0.001), with no statistically significant difference between the cardiovascular magnetic resonance and myocardial perfusion scintigraphy groups. Among the three strategies, there was no difference in short- term major adverse cardiovascular events or posi- tive angiography rates.

either cardiovascular magnetic resonance (n=481), myocardial perfusion scintigraphy (n=481), or guideline-directed inves- tigation (n=240) based on National Institute for Health and Care Excellence (NICE) guidelines. In the latter group, those with a pre-test likelihood of 10–29% (low risk for coronary heart disease based on age, gender, symptom characteristics, and clinical history) were scheduled for cardiac computed tomography. Those with a pre-test likelihood of 30% to 60% (intermediate risk) were scheduled for myocardial perfusion scintigraphy, and those with a high pre-test likelihood were sent directly to coronary angiography. The primary endpoint was unnecessary coronary angiogra- phy within 12 months, defined by the absence of significant stenosis as measured by fractional flow reserve or quantitative

Dr Greenwood noted, “Worldwide, myocardial perfusion scintigraphy is the most commonly used test to assess suspected coronary heart disease, but cardiovascular magnetic resonance is increasingly recognised as conferring high di- agnostic accuracy and prognostic value. Though the results of CE-MARC 2 showed no difference between the cardiovascular magnetic resonance and myocardial perfusion scintigraphy strate- gies in terms of unnecessary angiography rates, our original, 2012 CE-MARC study showed that cardiovascular magnetic resonance yielded higher diagnostic accuracy than myocardial per- fusion scintigraphy, and, as published in 2016, as a stronger predictor of risk of major adverse cardiovascular events.” Dr Greenwood concluded, “These results show that broader use of functional imaging (cardiovas- cular magnetic resonance or myocardial perfusion scintigraphy), in low-, intermediate-, and high-risk patient groups, could reduce rates of invasive angiography that ultimately shows no obstructive coronary disease. In addition, CE-MARC and CE- MARC 2 further support cardiovascular magnetic resonance as an alternative to myocardial perfusion scintigraphy for the diagnosis and management of patients with suspected coronary heart disease.”

PRACTICEUPDATE CARDIOLOGY

CORONARY HEART DISEASE

Benefits of omega-3 fatty acids from fish oil after acute MI: an off and on affair? Comment by Paul Thompson, MD I was pleasantly surprised by the

death via a fish oil effect on cardiac arrhythmia. Subsequent studies were less supportive of a beneficial effect of fish oil on cardiac arrhyth- mias and on AMI treatment in general. The OMEGA-REMODEL trial suggests that concentrated fish oil may have a beneficial effect on cardiac remodelling, and it offers a different possibility for GISSI’s success. OMEGA-REMODEL is a relatively small study, but well- designed and well-performed and suggests that cardiology’s affair with fish oil may be on again. So what are clinicians to do? This study was well-done, but it is premature to translate these promising results directly into patient care. We do not yet know whether these putative improve- ments in myocardial function and

fibrosis from concentrated fish oil, 4 gm daily, will have clinical significance. A larger, clinical out- comes study will be required before concentrated fish becomes standard of care. Some patients may learn of these results and start themselves on fish oil. Clinicians and such pa- tients should be aware that the fish oil preparation used in this study was highly concentrated, similar to the brand compound Omacor. Over-the-counter fish oil capsules have approximately one-third of the omega-3 fatty acids available in the concentrated products; so, over-the- counter fish oil would not provide the dose used in this study without taking 12 tablets daily.

change in non-infarct myocardial fibrosis (r = 0.65; P < 0.0001). The authors speculated that the omega-3 fatty acids decreased inflammation in the non-infarcted myocardium, thereby preserving LV function. Modern cardiology has had an on/off affair with concentrated fish oil. The GISSI, or Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico, study as- signed 11,324 AMI patients to 1 gm daily of omega-3 fatty acids or placebo in an open-label design. The patients receiving fish oil had a 20% reduction in mortality, which many attributed to a reduction in sudden

recently released results of the Omega-3 Acid Ethyl Esters on Left Ventricular Remodeling After Acute Myocardial Infarction, or OMEGA-REMODEL trial. The study randomised patients with documented acute myocardial in- farction (AMI) treated by acute an- gioplasty to either placebo (n=178) or 4 gm daily of concentrated fish oil using tablets containing ≈ 465 mg of ethyl esters of eicosapentae- noic acid (EPA) and ≈ 375 mg of docosahexaenoic acid (DHA). The placebo contained corn oil with ≈ 600 mg linoleic acid, no omega-3 fatty acids, and <0.05% of trans-fatty acids. Participants started treatment 14 to 28 days after their AMI and were treated for 6 months. Cardiac magnetic resonance imaging (cMRI) was performed at baseline and at 6 months to measure cardiac function and structure. Studies were read by blinded readers. There was high adherence to guideline-based treat- ment for AMI. Patients treated with the concen- trated fish oil had a 5.8% decrease in their left ventricular systolic volume index (LVSVI; P = 0.017) and 5.6% less fibrosis in their non- infarcted myocardium. Those with the greatest increase in red blood cell omega-3 fatty acid concentra- tion had the greatest decrease in LVSVI, demonstrating a dose effect of treatment. Omega-3 treatment was associated with decreases in the inflammatory markers myelop- eroxidase and lipoprotein-associated phospholipase A2 (Lp-PLA2) as well as decreases in ST2, a marker of myocardial fibrosis. The decrease in ST2 correlated directly with the

Dr Thompson is Chief of Cardiology, Hartford Hospital, Connecticut.

Effect of omega-3 acid ethyl esters on left ventricular remodeling after acute myocardial infarction: the OMEGA-REMODEL randomised clinical trial Circulation Take-home message • In this multicentre, double-blind trial, patients who suffered an acute MI were randomly assigned to 6 months of high-dose omega-3 fatty acids (n=180) or placebo (n=178). Significant reductions in left ventricular systolic volume index (−5.8%l; P = 0.017), non-infarct myocardial fibrosis (−5.6%; P = 0.026), and serum biomarkers of inflammation and myocardial fibrosis were observed in the omega-3 fatty acids group compared with the placebo group. In addition, increases in red blood cell omega-3 fatty acid correlated with decreases in left ventricular systolic volume index. • Following acute MI, high-dose omega-3 fatty acids had a beneficial effect on left ventricular remodeling, non-infarct myocardial fibrosis, and biomarkers of inflammation beyond standard-of-care therapy. Abstract

ventricular systolic volume index (–5.8%, P=0.017), and noninfarct myocardial fibrosis (–5.6%, P=0.026) in comparisonwith placebo. Per-protocol analysis revealed that those patients who achieved the highest quartile increase in red blood cell omega-3 index experienced a 13% reduction in left ventricular systolic volume index in comparisonwith the lowest quartile. In addition, patients in the omega-3 fatty acid arm underwent significant reductions in serumbiomarkers of systemic and vascular inflammation and myocardial fibrosis. There were no adverse events associated with highdose omega-3 fatty acid therapy. CONCLUSIONS Treatment of patients with acute myocardial infarction with high-dose omega-3 fatty acids was associated with reduction of adverse left ventricular remodeling, noninfarct myocardial fibrosis, and serum biomarkers of systemic inflam- mation beyond current guidelinebased standard of care. Circulation 2016;134:378-391, Heydari B, Abdullah S, Pottala JV, et al.

BACKGROUND Omega-3 fatty acids from fish oil have been associated with beneficial cardiovascular effects, but their role in modifying cardiac structures and tissue characteristics in patients who have had an acute myocardial infarction while receiving current guideline-based therapy remains unknown. METHODS In a multicenter, double-blind, placebo-controlled trial, participants presentingwith an acutemyocardial infarction were randomly assigned 1:1 to 6 months of high-dose omega-3 fatty acids (n=180) or placebo (n=178). Cardiac magnetic resonance imaging was used to assess cardiac structure and tissue char- acteristics at baseline and after study therapy. The primary study endpoint was change in left ventricular systolic volume index. Secondary endpoints included change in noninfarct myocardial fibrosis, left ventricular ejection fraction, and infarct size. RESULTS By intention-to-treat analysis, patients randomly assigned to omega-3 fatty acids experienced a significant reduction of left

Weekend admissions for non-STEMI associated with higher rates of inhospital mortality and lower rates of coronary angiography Comment by Shaista Malik, MD, PhD, MPH T he paper by Agarwal et al comparing in-hospital mortal- ity and frequency of coronary does not impact outcomes when it comes to STEMI due to concerted efforts to make medical care uniform in time-sensitive acute illnesses.

papers have found that significant differences in outcomes between weekend and weekday admission had largely dissipated, but many did not look at contemporary or large representative samples of the national inpatient population, and many didn’t examine NSTEMI and STEMI separately. Previous studies have shown that the day of the week

for utilisation of early invasive strat- egy. These results suggest that a targeted approach to improving pro- cesses of care in NSTEMI, as has been done in the past for STEMI, can have a significant impact on de- creasing mortality in these patients needing time-sensitive treatment. Uniformity in use of an early in- vasive approach and adherence to guidelines, regardless of day of the week, may ensure better quality of care and improved outcomes in patients admitted with NSTEMI.

angiography on weekend versus weekday admissions in patients with non-ST-segment elevation myocar- dial infarction (NSTEMI) shows that higher mortality on weekends may be explained by decreased use of an early invasive approach. Previous

Agarwal et al have shown in a large representative sample (3,625,271) that those admitted with NSTEMI have 2% higher odds of mortality if admitted over the weekend, and this disparity dissipates when adjusted

Comparison of inhospital mortality and frequency of coronary angiography on weekend versus weekday admissions in patients with non-ST-segment elevation acute myocardial infarction Abstract

Dr Malik is Associate Professor of Medicine,

significant after adjustment for differences in rates of utilization of EIS (OR 1.01; 95% CI 0.99 to 1.03; P = 0.11). In conclusion, this study demonstrates that among patients admittedwith a diagnosis of an acute NSTEMI, admission on aweekendwas associatedwith higher inhospital mor- tality compared with admission on a weekday and that lower rates of utilization of EIS contributed significantly to this disparity. Am J Cardiol 2016;118:632-634, Agrawal S, Garg L, Sharma A, et al.

A total of 3,625,271 NSTEMI admissions were identified, of which 909,103 (25.1%) were weekend and 2,716,168 (74.9%) wereweekday admissions. Admission on aweek- end versus weekday was independently associatedwith lower rates of coronary angiography (odds ratio [OR] 0.88; 95% confidence interval [CI] 0.89 to 0.90; P < 0.001) or utilization of an early invasive strategy (EIS) (OR 0.480; 95% CI 0.47 to 0.48; P < 0.001). Unadjusted inhospital mortality was significantly higher for the cohort of patients admitted on weekends (adjusted OR 1.02; 95% CI 1.01 to 1.04; P < 0.001). However, this disparity was no longer

Patients withmyocardial infarction admitted onweekends have been reported to less frequently undergo invasive angiography and experience poorer outcomes. We used theNationwide Inpatient Sample database (2003 to 2011) to compare differences in all-cause inhospital mortality between patients admitted on a weekend versus week- day for an acute non-ST-segment elevation myocardial infarction (NSTEMI) and to determine if rates and timing of coronary revascularization contributed to this difference.

Director, Susan Samueli Center of Integrative Medicine, Medical Director, Preventive Cardiology and Cardiac Rehab Director, Women’s Heart Program, University of California.

VOL. 1 • No. 2 • 2016

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