PracticeUpdate: Cardiology

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Volume 1 | Number 3 | 2016

VOL. 1 • No. 3 • 2016 ISSN 2206-4672

RESEARCH NEWS AND VIEWS FROM ELSEVIER

OPINIONS

AHA 2016’s superstars:

In GLAGOV, with the remarkable lipid lowering enabled by the combination of statin and anti- PCSK9 antibodies, we may be wringing as much “milk out of the stone” as we can by lessening lipid accumulation in the atheroma.

FUTURE, EUCLID, ART, PRECISION and GLAGOV Find out why they are practice-changers.

The findings not only add context

to knowledge of antiplatelet

monotherapy after revascularisation for peripheral artery disease, but they also highlight the need formore trials of antithrombotic agents after revascularisation. FUTUREmay cast some uncertainty on the future of the use of FFR in clinical practice. Further data are needed on the impact on decision making and how this 8 In the PRECISION post-hoc analyses of any CV, GI, or renal event, celecoxib had the lowest risk, naproxen had intermediate risk and ibuprofen the highest risk. These findings are striking as they grant absolution to a drug condemned in the cardiovascular community. 9 could be linked to adverse outcomes. 9

Special feature. 4–10

Association of systolic blood pressure variability with mortality, coronary heart disease, stroke, and renal disease Journal of the American College of Cardiology Results showed that the higher the variability (measured in standard deviation quartiles), the greater the association with all-cause mortality, CHD, stroke, and ERSD.

Coupling data mining and laboratory experiments to discover drug interactions causing QT prolongation Journal of the American College of Cardiology The use of data combined with laboratory experiments can identify QT-DDIs. There is a significantly increased risk of a prolonged QT interval in patients taking ceftriaxone and lansoprazole in combination.

Retinal vessel calibers in predicting long-term cardiovascular outcomes: the Atherosclerosis Risk in Communities Study Circulation This study validates the incremental benefit of retinal vessel caliber measurement for evaluating risk for ischemic stroke and death in the general population. It appears to be of particular value in predicting risk of coronary heart disease in women classified as low- risk by the 2013 PCE. 14

Life expectancy after myocardial infarction, according to hospital performance The New England Journal of Medicine Patients treated in high-performing hospitals following myocardial infarction have an extended life expectancy, consistent with a lower 30-day risk-standardized mortality rate, when compared with patients treated in low-performing hospitals.

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FEATURE ARTICLE

Reading our blueprints – nature’s lessons in pathophysiology found within our DNA Written by Allison B Goldfine MD and Alessandro Doria MD, PhD, MPH 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)

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

I n a study recently published in JAMA , Lotta and colleagues addressed this question by exploiting nature’s own experiments through a Mendelian randomisation study. 1 Specifically, LDL-lowering alleles in or near the HMGCR, NPC1L1, and PCSK9 gene encoding targets of LDL-lowering drugs (statins, ezetimibe, and PCSK9 inhibitors, respectively) and other LDL-C-related variants near the ABCG5/G8 and LDLR genes were used as proxies to assess whether associations between pharmacological LDL-C lowering and risk of diabetes is causal. In a meta-analysis of United States and European cohorts within large genetic association studies, each LDL-lowering variant was associated with a lower odds ratio for coronary artery disease, with similar effect sizes per 1 mmol/L (39 mg/ dL) reduction in LDL-C. However, consistent with the working hypothesis, variants in NPC1L1, and to a lesser extent HMGCR and PCSK9, were also significantly associated with an increased risk of diabetes. A nonsignificant trend toward a similar effect was also observed for ABCG5/G8 and LDLR. These findings agree with those by Swerdlow et al, who also found an association between HMGCR and increased risk of type 2 diabetes, and those by White et al, who described a similar diabetes-predisposing effect with a genetic risk score based on 130 LDL-C-associated SNPs. 2,3 Taken together, these studies provide strong support for LDL-C lowering contributing to development of diabetes. However, whether the culprit is LDL-C lowering, per se, or how this goal is achieved, remains unclear. Because not all the genes hosting variants associated with lower LDL-C showed statistically robust associations with diabetes in the study by Lotta et al, it is possible the molecule or metabolic function targeted by the LDL-C-lowering drug matters most for development of diabetes. 1 On the other hand, the

reductase inhibitors – statins – have profound beneficial effects on cardiovascular event rates but are also associated with a higher risk of incident type 2 diabetes. Whether this is attributable to low-density lipoprotein cholesterol (LDL-C) lowering, per se, or to direct or indirect off-target effects of statins remains poorly understood.

DISCLAIMER PracticeUpdate Cardiology provides highlights of key local and international conferences, timely and relevant news, expert opinions and journal article reviews for specialist medical professionals. Ideas and opinions expressed in this publication do not necessarily reflect those of the Publisher. Elsevier Australia will not assume responsibility for damages, loss, or claims of any kind arising from or related to the information contained in this publication, including any claims related to the products, drugs, or services mentioned herein. Please consult the full current Product Information before prescribing any medicationmentioned in this publication. For an annual print and/or digital subscription to PracticeUpdate Cardiology , email news.au@elsevier.com or visit www. elseviermedcomms.com.au To share your feedback with us, please email news.au@elsevier.com Conference news, expert opinions and journal article reviews are sourced from PracticeUpdate.com PracticeUpdate provides professional research, expert insights, and education resources in a single online destination. PracticeUpdate content is selected by medi- cal experts in cardiology for its relevance, timeliness, and importance. It is guided by world-renowned editorial and advisory boards that represent community practitioners and academic specialists with cross-disciplinary expertise. For in-depth insights that matter, discover PracticeUpdate.com today. ISSN 2206-4672

fact that an association with diabetes was demonstrated for a genetic score composed of variants inmany different genes involved in LDL-Cmetabolism supports amore diffused diabetogenic effect of LDL-C lowering. 3 Further studies are needed to settle this issue. It would be interesting to see whether the prediction of ezetimibe being diabetogenic based on the NPC1L1 genetic prediction, or if more potent LDL-C lowering with PCSK9 inhibitors can be confirmed in clinical practice. One caveat about theseMendelian randomisation findings is that most of the variants considered are in non-coding regions and could affect expression of additional genes that do not impact LDL-C metabolism but may nonetheless affect diabetes risk. Transcriptomic studies analysing the genome-wide impact of these variants in tissues relevant to diabetes could help address this concern. Using genetic markers as proxies of pharmacological interventions has intrinsic limitations. While genetic variants start acting at conception, lipid-lowering interventions are usually introduced later in life and for a few decades at most. Whether effects of lifelong exposures to genetic variants are representative of those associated with shorter exposure to LDL-C-lowering drugs remains to be determined. While thesefindingsmechanistically

support the diabetogenic potential of lipid-lowering drugs through LDL-C lowering, risk must always be interpreted alongside benefit. Although statins are associated with an approximate 9% increased risk of incident type 2 diabetes, the risk of death from any cause is reduced by 10% for each 1-mmol/L reduction in LDL-C with statins over a period of 4 years, and of similar magnitude in those with or without diabetes. 4,5 The net clinical benefit for people at moderate or high cardiovascular risk strongly favours LDL-C lowering. Thus, providers should continue to prescribe statins and other lipid-lowering therapy according to established guidelines to improve cardiovascular and total mortality in patients with established atherosclerotic disease or multiple risk factors. Nevertheless, recognising and confirming a direct role of LDL-C lowering with diabetes risk, as supported by this body of work, and subsequently understanding the potential mechanisms for which low LDL-C promotes diabetes may lead to new treatment or prevention approaches. References 1. Lotta LA, Sharp SJ, Burgess S, et al. JAMA 2016;316:1383-1391. 2. Swerdlow DI, Preiss D, Kuchenbaecker KB, et al. Lancet 2015;385:351-361. 3. White J, Swerdlow DI, Preiss D, et al. JAMA Cardiol 2016;1:692-699. 4. Sattar N, Preiss D, Murray HM, et al. Lancet 2010;375:735-742. 5. Cholesterol Treatment Trialists, Baigent C, Blackwell L, et al. Lancet 2010;376:1670-1681. Dr Goldfine is Associate Professor, Harvard Medical School, Co-Head, Section of Clinical Research, Joslin Diabetes Center in Boston, Massachusett. Dr Doria is Associate Professor in the Department of Epidemiology, Department of Epidemiology, Joslin Diabetes Center and Harvard Medical School in Boston.

New drugs and devices listing

THERAPEUTIC GOODS ADMINISTRATION (TGA) www.tga.gov.au Adalimumab (Humira) , Abbvie – uveitis Saxagliptin (Onglyza) , AstraZeneca - type 2 diabetes Saxagliptin/dapagliflozin (Qtern 5/10) , AstraZeneca – type 2 diabetes mellitus PHARMACEUTICAL BENEFITS SCHEME www.pbs.gov.au Armodafinil (Nuvigil) , Teva Pharma – narcolepsy, improve wakefulness Auranofin (Ridaura) , Amdipharma Mercury – rheumatoid arthritis Dexamethasone (Ozurdex) , Allergan – diabetic macular oedema

Imatinib (Imatinib-DRLA) , Dr Reddy’s Laboratories – chronic myeloid leukaemia, Ph+ acute lymphoblastic leukaemia, myelodysplastic/myeloproliferative diseases, aggressive systemic mastocytosis, hypereosinophilic syndrome, chronic eosinophilic leukaemia, dermatofibrosarcoma protuberans Ruxolitinib (Jakavi) , Novartis – disease-related splenomegaly or symptoms in myelofibrosis, polycythemia vera Please consult the full Product Information before prescribing.

Advertisers Novartis Entresto

6–7

VOL. 1 • No. 3 • 2016

CONFERENCE COVERAGE

American Heart Association Scientific Sessions 2016

12–16 NOVEMBER • NEW ORLEANS, USA This year’s American Heart Association Scientific Sessions brought together nearly 18,000 professional attendees who participated in lectures and discussions about basic, translational, clinical and population science. The PracticeUpdate Editorial Team brings you coverage of AHA 2016 fromNew Orleans, including key take-aways from Dr Peter Libby and Dr Joerg Herrmann. events in patients with type 2 diabetes, raised incidence of GI bleeds Over a median of 10 years, long-term therapy with low-dose aspirin did not affect cardiovas- cular events in Japanese patients with type 2 diabetes and without preexisting atherosclerotic cardiovascular disease. The therapy increased the hazard for gastrointestinal bleeding, reports the Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes (JPAD) trial. Y oshihiko Saito MD, PhD, of Nara Medical University, Nara, Japan, explained that long-term data on the efficacy and safety of low-dose aspirin for primary prevention of cardiovascular events in patients with type 2 diabetes remain inconclusive. Diabetes mellitus is a strong risk factor for cardiovascular events. Platelet activation plays a causative role in the develop- ment of cardiovascular events in the setting of type 2 diabetes in which platelet activation and aggregation are exaggerated. Guidelines published in the early 2000s recommended the use of low-dose aspirin for primary prevention in patients with diabetes over a certain age or in the presence of concomitant cardiovascular risk factors. This recommendation was largely based on results of randomised clinical trials that showed a positive effect of low-dose aspirin in healthy volunteers and patients with hypertension, and for secondary prevention in patients following myocardial infarction. In the early 2000s, however, little evidence directly supported low-dose aspirin for primary prevention of cardiovascular events in patients with diabetes. JPAD was a randomised, open-label, standard-care controlled trial examining whether low-dose aspirin affected cardiovas- cular events in 2539 Japanese patients with type 2 diabetes and without preexisting cardiovascular disease. Patients were randomised to aspirin (81 mg or 100 mg daily) or no aspirin. “At the end of the original JPAD trial,” Dr Saito said, Low-dose aspirin did not prevent CV

(85%) patients retained their original allocation. Low-dose as- pirin did not reduce cardiovascular events in the per-protocol cohort (hazard ratio 1.14; 95% CI 0.91–1.42). Multivariable Cox proportional hazard model adjusted for age, sex, glycaemic control, kidney function, smoking status, hypertension, and dyslipidaemia showed similar results (hazard ratio 1.04; 95% CI 0.83–1.30), with no heterogeneity of efficacy in subgroup analyses stratified by each of these factors. Sensitivity analyses on the intention-to-treat cohort yielded consistent results (hazard ratio 1.01; 95% CI 0.82–1.25). Gastrointestinal bleeding occurred in 25 (2%) patients in the aspirin group and 12 (0.9%) in the no-aspirin group (P = 0.03), though the incidence of haemorrhagic stroke did not differ between the two groups. Dr Saito concluded that, consistent with recent guidelines of the European Society of Cardiology, low-dose aspirin (81 or 100 mg once daily) did not help to prevent cardiovascular events, and increased risk for gastrointestinal bleeding in patients with type 2 diabetes in a primary prevention setting. Based on the absence of cardiovascular efficacy coupled with significantly increased gastrointestinal bleeding risk, low-dose aspirin is not recommended for Japanese patients with type 2 diabetes in the absence of prevalent atherosclerotic cardiovascular disease. Whether the findings apply to other patient populations is uncertain. International trials are underway to evaluate low- dose aspirin for primary cardiovascular prevention in patients with type 2 diabetes. “We hope to confirm,” said Dr Saito, “whether aspirin’s effect as observed in our study can be ap- plied to other populations, such as patients with hypertension, hyperlipidaemia, or chronic kidney disease, or healthy individu- als; or whether the dose of aspirin was adequate, especially in patients with type 2 diabetes.”

“low-dose aspirin had reduced cardiovascular events by about 20%, failing to reach statistically significance.” He continued, “If the reduction rate is maintained over the coming several years, the reduction will become statistically significant, but so far, the effect of aspirin has not been con- clusive. We decided to extend the follow-up period to 10 years to ascertain the true effect of low-dose aspirin in patients with type 2 diabetes and without preexisting cardiovascular disease.” After the trial ended in 2008, patients were followed until 2015, without changing the previously assigned therapy. Pri- mary endpoints were cardiovascular events, including sudden death, fatal or nonfatal coronary artery disease, fatal or nonfatal stroke, and peripheral vascular disease. For the safety analysis, haemorrhagic events, consisting of gastrointestinal bleeding, haemorrhagic stroke, and bleeding from any other sites, were also analysed. The primary analysis was conducted for cardiovascular events among patients who retained their original allocation (per-protocol cohort). Analyses on an intention-to-treat cohort were conducted for haemor- rhagic events and statistical sensitivity. The median follow-up period was 10.3 years. A total of 1621 (64%) patients were followed throughout the study, and 2160 We hope to confirm whether aspirin’s effect as observed in our study can be applied to other populations, such as patients with hypertension, hyperlipidaemia, or chronic kidney disease, or healthy individuals; or whether the dose of aspirin was adequate, especially in patients with type 2 diabetes.

PRACTICEUPDATE CARDIOLOGY

AHA 2016

Two treatment strategies of rivaroxaban reduce rehospitalisation in patients with AF undergoing intracoronary stenting In patients with atrial fibrillation who underwent intracoronary stenting, two rivaroxaban strategies reduced rehospitalisations potentially attributable to either bleeding or cardiovascular events. T his outcome of a study comparing rivaroxaban plus a P2Y12 inhibitor monotherapy or rivaroxaban plus dual antiplatelet therapy was reported at the AHA Scientific Sessions 2016. Michael Gibson, MS, MD, of Beth Israel Deaconess Medical Center, Boston, Massachusetts, explained that patients with atrial fibrillation who undergo intracoronary stenting traditionally are treated with a vitamin K antagonist plus dual antiplatelet therapy, though this treatment leads to high risk of bleeding. Dr Gibson and colleagues hypothesised that a regimen of rivaroxaban plus a P2Y12 inhibitor monotherapy or rivaroxaban plus dual antiplatelet therapy would reduce bleeding and exert a favourable impact on all-cause mortality and the need for rehospitalisation. Stented subjects with nonvalvular atrial fibrillation (n=2124) were randomised 1:1:1 to: • Group 1: reduced-dose rivaroxaban 15 mg daily plus a P2Y12 inhibitor for 12 months. • Group 2: rivaroxaban 2.5 mg twice daily with stratification to a prespecified duration of dual antiplatelet therapy of 1, 6, or 12 months. • Group 3: the reference arm of dose-adjusted vitamin K antagonist daily with similar dual antiplatelet therapy stratification. Post hoc analysis assessed the endpoint of all-cause mortality or recurrent hospitalisation for an adverse event, which was further classified as the result of bleeding, a cardiovascular, or another cause blinded to treatment assignment. The risk of all-cause mortality or recurrent hospitalisation was 34.9% in Group 1 (hazard ratio 0.79, 95% CI 0.66–0.94, P = 0.008 vs Group 3, number needed to treat 15); 31.9% in Group 2 (hazard ratio 0.75; 95% CI 0.62–0.90; P = 0.002 vs Group 3, number needed to treat 10); and 41.9% in Group 3 (vitamin K antagonist + dual antiplatelet therapy). Both all-cause death plus hospitalisation potentially resulting from bleeding (Group 1, 8.6% [P = 0.032 vs Group 3]; Group 2, 8.0% [P = 0.012 vs Group 3]; and Group 3, 12.4%); and all- cause death plus rehospitalisation potentially resulting from a cardiovascular cause (Group 1, 21.4% [P = 0.001 vs Group 3], Group 2, 21.7% [P = 0.011 vs Group 3]; and Group 3, 29.3%) were reduced in the rivaroxaban arms vs the vitamin K antagonist arm, but other forms of rehospitalisation were not. Dr Gibson concluded that among patients with atrial fibrillation undergoing intracoronary stenting, administration of either rivaroxaban 15 mg daily plus P2Y12 inhibitor monotherapy or 2.5 mg rivaroxaban twice daily plus dual antiplatelet therapy was associated with a reduced risk of all- cause mortality or recurrent hospitalisation for adverse events vs standard-of-care vitamin K antagonism plus dual antiplatelet therapy. grafting does not add further clinical benefit but may increase the risk of sternal wound complication especially in at risk populations. >9 In summary, adding onemore IMA graft to patients undergoing CABGwith LIMA

While ticagrelor was nomore effective in reducing risk than clopidogrel, we learned valuable information about this population, specifically, that patients with a history of lower extremity revascularisation are at higher risk of acute limb events and cardiovascular events. >8

With the remarkable lipid lowering enabled by the combination of statin and anti-PCSK9 antibodies, wemay be wringing asmuch “milk out of the stone” as we can by lessening lipid accumulation in the atheroma. >8

Reconstituted apolipoprotein A-I CSL112 enhances cholesterol efflux after acute MI The reconstituted, infusible, plasma-derived apolipoprotein A-I has been shown to enhance choles- terol efflux after acute myocardial infarction, with no significant alterations in liver or kidney function or other safety concern, reports the Apo-I Event Reducing in Ischemic Syndromes I (AEGIS-I) trial. M ichael Gibson, MS, MD, of Beth Israel Deaconess Medical Center, Boston, of 5%. CSL112 was associated with increases in apolipoprotein A-I and ex vivo cholesterol efflux similar to that achieved in patients with stable coronary artery disease.

Coprimary safety endpoints were the occurrence of either a hepatic safety event (an increase in alanine transaminase more than three times the upper limit of normal or an increase in total bilirubin more than twice the upper limit of normal) or a renal safety event (an increase in serum creatinine >1.5 times the baseline value or a new requirement of renal replacement therapy). A total of 1258 patients were randomised, and 91.2% received all four infusions. The difference in incidence rates for an increase in alanine transaminase or total bilirubin between both CSL112 arms and placebo was within the protocol-defined noninferiority margin of 4%. Similarly, the difference in incidence rates of an increase in serum creatinine or a new requirement for renal replacement therapy was within the protocol-defined noninferiority margin

assachusetts, explained that human or recombinant apolipoprotein A-I has been shown to increase high-density lipoprotein – mediated cholesterol efflux capacity and to regress atherosclerotic disease in animal and clinical studies. CSL112 is an infusible, plasma-derived apolipoproteinA-I that has been studied in normal subjects or those with stable coronary artery disease. AEGIS-I was a multicentre, randomised, double-blind, placebo- controlled, dose-ranging phase 2b trial. Patients with myocardial infarction were stratified by renal function and randomised 1:1:1 to CSL112 (2 g apolipoprotein A-I per dose) and high- dose CSL112 (6 g apolipoprotein A-I per dose), or placebo for four consecutive weekly infusions.

With regard to the secondary efficacy endpoint, the risk for the composite of major adverse cardiovascular events among the groups was similar. Dr Gibson concluded that among patients with acute myocardial infarction, four weekly infusions of CSL112 were shown to be feasible, well tolerated, and not associated with any significant alterations in liver or kidney function or other safety concern. The ability of CSL112 to acutely enhance cholesterol efflux was confirmed. The potential benefit of CSL112 to reduce major adverse cardiovascular events needs to be assessed in an adequately powered phase 3 trial.

VOL. 1 • No. 3 • 2016

CONFERENCE COVERAGE

Ticagrelor no more effective than clopidogrel in patients with prior lower extremity revascularisation for peripheral artery disease In the Examining Use of tiCagreLor In paD (EUCLID) trial, ticagrelor did not reduce the primary composite endpoint of cardiovascular mortality, myocardial infarction, or ischaemic stroke versus clopidogrel in patients with peripheral artery disease and a history of lower extremity revascularisation. S chuyler Jones, MD, of the Duke University School of Medicine, Durham, North Carolina, The findings not only add context to knowledge of antiplatelet monotherapy after revascularisation for peripheral artery disease, but they also highlight the need for more trials of antithrombotic agents after revascularisation.

EXPERT OPINION Dr Peter Libby on the GLAGOV study Written by Peter Libby MD T he introduction of antibodies that inhibit proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors promises to revolutionise the treatment of hypercholesterolaemia due to elevations in low-density lipoprotein (LDL). Numerous studies have shown the ability of these new agents to lower LDL profoundly even in patients well treated with statins. Preliminary compilations of data from smaller studies provide encouraging evidence regarding clinical benefit. Two large-scale outcome trials in progress will inform us within the next few years regarding the ability of these monoclonal antibody therapies that target PCSK9 to lower cardiovascular events in patients at risk. The Global Assessment of Plaque Regression With a PCSK9 Antibody as Measured by Intravascular Ultrasound (GLAGOV) study furnishes insight into how treatment with anti-PCSK9 agents might alter atherosclerotic plaques and the mechanisms by which they might provide clinical benefit. In this clinical trial, 968 patients with coronary disease, almost all treated with statins, received the anti-PCSK9 monoclonal antibody evolocumab or placebo for 76 weeks and underwent serial intravascular ul- trasound (IVUS) study to quantify coronary atheroma volume. The evolocumab-treated group had reduced LDL concentra- tions compared to those receiving placebo (36.6 vs 93.0mg/dL). Those receiving placebo slightly increased the mean percent atheroma volume over the approximately 18-month observation period (+0.05%) while the evolocumab-treated group showed a reduction in this measure of plaque volume (−0.95%, P < 0.02 vs placebo). GLAGOV shows that beyond statin treatment, the additional LDL lowering altered plaque volume about 1%, on the same order of reduction of statin treatment versus placebo in prior ultrasound studies. Statin treatment confers a disproportionate reduction in clinical events (~20–45%) compared to the small percent- age improvement in mean plaque volume (~1%). This finding indicates that changes in qualitative features of plaques invisible to ultrasound, not just quantity of plaque, may influence the ability of LDL-lowering agents to prevent cardiovascular events. Experimental studies have shown that lipid lowering can re- duce plaque inflammation and reinforce the plaque’s extracellular matrix, thus altering functional characteristics of plaques related to their liability to cause clinical complications. Indeed, some of the clinical benefit of statins likely derives from direct anti- inflammatory actions independent of LDL lowering. In contrast to statins, this and other studies show that anti-PCSK9 agents do not lower the marker of inflammation, C-reactive protein (CRP). We must await analysis of the ongoing large-scale clinical endpoints studies to ascertain whether the decrement in LDL conferred by adding anti-PCSK9 agents to statins will yield a further reduction in clinical events out of proportion to the relatively modest decrease in plaque volume, as in the case of statin treatment. In GLAGOV, about half of the statin-treated patients showed atheroma regression by the ultrasound metrics evaluated. With the addition of the biologic agent, about two-thirds of patients showed regression over the 18-month study duration. While longer treatment with the stringent lipid-combination would likely produce further regression of lesion volume, the authors point out that shrinking atherosclerotic plaques by targeting LDL alone may reach diminishing returns. With the remarkable lipid lowering enabled by the combination of statin and anti-PCSK9 antibodies, we may be wringing as much “milk out of the stone” as we can by lessening lipid accumulation in the atheroma. This consideration indicates that we may be plumbing the limits of clinically beneficial LDL lowering with the remarkable therapies we have at hand today. In an era of striving for “precision” medi- cine, we should prepare to address a residual burden of events in patients despite extreme LDL lowering by targeting other potential drivers of cardiovascular risk including inflammation or other lipid risk factors such as triglyceride-rich glycoproteins.

explained that peripheral artery disease is considered a systemic manifestation of atherosclerosis. It affects the arteries of the lower extremities, and is often thought to constitute a coronary heart disease risk equivalent due to associated high cardiovascular morbidity and mortality. He said, “Considering the uncertainty about long-term risk reduction after vascular intervention and dramatic variation in antiplatelet use after vascular intervention, we were interested in ascertaining patient risk after pulmonary vein isolation and whether we could demonstrate (in the largest subgroup of EUCLID patients) ticagrelor’s effectiveness in reducing cardiovascular risk. Symptomatic patients most commonly present with either intermittent claudication or critical limb ischaemia. These symptoms are often the focus of treatment strategies to revascularise the limb. Unlike patients with coronary artery disease, how to reduce cardiovascular risk in patients with symptomatic peripheral artery disease (whether treated with revascularisation or medical therapy) is not well understood. Clinicians often rely on data from subgroup analyses of patients with peripheral artery disease in antiplatelet and statin studies to guide cardiovascular risk reduction strategies. With limited proven medical therapies to reduce symptoms in patients with peripheral artery disease, peripheral endovascular and surgical revascularisation for the symptomatic management of patients with peripheral artery disease has increased dramatically over the past two decades. Compared with revascularisation for coronary artery disease, little evidence guides clinicians on the choice and use of antiplatelet medications in patients who have undergone a peripheral revascularisation procedure. The optimal antithrombotic regimen for long-term management of patients with peripheral artery disease after revascularisation is poorly defined and often extrapolated from trials of patients undergoing a percutaneous coronary intervention. Two critical questions surround long-term prognosis and management of patients who have undergone prior lower extremity revascularisation: 1. Are patients who have been revascularised at heightened risk for cardiovascular and limb events vs those who have not undergone prior revascularisation? 2. Are more intensive antiplatelet medications more effective yet safe in this population?

ratio 1.03, 95% CI 0.78–1.36); or major bleeding (1.9% vs 1.8%; hazard ratio 1.15, 95% CI 0.83–1.59). The median duration of follow-up was approximately 30 months. Dr Jones said that after adjustment for baseline characteristics, patients enrolled based on prior revascularisation for peripheral artery disease experienced higher rates of myocardial infarction and acute limb ischaemia with similar composite rates of cardiovascular death, myocardial infarction, and stroke versus patients enrolled based on the ankle-brachial index criterion. No significant differences between ticagrelor and clopidogrel were observed in reduction of cardiovascular or acute limb events. The findings suggest that patients with prior revascularisation have a substantial residual rate of cardiovascular and acute limb events, despite high adherence to antiplatelet and statin medications, and require further study. The findings not only add context to knowledge of antiplatelet monotherapy after revascularisation for peripheral artery disease, but they also highlight the need for more trials of antithrombotic agents after revascularisation. Specifically, whether patients should be treated with one or two antiplatelet agents, which agents should be used, the duration of antiplatelet monotherapy or dual therapy, and whether antithrombotics that utilise different mechanistic pathways (for example, P2Y12 receptor antagonists, factor Xa inhibitors) should be used in isolation or in combination for these complex patients to reduce their long- term rates of cardiovascular events and acute limb ischaemia have not been determined. Finally, while the optimal anti- platelet medication regimen is being studied and developed, the impact of disease presentation, anatomic burden of disease, and type of revascularisa- tion procedures need to be understood. “While ticagrelor was no more effec- tive in reducing risk than clopidogrel,” Dr Schuyler Jones said, “we learned valuable information about this popu- lation, specifically, that patients with a history of lower extremity revasculari- sation are at higher risk of acute limb events and cardiovascular events.”

Ticagrelor is a potent P2Y12 receptor antagonist with evidence of benefit in patients with acute coronary syndromes and those with prior myocardial infarction. The EUCLID trial was designed to evaluate treatment, specifically in patients with peripheral artery disease. EUCLID tested the hypothesis that monotherapy with ticagrelor would be superior to clopidogrel in preventing cardiovascular endpoints in patients with peripheral artery disease. Dr Jones described findings in the subgroup of patients who were enrolled based on their history of a prior lower extremity revascularisation. EUCLID randomised 13,885 patients with peripheral artery disease to ticagrelor 90 mg twice daily or clopidogrel 75 mg daily. Patients were enrolled based on an abnormal ankle- brachial index ≤ 0.80 or a prior lower extremity revascularisation. The analysis focused on the 7875 (57%) patients enrolled based on prior lower extremity revascularisation. Patients could not be enrolled within 30 days of their most recent revascularisation, and patients with an indication for dual antiplatelet therapy were excluded. The primary efficacy endpoint was a composite of cardiovascular death, myocardial infarction, or ischaemic stroke. The primary safety endpoint was major bleeding. Patients who had undergone prior revascularisation were a mean age of 66 years, 73% were male, and median baseline ankle-brachial index was 0.78. After adjustment for baseline characteristics, patients enrolled based on prior revascularisation experienced similar rates of the primary composite endpoint (hazard ratio 1.10, 95% CI 0.98–1.23) and statistically significantly higher rates of myocardial infarction (hazard ratio 1.29, 95% CI 1.08–1.55, P = 0.005) and acute limb ischaemia (hazard ratio 4.23, 95% CI 2.86–6.25, P < 0.001) than patients enrolled based on ankle-brachial index criteria. No differences in ticagrelor- versus clopidogrel-treated patients were observed for the primary efficacy endpoint (11.4% vs 11.3%, hazard ratio 1.01, 95% CI 0.88–1.15); all- cause mortality (9.2% vs 9.2%, hazard ratio 0.99, 95% CI 0.86–1.15); acute limb ischaemia (2.5% vs 2.5%; hazard

Dr Libby is Chief of Cardiovascular Medicine, Brigham and Women’s Hospital and Mallinckrodt Professor of Medicine, Harvard Medical School in Boston, Massachusetts.

PRACTICEUPDATE CARDIOLOGY

AHA 2016

EXPERT OPINION Dr Joerg Herrmann on the FUTURE, EUCLID, ART and PRECISION trials

Written by Joerg Herrmann MD

The FUTURE trial The FUTURE trial set out to randomise over 1,700 patients with multivessel CAD that had to include the LAD to either FFR or angiography alone in order to test if FFR helps guide treatment strategy and thereby improves outcome. The study was powered to detect a 30% relative reduction in the risk of MACE. However, at just over 900 patients, the data safety monitoring and steering committee advised to stop the trial in view of an >2-fold increase in overall mortality in the FFR group. One-year outcome data available for nearly 800 patients does not show a significant difference in overall MACE and only a trend towards higher overall and CV mortality in the FFR group. In summary, this trial may cast some uncertainty on the future of the use of FFR in clinical practice. Further data are needed on the impact on decision making and how this could be linked to adverse outcomes. By itself the FFR procedure does not increase the risk and nothing else is evident and intuitive. However, the trial is a good reminder that one of the greatest benefit in all previous FFR trials was the reduction of stent implantations when haemodynamically not required, and thereby a reduction of costs and related risks. The EUCLID trial Encouraged by the results of the PLATO trial of superior outcomes of ticagrelor compared with clopidogrel in ACS patients and the PEGASUS trial on the benefits of ticagrelor over aspirin in patients with PAD,

In the post-hoc analyses of any CV, GI, or renal event, celecoxib had the lowest risk, naproxen had intermediate risk and ibuprofen the highest risk. These findings are striking as they grant absolution to a drug condemned in the cardiovascular community.

analyses it was associated with a lower risk of cardiovascular events and mortality compared with ibuprofen. Celecoxib was associated with a lower risk of major GI events compared with both naproxen and ibuprofen and a lower risk of serious renal events than ibuprofen and even naproxen in the on-treatment analyses. In the post-hoc analyses of any CV, GI, or renal event, celecoxib had the lowest risk, naproxen had intermediate risk and ibuprofen the highest risk. These findings are striking as they grant absolution to a drug condemned in the cardiovascular community. These charges date back to COX-2 inhibitor story, which made headlines just over a decade ago, pointing out the increased risk of cardiovascular events with these drugs. Vioxx was the prime contender and eventually left the market in 2004; Bextra followed in 2005. This has left Celebrex as the sole COX-2 inhibitor on the US market with stern black box warnings. Other NSAIDs have also been confronted with heightened levels of concern eg, ibuprofen, whereas Naproxen has prevailed in current opinion as one of the safer representatives in his class. PRECISION would attest that it is safer than ibuprofen, but even so, the winner is, this time: celecoxib, but against NSAIDS that also carry a risk.

5 years of follow-up. However, the incidence of sternal wound complication and reconstruction was 2 and 3-fold higher, respectively, with bilateral IMA bypass grafting, and all of these events occurred in the first year and mainly in diabetics and those with high BMI. Of further note, 14% of patients assigned to bilateral IMA underwent single IMA only versus 2.4% of patients assigned to single IMA undergoing bilateral IMA bypass surgery. In summary, adding one more IMA graft to patients undergoing CABG with LIMA grafting does not add further clinical benefit but may increase the risk of sternal wound complication especially in at risk populations. The PRECISION trial This mega trial involved nearly 1,000 centres worldwide that enrolled 24,000 osteoathritis or RA patients with CV disease or risk requiring NSAID therapy for at least 6 months. Patients were randomly assigned to celecoxib 100 mg bid, ibuprofen 600 mg tid, or naproxen 375 mg bid in conjunction with esomeprazole. Celecoxib was not inferior to naproxen and ibuprofen with regards to major adverse cardiovascular events in the intention- to-treat analyses. In fact, in the on treatment

the EUCLID trial was pursued. This was a trial assessing the incidence of cardiovascular death, MI, and stroke in nearly 14,000 patients with symptomatic PAD randomised to ticagrelor or clopidogrel. No difference in the primary composite endpoint was found, even though there was a significant, 20% lower rate of ischaemic stroke in the ticagrelor group. There was no difference in bleeding events. Even though contrary to the study hypothesis, one important point is that poor metabolisers of clopidogrel were excluded from this trial. Thus, in essence this trial then shows that clopidogrel is as effective as ticagrelor in this population when effectively metabolised. The observation of the difference of a lower rate of strokes with ticagrelor needs further exploration. These findings are opposite to the PLATO trial results. The ART trial The ART trial randomised >3000 patients scheduled for coronary artery bypass grafting (CABG) to either left or bilateral internal mammary (IMA) bypass grafting (of note, over three quarters of patients had two or three additional grafts). No significant differences in major cardiovascular outcomes were found over

Dr Herrmann is Associate Professor of Medicine at Mayo Graduate School of Medicine, Rochester, Minnesota.

Extended-duration betrixaban reduces stroke risk vs standard-dose enoxaparin in hospitalised medically ill patients

T his outcome of a substudy of the Acute Medically Ill Venous Thromboembolism Prevention with Extended Duration Betrixaban (APEX) trial was reported at the AHA Scientific Sessions 2016. Michael Gibson, MS, MD, of Beth Israel Deaconess Medical Center, Boston, Massachusetts,

Among hospitalised medically ill patients, extended-duration betrixaban has been shown to significantly reduce all-cause and ischaemic stroke versus standard-of-care enoxaparin through 77 days.

to treat 233) and ischaemic strokes (0.48% vs 0.91%, relative risk 0.53 [0.30–0.94], P = 0.026; absolute risk reduction 0.43%, number needed to treat 233) were observed among patients treated with betrixabanthan with enoxaparin through 77 days offollow-up. Among high-risk subjects (those with congestive heart failure or ischemic stroke as their index event) betrixaban reduced the risk of all-cause stroke (0.72% vs 1.48%, relative risk 0.49 [0.26–0.90], P = 0.019; absolute risk reduction 0.76%, number needed to treat 132); and ischaemic stroke (0.63% vs 1.38%, relative risk 0.45 [0.24– 0.87], P = 0.014, absolute risk reduction 0.75%, number needed to treat 134) vs enoxaparin. Dr Gibson concluded that among hospitalised medically ill patients, extended-duration betrixaban significantly reduced all-cause stroke and ischaemic stroke through 77 days of follow-up. Extended-duration thrombo- prophylaxis with an experimental oral factor Xa inhibitor may reduce the risk of stroke among hospital- ised medically ill patients.

Little is known, however, about the effectiveness of novel oral anticoag- ulants for stroke prevention in this context. APEX evaluated extended- duration thromboprophylaxis with the oral anticoagulation betrixa- ban in the prevention of venous thromboembolism. In this retrospective substudy, Dr Gibson and colleagues compared extended-duration betrixaban versus standard thromboprophylactic enoxaparin in the reduction of stroke among hospitalised medically ill patients. Hospitalised acutely medically ill subjects (n=7513) were randomised in a double- dummy, double-blind fashion to either extended-duration oral betrixaban (80 mg once daily for 35 to 42 days) or standard-dose subcutaneous enoxaparin (40 mg once daily for 10 ± 4 days) for venous thromboprophylaxis. Mean participant age was 76 years, 45% were male, 13% had a stroke, and 45% had congestive heart failure. Fewer all-cause strokes (0.54% vs 0.97%; relative risk 0.56 [0.32– 0.96], P = 0.032, absolute risk reduction 0.43%; number needed

explained that stroke is a leading cause of morbidity and mortality worldwide. In-hospital stroke complicates 0.04% to 0.06% of all hospitalisations and constitutes 2.2% to 15.2% of all strokes. Stroke among patients hospi- talised for acute medical illness portends a less favourable outcome than community-onset stroke.

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AHA 2016

Excess CV risk in women linked to very low coronary flow reserve, not obstructive disease

Read more on AHA 2016 including exclusive take-aways by the PracticeUpdate Cardiology editorial team at PracticeUpdate.com

T his conclusion was based on results of a 3-year, single-centre observational study led by Viviany R. Taqueti, MD, MPH, of Brigham and Women’s Hospital, Boston, Massachusetts. Over the last 3 decades, case fatality rates for cardiovascular disease in the US have been higher for women than for men, yet obstructive coronary artery disease is less prevalent in women, leading to an unexplained “coronary artery disease paradox” for women and heart disease. As Dr Taqueti explained, “While luminal coronary angiography may be the gold standard for diagnosing obstructive coronary artery disease – and remains a cornerstone of care in patients with cardiovascular disease – it is not used to evaluate how well the coronary arteries can respond to and accommodate normal stress (as captured by coronary blood flow reserve) and often misses diffuse atherosclerosis and small-vessel disease because technique resolution is limited. And yet, growing data suggest that diffuse atherosclerosis and small-vessel disease may contribute to adverse cardiovascular events including acute coronary syndromes, heart failure, and death due to cardiovascular disease from plaque erosion, impaired coronary vasoreactivity, and microvascular dysfunction. Coronary flow reserve, as assessed noninvasively using stress testing with positron emission tomography, provides a combined physiologic measure of large- and small- vessel coronary artery disease and myocardial ischaemia. Coronary flow reserve assessment also identifies patients at risk of cardiovascular events, independent of traditional measures of stress-induced ischaemia and left ventricular ejection fraction. Coronary flow reserve has not been measured routinely in clinical practice. Hypothesising that some of the excess risk in women may be attributable to impaired coronary flow reserve rather than visible plaque, Dr Taqueti and colleagues sought to investigate the impact of sex, coronary flow reserve, and the severity of angiographic coronary artery disease on adverse cardiovascular events. They followed 329 consecutive patients (43% women) referred for invasive coronary angiography after stress testing with positron emission tomographic myocardial perfusion and with preserved left ventricular ejection fraction for a median of 3 years for a composite endpoint of major adverse cardiovascular events, including cardiovascular death and hospitalisation for nonfatal myocardial infarction or heart failure. When stratified by sex and coronary flow reserve, only women with severely impaired coronary flow reserve demonstrated significantly increased adjusted risk of cardiovascular disease events (P < 0.0001, P for interaction 0.04). Interestingly, the differential effect of sex on outcomes was amplified in patients with very low coronary flow reserve (<1.6), in whom more men than women harboured multivessel obstructive coronary artery disease and underwent surgical revascularisation, possibly mitigating their risk. Thus, though symptomatic high-risk women demonstrated a significantly lower burden of obstructive coronary artery disease relative to men, they were not protected from cardiovascular disease events. Dr Taqueti noted, “The excess cardiovascular risk in women was independently associated with impaired coronary flow reserve, which may have represented a hidden biological risk, and a phenotype less amenable to revascularisation, a treatment strategy fundamentally targeted at opening or bypassing obstructive plaques”. Dr Taqueti stated, “Our results suggest that current therapies, possibly in a sex- specific manner, are insufficient to restore coronary vascular function. A clearer understanding of the relationship between microvascular dysfunction and conditions comorbid with coronary artery disease, including insulin resistance and heart failure, may guide development of novel systemic therapies to harness the benefit of more ‘complete revascularisation’ in a manner not defined by anatomy alone.” She added, “Coronary flow reserve may represent an important biomarker of risk not only for prospective studies evaluating the role of ischaemia and revascularisation, but also as a target of emerging anti-inflammatory, lipid-lowering, and neurohormonal- modulating agents (for example, inhibitors of interleukin-1, PCSK9, neprilysin, and the sodium/glucose cotransporter 2) on cardiovascular outcomes, especially in women.”

Excess cardiovascular risk in women relative to men with stable ischaemic heart disease symptoms, who were referred for coronary angiography, has been shown to be associated with severely impaired coronary flow reserve, not obstructive disease.

CARDIOLOGY CONFERENCES 2017

JANUARY 26–27 January 2017 | Barcelona, Spain Eurovalve Congress 2017 http://eurovalvecongress.com MARCH 24–27 February 2017 | Hong Kong CardioRhythm 2017 www.cardiorhythm.com

Fully closing the ‘gender gap’ in ischaemic heart disease will likely require more than equitable application of current guidelines. We need to think creatively about the biological contributions underlying what may be a surprisingly common phenotype with a disproportionate impact on women’s cardiovascular health.

17–19 March 2017 | Washington, USA American College Of Cardiology 66th Annual Scientific Sessions & Expo 2017 https://accscientificsession.acc.org JUNE 28–30 June 2017 | Hamilton, New Zealand CSANZ New Zealand Annual Scientific Meeting 2017 http://www.csanzasm.nz/

JULY 6–8 July 2017 | Singapore Asian Pacific Society of Cardiology Congress 2017 www.apsc2017.com

Recognising important limitations of the observational nature of these data, this hypothesis-generating work may help to explain the observed gap between cardiovascular disease events and a diagnosis of coronary artery disease in women relative to men by quantifying the hidden risk of ischaemic heart disease in this population. Dr Taqueti added, “These findings suggest that low coronary flow reserve may represent a novel target for cardiovascular disease risk reduction, especially in patients without traditional obstructive coronary artery disease. Fully closing the ‘gender gap’ in ischaemic heart disease will likely require more than equitable application of current guidelines. We need to think creatively about the biological contributions underlying what may be a surprisingly common phenotype with a disproportionate impact on women’s cardiovascular health.”

AUGUST 8–10 August 2017 | Perth, Australia Australia & New Zealand Endovascular Therapies Meeting 2017 www.anzet.com.au

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