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Meeting Reports

European Society of Cardiology Congress 2013 (ESC)
August 31 - September 4, 2013
Amsterdam, Netherlands

MAJOR ESC CLINICAL PRACTICE GUIDELINES ISSUED


New guidelines have been issued by the European Society of Cardiology (ESC) and partnering organizations for the management of stable coronary artery disease (CAD); diabetes, prediabetes, and cardiovascular disease (CVD); cardiac pacing and cardiac resynchronization therapy (CRT), and arterial hypertension.



STABLE CORONARY ARTERY DISEASE


Gilles Montalescot, MD, PhD, Pitié-Salpétrière Hospital, Paris, France, and Udo Sechtem, MD, Robert-Bosch Hospital, Stuttgart, Germany, presented an overview of the new ESC guidelines for the management of stable CAD [Montalescot G et al. Eur Heart J 2013]. These updated guidelines gave added prominence to modern imaging techniques such as CV magnetic resonance imaging and coronary computed tomography angiography (CCTA) for use in the diagnosis of CAD. Additionally, the diagnostic algorithm of patients with suspected CAD is now based on the pretest probability of chest pain being related to CAD. Patients at high pretest probability of CAD, defined as >85%, do not need to undergo a battery of tests before being directed to invasive coronary angiography.


In order to prevent the overuse of CCTA, the guidelines define which patients should receive CCTA. CCTA is most helpful in patients at the lower range of intermediate pretest probabilities (an intermediate pretest probability is considered 15% to 85%) as a noninvasive technique to exclude coronary stenoses.


The guidelines focus on the need to control heart rate in patients being treated medically for stable angina. β-blockers or heart rate-lowering calcium channel blockers remain the first-line therapy to achieve this goal. Second-line treatment includes long-acting nitrates and the newer agents such as ivabradine, nicorandil, ranolazine, and trimetazidine.

As in the 2006 guidelines, revascularization was recommended for patients at high risk for coronary events, defined as an estimated annual mortality ≥3% or angina refractory to medical therapy. Before any discussion about revascularization, patients should receive optimal medical therapy. Moreover, revascularization should only be considered in patients with evidence of regional ischemia as assessed by either perfusion imaging or fractional flow reserve, said Prof. Montalescot.



DIABETES, PREDIABETES, AND CARDIOVASCULAR DISEASES


Lars Rydén, MD, Karolinska Institute, Stockholm, Sweden, and Peter J. Grant, MD, University of Leeds, Leeds, United Kingdom, presented the new guidelines on prediabetes, and CVD. Produced by the ESC in collaboration with the European Association for the Study of Diabetes, these new guidelines introduce a new recommendation that endorse the use of HbA1C levels in the diagnosis of diabetes [Rydén L et al. Eur Heart J 2013]. If either HbA1C or fasting plasma glucose is elevated, the patient is diagnosed with diabetes. If there is strong suspicion that the patient has diabetes but the diagnosis is in doubt (eg, HbA1C or fasting plasma glucose is not elevated), an oral glucose tolerance test may be appropriate, said Prof. Rydén.


CV risk assessment has been simplified in the guidelines, and risk scores are no longer utilized to categorize people as having low, moderate, high, or very high risk for CVD. Patients with diabetes are considered to be at high risk for the development of CAD and CV events. In addition, patients with diabetes and CVD (eg, myocardial infarction, angina pectoris, or peripheral vascular disease) are at very high risk of recurrent CV events.


Recommendations on revascularization have undergone two major changes. In patients with stable CAD and no complex coronary lesions, medical therapy is recommended before revascularization unless there are large areas of ischemia or significant stenosis in either the left main or proximal left anterior descending artery. Also, bypass surgery is preferable in patients with diabetes who have complex coronary artery stenoses or elevated SYNTAX scores.


Multifactorial medical management is endorsed, including combinations of blood pressure-lowering agents that incorporate blockers of the renin-angiotensin-aldosterone system (RAAS), statins for the control of lipids, antiplatelet therapy, and a combination of glucose-lowering therapies. Aspirin is not recommended for the primary prevention of CV events in patients with diabetes who are at low risk of CV events. Aspirin is indicated for secondary prevention in patients with diabetes. Additionally, patients with diabetes who have an acute coronary syndrome should be treated with a P2Y12 receptor blocker (preferably prasugrel or ticagrelor) for 1 year.


Prof. Grant then explained that glycemic control should be individualized (Table 1) based on the patient. HbA1C should continue to be used to determine the need for intensification of diabetes control. The target HbA1C is lower (≤7.0%) in young patients recently diagnosed with diabetes who have no known CVD. The target HbA1C should be higher (7.5% to 8.0%) in older patients with long-standing diabetes and CV complications in order to avoid adverse events related to hypoglycemia.


Table 1. Glycemic Control: Individualized Care



The general blood pressure (BP) target for patients with diabetes is <140/85 mm Hg. In patients who also have evidence of renal dysfunction, the target BP is <130/85 mm Hg. A systolic BP target <130 mm Hg may be considered in the presence of nephropathy with overt proteinuria.


Type 2 diabetes and heart failure (HF) often co-exist. Pharmacologic management of HF should include a RAAS blocker, β-blocker, and a mineralocorticoid receptor antagonist, with consideration given to supplementing these therapies with a diuretic and ivabradine.



CARDIAC PACING AND CARDIAC RESYNCHRONIZATION THERAPY


Michele Brignole, MD, Ospedali del Tigullio, Italy, delivered highlights of the 2013 ESC guidelines on cardiac pacing and CRT developed in collaboration with the European Heart Rhythm Association [Brignole M et al. Eur Heart J 2013; Europace 2013]. The Task Force created a new classification system for bradyarrhythmias (Figure 1) in which the recommendations are dependent upon the patient’s clinical presentation (persistent or intermittent bradyarrhythmia) and whether it has been documented with an electrocardiogram.


Figure 1. Classification of Bradyarrhythmias Based on Patient Clinical Presentation

 


AV=atrioventricular; AVB=atrioventricular block; BBB=bundle branch block; ECG=electrocardiogram; PM=pacemaker; SSS=sick sinus syndrome.


Reproduced from Brignole M et al. 2013 ESC Guidelines on cardiac pacing and cardiac resynchronization therapy: The Task Force on cardiac pacing and resynchronization therapy of the European Society of Cardiology. Developed in collaboration with the European Heart Rhythm Association. Eur Heart J 2013;34(29):2281-2329. With permission from Oxford University Press.

 

Indications and potential for pacing according to the new guidance (Table 2):

 

  • Symptomatic sinus node dysfunction, with consideration given to pacing in the absence of conclusive evidence if symptoms are likely caused by bradycardia
  • Third-degree or type 2 second-degree atrioventricular block (AVB)
  • Consider pacing in patients aged ≥40 years with recurrent, unpredictable neurocardiogenic syncope and documented symptomatic pauses despite alternative therapies
  • Syncope with bundle branch block (BBB) and a His-ventricular interval ≥70 ms or pathologic AVB during atrial pacing
  • Alternating BBB, even if the patient is asymptomatic 

Table 2. Indications for CRT in Patients in Sinus Rhythm


 

* Patients should generally not be implanted during admission for acute decompensated HF. In such patients, guideline-indicated medical treatment should be optimized and the patient reviewed as an out-patient after stabilization. It is recognized that this may not always be possible.


CRT=cardiac resynchronization therapy; HF=heart failure; LBBB=left bundle branch block; LVEF=left ventricular ejection fraction; NYHA=New York Heart Association.


 

ARTERIAL HYPERTENSION


The 2013 guidelines for the management of arterial hypertension were produced jointly by the ESC and European Society of Hypertension (ESH) [Mancia G et al. Eur Heart J 2013; J Hypertens 2013]. Task Force chairs Giuseppe Mancia, MD, PhD, University of Milano-Bicocca, Milan, Italy, and Robert Fagard, MD, PhD, KU Leuven University, Leuven, Belgium, presented the overview.


Out-of-office BP monitoring takes on a more important role in the new guidelines, and should be considered an adjunct to office BP recording in the diagnostic evaluation. The definition for hypertension is an office BP ≥140/≥90 mm Hg or a daytime ambulatory/home BP of ≥135/≥85 mm Hg. One specific indication for ambulatory BP monitoring is a marked discordance between office BP and home BP.


The guidance indicated no treatment for patients with high normal BP (130 to 139/85 to 89 mm Hg). A major development was the decision to recommend a single systolic BP target of 140 mm Hg for almost all patients, reversing the separate targets for moderate- to low-risk patients (140/90 mm Hg) and high-risk patients (130/80 mm Hg) in the 2007 version of the guidelines.


A greater emphasis on assessing total CV risk is contained in the 2013 guidelines (Table 3). Additional risk factors such as organ damage, diabetes, and other CV risk factors need to be considered before initiating treatment and during follow-up. For patients aged ≥65 years, there is solid evidence to recommend reducing systolic BP to 150 to 140 mm Hg, said Prof. Fagard.


Table 3. Total Cardiovascular Risk Stratification

 


CKD=chronic kidney disease; CVD=cardiovascular disease; DBP=diastolic blood pressure; HT=hypertension; OD=organ damage/disease; RF=risk factor; SBP=systolic blood pressure. Risk factors include age, male sex, smoking, dyslipidemia, glucose intolerance, obesity and family history of premature CVD. Asymptomatic organ damage mainly involves left ventricular hypertrophy, evidence of vascular damage and microalbuminuria.


There is no specific preference for single-drug therapy, and an updated protocol for drugs taken in combination. The beneficial effect of hypertension depends largely on BP lowering rather than the choice of drug, so no hierarchy of drugs is suggested.



SAXAGLIPTIN AND ALOGLIPTIN NONINFERIOR FOR CV ISCHEMIC EVENTS IN PATIENTS AT HIGH-RISK WITH T2DM AND CORONARY DISEASE


Antihyperglycemic therapies have been shown to reduce microvascular events (ie, blindness, amputation, and kidney failure); however, their impact on macrovascular events (ie, cardiovascular [CV] death, myocardial infarction [MI], and stroke) has not been well established. In addition, concerns of increased risk of CV events with some antihyperglycemic therapies prompted the United States Food and Drug Administration and European Medicines Agency to require demonstration of CV safety for all new diabetes therapies [Food and Drug Administration. Guidance for Industry. 2008. [http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatory Information/Guidances/ucm071627.pdf]. As a result, well-powered trials of CV outcomes in high-risk patients with type 2 diabetes mellitus (T2DM) are being conducted to establish CV safety with new antihyperglycemic drugs.


Saxagliptin and alogliptin, both selective dipeptidyl peptidase 4 (DPP-4) inhibitors, are incretin-based antihyperglycemic therapies that improve glycemic control in T2DM. A meta-analysis of the Phase 2-3 clinical development trials of saxagliptin suggested it may reduce the risk of major adverse cardiac events (MACE) in T2DM but these overall findings were based on few outcomes [Frederich R et al. Postgrad Med 2010].


The purpose of the SAVOR-TIMI 53 and EXAMINE trials was to determine if treatment with saxagliptin or alogliptin, respectively, would be noninferior to placebo for MACE in patients with T2DM at heightened risk of CV events [Scirica BM et al. Am Heart J 2011; White WB et al. N Engl J Med 2013].


Saxagliptin treatment in patients with T2DM and stable atherosclerotic vascular disease or risk factors does not increase the risk of MACE. Deepak L. Bhatt, MD, MPH, Brigham and Women’s Hospital, Boston, Massachusetts, USA, presented data from the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus TIMI 53 trial [SAVOR-TIMI 53; Scirica BM et al.N Engl J Med 2013].


In the international, Phase 4 SAVOR-TIMI 53 trial, 16,492 patients with T2DM and a history of or at risk for CV events were randomized to receive saxagliptin 5 mg daily (2.5 mg in patients with an estimated GFR of ≤50 mL/minute) or placebo for a median follow-up of 2.1 years [Scirica BM et al. N Engl J Med 2013]. Eligible patients with established CV disease had to be aged ≥40 years, with documented coronary, cerebrovascular, or peripheral artery atherosclerosis. Patients with risk factors were eligible if they were aged ≥55 (males) or ≥60 (females) years, and had a history of dyslipidemia, hypertension, or active tobacco use. Patients were ineligible if already treated with incretin-based therapy within the last 6 months, or had a history of end-stage renal disease, long-term dialysis, renal transplantation, or serum creatinine levels of ≥6.0 mg/dL (530 μmol/L).


The primary endpoint was a composite of CV death, nonfatal MI, or nonfatal ischemic stroke. Secondary endpoints included the primary endpoint plus hospitalization due to heart failure (HF), coronary revascularization, or unstable angina, and each component of the composite CV endpoints.


The occurrence of the primary endpoint at 2 years was similar in both study arms (7.3% saxagliptin vs 7.2% placebo; HR, 1.00; 95% CI, 0.89 to 1.12; superiority p=0.99; noninferiority p<0.001). The broader secondary endpoint was also similar (12.8% with saxagliptin vs 12.4% with placebo; HR, 1.02; 95% CI, 0.94 to 1.11; superiority p=0.66; noninferiority p<0.001).

Individual CV outcomes were consistently similar between both treatment arms with the exception of hospitalization for HF, which occurred more frequently in the saxagliptin arm (3.5%) compared with the placebo arm (2.8%; HR, 1.27; 95% CI, 1.07 to 1.51; p=0.007). Major hypoglycemic events (defined when the event required a third party to intervene actively) occurred more frequently with saxagliptin (2.1% vs 1.7%; p=0.047); however, hospitalizationfor hypoglycemia was similar in both arms (p=0.33). Cases of acute and chronic pancreatitis (p=0.77), and pancreatic cancer (p=0.095), were infrequent and similar between both arms.


In the EXAMINE trial, alogliptin therapy in patients with T2DM with recent acute coronary syndrome (ACS) similarly did not increase the risk of MACE. William B. White, MD, University of Connecticut School of Medicine, Farmington, Connecticut, USA, presented data from the Cardiovascular Outcomes Study of Alogliptin in Subjects With Type 2 Diabetes and Acute Coronary Syndrome [EXAMINE; White WB et al. N Engl J Med 2013].


In the international, double-blind EXAMINE trial, 5380 patients with T2DM and recent ACS (acute MI or hospitalization for unstable angina within 15 to 90 days) were randomized to receive alogliptin QD (n=2701) or placebo QD (n=2679) and followed for a median of 18 months. All patients were currently on antidiabetic treatment with an agent other than a DPP-4 inhibitor or glucagon-like peptide-1 analog (ie, incretin-based therapy). Exclusion criteria included type 1 diabetes, unstable cardiac disorders such as HF, refractory angina, uncontrolled arrhythmias, severe valvular heart disease, uncontrolled hypertension, and recent dialysis.


The primary endpoint of the EXAMINE trial was a composite of CV death, nonfatal MI, and nonfatal stroke. The secondary endpoint included the primary endpoint plus urgent revascularization due to unstable angina within 24 hours after hospitalization.


The primary endpoint was similar between groups (11.3% with alogliptin vs 11.8% with placebo; HR, 0.96; upper boundary of one-sided repeated CI, 1.16; superiority p=0.32; noninferiority p<0.001). The incidence of the secondary endpoint was also similar (12.7% vs 13.4%; HR, 0.95; upper boundary of one-sided repeated CI, 1.14; superiority p=0.26). In addition, there was no significant difference between alogliptin and placebo for CV death (p=0.21), nonfatal MI (p=0.47), nonfatal stroke (p=0.71), or all-cause death (p=0.23). Hospitalization for HF was not part of the primary endpoint.


The incidence of hypoglycemia was similar (~6.6%) between study arms, as was the incidence of acute (~0.4%) and chronic (~0.2%) pancreatitis. There were no reports of pancreatic cancer occurring during the trial.


Dr. Bhatt concluded that SAVOR-TIMI 53 demonstrated noninferiority of saxagliptin for major ischemic events in patients with T2DM with heightened CV risk. Similarly, Dr. White noted that the EXAMINE trial found that MACE rates were not increased with alogliptin compared with placebo in patients with T2DM and recent ACS. In both trials, the rates of pancreatitis and pancreatic cancer were reassuring. Dr. Bhatt also pointed out that further study to elucidate the mechanism behind the unexpected increased incidence of hospitalization for HF in the saxagliptin arm observed in the SAVOR-TIMI 53 study is needed.


Science Advisor’s Note: Hospitalization for HF was not reported in the primary EXAMINE publication but was recorded as an exploratory CV endpoint [White WB et al. Am Heart J 2011;162:2634-53 (Appendix A)]. Given the results of SAVOR-TIMI 53, further description of this endpoint in EXAMINE will be important in determining whether this is a class effect and clarifying the underlying mechanism.




CATHETER-BASED RENAL ARTERY DENERVATION – SUSTAINED BLOOD PRESSURE LOWERING WITH REASSURING SAFETY AT 3 YEARS


Catheter-based renal artery denervation appears to result in sustained blood pressure (BP) reduction with a favorable safety profile in patients through 3 years with consistent benefit across age, diabetes status, and renal function, according to Henry Krum, MBBS, PhD, Monash University, Melbourne, Australia, who presented the final 3-year results from the Renal Denervation in Patients With Refractory Hypertension trial [Symplicity HTN-1; NCT00664638].


Although percutaneous renal denervation (RDN), an endovascular catheter-based procedure using radiofrequency energy, has been shown to successfully reduce BP for 1 year in patients with resistant hypertension [Krum H et al. Lancet 2009], its long-term efficacy may potentially be attenuated by sympathetic nerve regrowth and functional re-innervation.


The Symplicity HTN-1 was a series of pilot trials designed to evaluate the safety and BP-lowering efficacy of RDN using the Symplicity catheter system in refractory hypertension. These nonrandomized open-label studies were conducted among 19 centers in the United States, Australia, and Europe. Inclusion criteria were systolic BP (SBP) ≥160 mm Hg, despite full doses of ≥3 antihypertensive agents, and estimated glomerular filtration rate ≥45 mL/min. Exclusion criteria included type 1 diabetes, known secondary causes of hypertension, current clonidine, rilmenidine, or moxonidine therapy, and renovascular abnormalities.


The primary endpoints of the Simplicity HTN-1 were office BP and safety data before and at 1, 3, 6, 9, and 12 months after RDN. The secondary endpoints were the effects of RDN on renal noradrenaline spillover and renal function.

Of the 153 individuals enrolled, 65 patients (42.5%) were not included in the final analytic cohort because of missing baseline BP data, withdrawal of consent, loss to follow-up, or death. Results were presented for the remaining 88 patients (58%) who successfully completed the 36-month study.


In the 58% of patients who completed the study through to 36 months, renal function was demonstrated to remain stable, and few significant late-stage adverse events were reported (Table 1).


Table 1. Late-Stage Adverse Events


 

RDN was associated with significant (p<0.01) and sustained BP reductions (mean -32/-14 mm Hg) in patients who completed the study to 36-month follow-up. Still further, 50% of patients were able to achieve a target SBP <140 mm Hg (Figure 1). The BP reduction associated with RDN was consistent regardless of patient age, diabetes status, and baseline renal function.


Figure 1. Changes in SBP Through 36 Months

 

Reproduced with permission from H Krum, MBBS, PhD.


Prof. Krum concluded that Symplicity HTN-1 is the first and longest running clinical trial for RDN to date, comprising the largest cohort of patients. Although the proportion of the cohort with follow up (n=88 of 153) was limited and longer-term evaluation of this therapy in blinded control trials is required, the results of this study suggest that RDN has a favorable safety profile and sustained BP-lowering over 36 months in patients with refractory hypertension.



PROMISES AND QUESTIONS IN RENAL DENERVATION FOR RESISTANT HYPERTENSION


Renal denervation (RDN) is a promising emerging treatment option for resistant hypertension, as well as other diseases that appear to be associated with sympathetic activation. Alexandra O. Konradi, MD, PhD, Almazov Federal Center for Heart, Blood and Endocrinology, St. Petersburg, Russia, presented guideline recommendations for the diagnosis and conventional treatment of resistant hypertension.


Prof. Konradi highlighted an algorithm adapted from the 2008 American Heart Association guidelines for resistant hypertension [Calhoun DA et al. Hypertension 2008] that addresses many important underlying issues in the diagnosis and management of resistant hypertension (Figure 1). According to the 2013 European Society of Hypertension/European Society of Cardiology guidelines, resistant hypertension can be caused by lifestyle factors such as obesity, excessive alcohol or sodium intake, chronic use of vasopressor or sodium-retaining agents, obstructive sleep apnea (OSA), secondary forms of hypertension, or advanced or irreversible organ damage [Mancia G et al. J Hypertens 2013]. Therefore, physicians should screen patients for OSA and agents that can increase blood pressure (BP), including nonsteroidal anti-inflammatory drugs, diet pills, and oral contraceptives among others. In addition, treatment adherence is highly important and should be assessed routinely [Mancia G et al.J Hypertens 2013]. In addition, physicians should exclude secondary causes of hypertension when appropriate and continually work to optimize antihypertensive regimens.


Figure 1. Algorithm to Validate Resistant Hypertension in Presenting Patients


ABPM=ambulatory blood pressure monitoring; Aldo=aldosteronism; BP=blood pressure; HBPM=home blood pressure measurement; OSA=obstructive sleep apnea; Pheo=pheochromocytoma. 

Adapted from Calhoun DA et al. Hypertension 2008.


Markus Schlaich, MD, PhD, Neurovascular Hypertension & Kidney Disease Laboratory, Melbourne, Australia, discussed the principles underlying RDN as a treatment of resistant hypertension. When the sympathetic nervous system is overactive, norepinephrine acts to stimulate the kidneys, heart, veins, and arterioles. Sympathetic stimulation of the kidneys results in sodium retention, renin release, and vasoconstriction. Stimulation of the heart increases heart rate and stroke volume, with chronic activation by norepinephrine leading to arrhythmias and left ventricular hypertrophy. In addition, norepinephrine affects the metabolism by stimulating lipolysis in adipocytes, gluconeogenesis in the liver, altering insulin release by the pancreas and rarefaction of the skeletal arterioles.


Prof. Schlaich highlighted multiple factors that can cause chronic activation of the sympathetic nervous system. For example, obesity may be associated with chronic sympathetic activation and it has been observed that individuals who lose ~8% to 9% of their body weight through diet or diet plus exercise demonstrate a significant decrease in sympathetic nerve activity [Straznicky NE et al. Diabetes 2010]. Moreover, ~70% to 80% of patients with resistant hypertension also have OSA, and OSA is associated with high sympathetic nervous activation.


Henry Krum, MBBS, PhD, Centre of Cardiovascular Research & Education in Therapeutics, Monash University, Melbourne, Australia, presented data of RDN efficacy and safety. The Symplicity HTN Program included three trials that evaluated RDN in refractory hypertension. In Symplicity HTN-1, 153 patients with ≥160 mm Hg systolic BP (SBP) despite treatment with ≥3 antihypertensive agents and an estimated glomerular filtration rate (eGFR) of ≥45 mL/min/1.73 m2 received RDN [Symplicity HTN-1 Investigators. Hypertension 2011; Krum H et al. Lancet 2009]. Patients undergoing RDN had reductions in office BP with a mean change from baseline of –27 mm Hg in SBP and –17 mm Hg in diastolic BP (DBP) at 12 months (p<0.001) and –32 and –14 mm Hg in SBP and DBP, respectively, at 36 months (in those patients for which follow up was available 88 patients, 58%).


In the Symplicity HTN-2 Study, 106 patients with uncontrolled hypertension of ≥160 mm Hg SBP despite ≥3 antihypertensive agents were randomized to receive RDN or control treatment [Esler MD et al. Lancet 2010]. Patients that received RDN demonstrated a 32 and 12 mm Hg reduction in SBP and DBP, respectively, compared 30 October with baseline at 6 months (p<0.0001), compared with a +1 mm Hg in SBP and no change in DBP in patients who received the control treatment (Figure 2). The randomized Symplicity HTN-3 trial is currently ongoing with results expected in 2016.


Figure 2. Effect of RDN on Office BP in Symplicity HTN-2


RDN=renal denervation.

Reproduced from Symplicity HTN-2 Investigators. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet 2010;376(9756):1903-1909. With permission from Elsevier.


Similar results were demonstrated in the EnLigHTN trial, which used a different catheter for the RDN procedure. In the EnLigHTN study, RDN was associated with a 26 and 10 mm Hg decrease in office-based SBP and DBP, respectively, compared with baseline [Worthley SG et al. Eur Heart J 2013]. Prof. Krum pointed out that multiple trials support the benefits of RDN in resistant hypertension though acknowledged that there are several case reports demonstrating no effect of RDN or even a paradoxical increase in BP [Baumbach A et al. Int J Cardiol 2013; Persu A et al. J Hypertens 2013 (abstr LB01.06); Vonend O et al. Lancet 2012]. Still further, Prof. Krum noted that there needs to be more robust safety analyses and suggested that the findings of the Symplicity HTN-3 trial would be very important. There were 4 complications out of 153 patients in Symplicity HTN-1, which included renal artery dissection and access site complications [Symplicity HTN-1 Investigators. Hypertension 2011]. In addition, reports of renal artery stenosis, hypotensive episodes, hypertensive episodes, and death due to myocardial infarction, sudden cardiac death, or cardio-respiratory arrest have been published.


Importantly, ~10% of the patients in Symplicity HTN-2 did not respond to RDN [Esler MD et al. Lancet 2010]. Prof. Mancia pointed out that nonresponse maybe due to a variety of factors such as nonsympathetic factors or incomplete RDN. Therefore, it is important to determine which patients will benefit from RDN and the completeness of the denervation should be assessed.


Michael Böhm, MD, PhD, Saarland University Hospital, Homburg/Saar, Germany, presented other investigational indications for RDN therapy. These indications include atrial fibrillation (AF), ventricular arrhythmias, insulin resistance and diabetes, OSA, chronic kidney disease, and chronic heart failure.


In the Symplicity trials, it was observed that some patients that had received RDN experienced improved blood glucose control [Böhm M et al. EuroIntervention 2013]. One hypothesis states that due to vasoconstriction, blood flow is directed away from insulin-sensitive organs such as the skeletal muscle, which can lead to insulin resistance. RDN is thought to restore the blood flow to insulin-sensitive organs, thus improving insulin sensitivity. In a pilot study of Symplicity data, patients with impaired fasting glucose that received RDN demonstrated a significant improvement in fasting glucose, fasting insulin, and the Homeostasis Model of Assessment-Insulin Resistance index from baseline compared with control patients at 1 and 3 months [Mahfoud F et al. Circulation 2011].


In a study of patients with moderate to severe chronic kidney disease, RDN resulted in stabilization of the disease as measured by eGFR [Hering D et al. J Am Soc Nephrol 2013]. In chronic heart failure, renal norepinephrine spillover is associated with significantly greater cumulative mortality (p=0.003), whereas total body spillover was not significantly associated (p=0.2) [Petersson M et al. Eur Heart J 2005]. In AF, RDN appears to decrease left ventricular hypertrophy beginning at 1 month following the intervention [Brandt MC et al. J Am Coll Cardiol 2012]. RDN also appeared to improve OSA; in a porcine model, RDN led to a reduction in atrial effective refractory period-shortening and AF-inducibility [Linz D et al. Hypertension 2012]. In a porcine model of ventricular arrhythmia, RDN resulted in reduced extra beats due to acute ventricular ischemia [Linz D et al. Hearth Rhythm 2013]; however, reperfusion-induced arrhythmias are not affected by RDN.


Guiseppe Mancia, MD, PhD, University of Milano-Biccoca, Monza, Italy, discussed the reasons behind the popularity and success of RDN, which include a robust pathophysiological rationale and evidence in small studies of a durable decrease in office BP over 3 years. However, Prof. Mancia warned that the long-term efficacy and safety of RDN on BP control has not yet been demonstrated and important questions remain about fiber regeneration and the long-term safety of multiple renal artery interventions.



UPDATE ON DYSLIPIDEMIA AND CARDIOVASCULAR DISEASE


Despite the use of statins in patients who are dyslipidemic, residual risk of cardiovascular disease (CVD) remains increased in many individuals [Libby P. J Am Coll Cardiol 2005]. New therapies are therefore needed to enhance the current standard of care for patients with high cardiometabolic risk [Chapman MJ et al. Eur Heart J 2009].


Key opinion leaders discussed the role of other available options for elevating high-density lipoprotein cholesterol (HDL-C). Jean-Pierre Després, PhD, Laval University, Quebec City, Quebec, Canada, explored the issue of raising HDL-C levels. Although low HDL-C levels predict coronary heart disease (CHD) risk in statin-treated patients [Kearney PM et al. Lancet 2008], he indicated that the solution to reducing CV risk is not as simple as increasing HDL-C levels, since both HDL-C particle size and concentration are independently associated with other CV risk factors, as well as risk for coronary artery disease [El Harchaoui K et al. Ann Intern Med 2009].


Lale Tokgözoglu, MD, Hacettepe University, Ankara, Turkey, presented data from trials on the therapeutic action of fibrates in atherogenic dyslipidemia. These agents are agonists of peroxisomal proliferator activated receptor-α, a transcription factor involved in fatty acid, lipid, and lipoprotein metabolism [Chapman MJ. Atherosclerosis 2003]. Prof. Tokgözoglu discussed data from two of the largest outcome studies in patients with type 2 diabetes mellitus (T2DM), the Fenofibrate Intervention and Event Lowering in Diabetes study [FIELD; Scott R et al. Diabetes Care 2009], and the Action to Control Cardiovascular Risk in Diabetes lipid trial [ACCORD; ACCORD Study Group. N Engl J Med 2010].


FIELD evaluated the efficacy of fenofibrate in subjects with T2DM [Scott R et al. Diabetes Care 2009]. Patients with severe dyslipidemia (triglycerides ≥2.3 mmol/L and low HDL-C were shown to be at the highest risk of CVD (17.8% over 5 years). Overall, fenofibrate did not significantly reduce the primary endpoint of CHD death or nonfatal myocardial infarction (MI; relative risk reduction [RRR],11%; p=0.16) [Sacks FM. Am J Cardiol 2008]. However, fenofibrate treatment reduced the incidence of CV events in patients with low HDL-C or hypertension, with the largest effect seen in those with marked dyslipidemia (RRR 27%; 95% CI, 9 to 42; p=0.005; Figure 1). Risk reductions were also greatest in patients without prior CVD [Scott R et al. Diabetes Care 2009].


Figure 1. Relative Risk of Cardiovascular Events in Patients in the FIELD Trial


CVD=cardiovascular disease; HDL-C=high-density lipoprotein cholesterol; TG=triglycerides.


The ACCORD Lipid Trial compared statin monotherapy with a statin plus fibrate on CV death, nonfatal MI and nonfatal stroke in >5500 subjects with T2DM [ACCORD Study Group. N Engl J Med 2010; MD Conference Express. ACC 2010]. Although there was no significant difference in the primary outcome (first occurrence of a major CV event, including nonfatal MI, nonfatal stroke, or death from CV causes) with fenofibrate compared with placebo (2.2% vs 2.4%; HR in the fenofibrate group, 0.92; 95% CI, 0.79 to 1.08; p=0.32), two hypothesis-generating observations in subgroup analyses warrant attention. Patients who had an elevated triglyceride level in the highest third of those studied (≥204 mg/dL [≥2.30 mmol/L]) and also had the lowest HDL-C levels (≤34 mg/dL [≤0.88 mmol/L]) had 31% fewer CV events with fenofibrate therapy (12.4% vs 17.3%; p=0.03) compared with all other patients (10.1% vs 10.1%; p=NS; p-interaction=0.057). Secondly, the effect of fenofibrate was significantly modified by sex (p-interaction=0.01), with a reduced CV event rate by 16% in men (11.2% vs 13.3%) compared with a 38% increase CV risk in women (9.1% vs 6.6%).


Although these data do not support routine addition of fenofibrate to background statin therapy to reduce CV risk in most patients with T2DM, they suggest potential benefit in helping to reduce residual risk in those with elevated triglycerides and low HDL-C, and perhaps in men but not women, that warrants further study [ACCORD Study Group. N Engl J Med 2010; Scott R et al. Diabetes Care 2009].


Philip Barter, MD, PhD, University of New South Wales, Sydney, Australia, reviewed data from the large, randomized Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events [HPS-2 THRIVE; Armitage J et al. Eur Heart J 2013] study that examined the use of combining extended-release niacin and laropiprant with statin treatment for the reduction of major CV events in more than 25,000 patients. The study demonstrated no significant reduction in major CV events with the addition of extended-release niacin/laropiprant to statin. Furthermore, serious adverse events (AEs), including increased risk of myopathy, gastrointestinal bleeding, stroke, and infection, were reported in ~30 patients per 1000 throughout the almost 4-year course of the trial.


According to Raul D. Santos, MD, PhD, MSc, Heart Institute-InCor, University of São Paulo, São Paulo, Brazil, adjunctive therapy with ezetimibe has also been a controversial issue owing to randomized trials that have provided conflicting results about atherosclerotic plaque regression via carotid intima-media thickness, as well as a concern about a possible increase cancer risk [Peto R et al. N Engl J Med 2008].


The Improved Reduction of Outcomes: Vytorin Efficacy International Trial [IMPROVE-IT; NCT00202878] is a randomized, clinical outcomes study comparing simvastatin 40 mg plus ezetimibe 10 mg with simvastatin 40 mg alone in over 18,000 patients with a recent acute coronary syndrome followed for a minimum of 2.5 years. The primary outcome is time to first major vascular event (CV death, nonfatal MI, hospital admission for unstable angina, revascularization >30 days, and nonfatal stroke). Data from the study are expected next year.


Low-dose supplementation with n-3 fatty acids, however, may lower the risk of major CV events in post-MI patients who are not treated with statins, said Daan Kromhout, MD, MPH, PhD, Wageningen University, Wageningen, The Netherlands. He presented data from the multicenter Alpha Omega Trial, the first, double-blind, placebo-controlled study to assess the efficacy of low doses of n-3 fatty acids (400 mg/day eicosapentaenoic acid [EPA]–docosahexaenoic acid [DHA], and/or 2 g/day α-linolenic acid [ALA]) on the risk of fatal and nonfatal major CV events [Eussen SRBM et al. Eur Heart J 2012].

In the trial overall, the primary endpoint of major CV events occurred in 14% of EPA-DHA versus 13% in placebo (adjusted HR, 1.05; 95% CI, 0.82 to 1.34; adjusted p=0.72). Although providing additional n-3 fatty acids to statin users did not reduce CV events, only 9% of statin nonusers who received EPA–DHA plus ALA experienced an event, compared with 18% in the placebo group (adjusted HR, 0.46; 95% CI, 0.21 to 1.01; p=0.051). For some post-MI patients who do not tolerate statins, omega-3 fatty acids may represent an alternative therapy to reduce major CV events that warrants further study [Eussen SRBM et al. Eur Heart J 2012].


Decisions about statin treatment for CVD prevention should be guided by anticipated benefits and potential AEs, stressed Guy De Backer, MD, PhD, University of Ghent, Ghent, Belgium. He presented data from a meta-analysis that evaluated results from 135 studies on different statins, to determine their comparative tolerability and harms [Naci H et al. Circ Cardiovasc Qual Outcomes 2013].


There was no difference in the occurrence of myalgia, creatine kinase elevation, cancer, and drug discontinuations due to adverse events (AEs), between individual statins and control. Statin treatment in general, however, significantly increased the odds of developing diabetes (OR, 1.09; 95% CI, 1.02 to 1.16) and transaminase elevations (OR, 1.51; 95% CI, 1.24 to 1.84) [Naci H et al. Circ Cardiovasc Qual Outcomes 2013]. Given these data, clinicians should therefore advise patients of the modest risks prior to initiating statin therapy and monitor for development of these AEs. However, the implications of increased incident diabetes remain unclear in these studies, since statin treatment substantially reduced CV risk.


Alberico L. Catapano, MD, University of Milan, Italy, discussed data on proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, a new class of cholesterol-lowering drugs. PCSK9 is a protein in plasma that binds to low-density lipoprotein (LDL) receptors, resulting in their degradation such that fewer are present on the hepatic cell surface to remove excess LDL from the blood. PCSK9 inhibition therefore represents a new treatment strategy for dyslipidemia and associated CVD, and of the various classes of agents in development, two monoclonal antibodies, alirocumab and AMG 145, are in Phase 3, and several more are in Phase 2 development (Table 1).


Table 1. PCSK9 Inhibitors in Development


Prof. Catapano presented data from the Phase 2 Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects study [GAUSS], a double-blind placebo-controlled trial in 160 patients intolerant of statins that evaluated the efficacy and safety of AMG 145 compared with ezetimibe control [Sullivan D et al. JAMA 2012; MD Conference Express. AHA 2012].


Patients were randomized to 1 of 5 groups (AMG 145 at doses of 280, 350, or 420 mg; AMG 145 at 420 mg plus ezetimibe 10 mg; ezetimibe 10 mg plus placebo) and were treated for 12 weeks. The primary endpoint was the percent change in LDL cholesterol (LDL-C) from baseline at 12 weeks [Sullivan D et al. JAMA2012]. At Week 12, LDL-C levels in AMG 145-treated groups were significantly lower (p<0.001) than in ezetimibe-controlled group. Mean changes in LDL-C levels ranged from –40.8% to –50.7% in the AMG 145-only groups, compared with the AMG 145/ezetimibe group at –63.0% and placebo at –14.8% (Figure 2) [Sullivan D et al. JAMA 2012].


Figure 2. AMG 145-Induced Changes in LDL-C Levels

 

Reproduced with permission from AL Catapano, MD.


Four serious AEs were reported with AMG 145 treatment versus zero with control. Myalgia was the most common treatment-associated AE (in 15.6% of subjects in the 280-mg group; 3.2% in the 350-mg group; 3.1% in the 420-mg group; 20.0% in the 420-mg AMG 145 plus ezetimibe group; and 3.1% in the ezetimibe plus placebo group). Further evaluation of the longer-term efficacy and safety of AMG 145 is underway in the FOURIER study [NCT01764633], a trial of 22,500 patients with prior CVD.


Børge G. Nordestgaard, MD, DMSc, Copenhagen University Hospital, Copenhagen, Denmark, discussed evidence suggesting that lipoprotein-a (Lp[a]) serves as an independent, genetic risk factor for CVD, with elevated levels associated with an increased risk of MI [Kamstrup PR et al. JAMA 2009].


In a study of patients without CVD, additional information on lipid-related markers (apolipoprotein B and A-I, Lp(a), or lipoprotein-associated phospholipase A2 mass) to total cholesterol and HDL-C improved CVD prediction [Di Angelantonio E et al. JAMA2012]. Furthermore, extremely high Lp(a) levels can further improve CV risk prediction beyond conventional risk factors. In another study involving 8720 patients, Lp(a) levels ≥80th percentile (≥47 mg/dL) significantly improved MI (23%) and CHD (12%) risk prediction (p<0.001) [Kamstrup P et al. J Am Coll Cardiol 2013].


Prof. Nordestgaard concluded that while the relationship between Lp(a) and CV events requires further evaluation to determine its role as a marker of clinical risk, therapeutic options for its manipulation remain limited, and lipid-modifying strategies such as fibrates and statins have limited and variable effects [Nordestgaard BG et al. Eur Heart J 2010]. In the short-term (12 weeks), the PCSK9 inhibitor AMG 145 reduced Lp(a) by up to 32% compared with placebo [Desai NR et al. Circulation2013]. Additional data with novel therapies to reduce Lp(a) over the long-term and to assess the impact on clinical outcomes are needed.


THE CHANGING LANDSCAPE OF DIABETES DIAGNOSIS AND SCREENING


According to the International Diabetes Federation, the number of people with the disease is increasing in every country. In 2011, diabetes affected 366 million individuals worldwide, and that figure is expected to rise to 552 million by 2030. Over 180 million people with diabetes (50%) are undiagnosed [International Diabetes Federation. IDF Diabetes Atlas: Fifth Edition, 2011. www.idf.org/diabetesatlas/5e/the-global-burden].


The main objective in caring for type 2 diabetes mellitus (T2DM) patients is the prevention of microvascular and potentially macrovascular complications with improved glycemic control along with management of other risk factors [Konig M et al. Curr Diabetes Rev 2013]. Diabetes is associated with both kinds of complications, affecting numerous organs, including the heart, brain, and kidneys [Cade WT. Phys Ther 2008]. While improving glycemic control has been shown to reduce microvascular complications, the impact on macrovacular complications has been less clearly established.


Glycated hemoglobin (HbA1C) is emerging as an important tool for formally diagnosing diabetes in the United States [American Diabetes Association. Diabetes Care 2010]. Screening for diabetes previously performed with standard fasting blood glucose or glucose challenge testing may now be done with HbA1C [Preiss D et al. Diabet Med 2011]. Naveed Sattar, MD, University of Glasgow, Glasgow, Scotland, United Kingdom, discussed new ways to diagnose diabetes and identify those at high risk using HbA1C.


The adoption of HbA1C into diagnostic criteria will facilitate diabetic screening and may help refine assessment of cardiovascular risk (Figure 1) [Sattar N, Preiss D. Diabetologia 2012]. As a diabetes risk assessment and screening option, it requires no fasting and can dovetail with existing vascular screening. This makes it a very attractive way to greatly improve early detection and management of individuals at high risk of cardiovascular disease (CVD) and/or diabetes [Preiss D et al. Diabet Med 2011]. Based on such evidence, HbA1C has now been accepted into the European Society of Cardiology/European Association for the Study of Diabetes guidelines for the diagnosis of diabetes.


Figure 1. HbA1C as Diagnostic Criteria Will Facilitate Combined CV and Diabetic Screenings


 

CV=cardiovascular; FPG=fasting plasma glucose; IGT=impaired glucose tolerance; OGTT=oral glucose tolerance test.

Adapted from Sattar N, Preiss D. Diabetologia 2012.


As the interplay between CV risk and diabetes risk becomes clearer the case for combined diabetes/other CV risk factor screening (generally using HbA1C and nonfasting lipids) has now gained support [Sattar N.Diabetologia 2013]. Prof. Sattar discussed this and other new paradigms in play, including those that obviate conventional wisdom.


More recent data suggest that the duration of T2DM is associated with CVD; both early and late onset of diabetes are associated with increased risk; however, only early onset (associated with a duration >10 years) seems to portend risk equivalent to coronary heart disease [Wannamethee SG et al. Arch Intern Med 2011].


Whereas blood glucose was once considered a linear risk factor for CVD with a dose-response relationship [Levitan EB et al. Arch Intern Med 2004], Sarwar et al. [Lancet 2010] report that fasting blood glucose has a J-shaped relationship with vascular risk, with little if any risk at concentrations between 3.90 and 5.59 mmol/L, and risk escalating appreciably around current diagnostic cutoffs (ie, 7 mmol/L).


The ADVANCE trial investigated the relationship between HbA1C and the risk of vascular complications and death in patients with T2DM [Zoungas S et al. Diabetologia 2012]. The trial found that reducing HbA1C levels was associated with lower risks of microvascular events down to a threshold of 6.5%, and macrovascular events and death down to a threshold of 7.0% (Figure 2).


Figure 2. The Association of HbA1C With Risk in Diabetes


 

Adapted from Zoungas S et al. Association of HbA1c levels with vascular complications and death in patients with type 2 diabetes: evidence of glycaemic thresholds. Diabetologia 2012;55(3):636-643.



UPDATE ON MANAGING DYSGLYCEMIA IN ACUTE CORONARY SYNDROMES


According to Anna Norhammer, MD, PhD, Karolinska University Hospital, Stockholm, Sweden, managing dysglycemia in the coronary care unit has evolved with insight from trials of glycemic control in the intensive care unit setting. The first DIGAMI trial, published in 1995, showed a clear mortality reduction with glucose control during and after the acute phase of a myocardial infarction, aiming at blood glucose levels between 7 to 10 mmol/L (plasma 7.7 to 11 mmol/L) during the acute phase. Since then trials from the intensive ward have reported conflicting results when it comes to lowering glucose during hospitalization [Malmberg K, Ryden L. J Am Coll Cardiol 1995].


In 2001, van den Berghe et al. [N Engl J Med] found that intensive insulin therapy to maintain blood glucose at or below 110 mg/dL reduced both morbidity and mortality among critically ill patients in the surgical intensive care unit (ICU). In 2009, Finfer et al. [N Engl J Med] demonstrated that intensive glucose control increased mortality among adults in the ICU, with a more lenient blood glucose target of ≤180 mg/dL resulting in lower mortality compared with a more intense target of 81 to 108 mg/dL. These data demonstrate a consistent pattern across care settings of increased CV risk associated with both hyperglycemia as well as hypoglycema.


This year’s European Society of Cardiology Guidelines on Diabetes, Pre-diabetes, and Cardiovascular Diseases (developed in collaboration with the European Association for the Study of Diabetes) recommend that insulin-based glycemic control should be considered in acute coronary syndrome (ACS) patients with significant hyperglycemia of >180 mg/dL (>10 mmol/L), with the target adapted in the presence of comorbidities [Rydén L et al. Eur Heart J 2013]. In addition, glycemic control that may be accomplished by different glucose-lowering agents should be considered in DM and ACS.


Remaining questions, said Prof. Norhammer, include the role and optimal level of glycemic control for the outcome in ACS patients; and whether it is possible to reduce final infarct size by means of very early glucose-insulin-potassium administration after symptoms of myocardial infarction. Prof. Norhammar concluded that we should keep measuring glucose in the cardiac care unit and suggested that aiming at glucose levels between 7.8 to <11 mmol/L should be safe while the risk for hypoglycemia probably will increase if targeting values lower than 7 mmol/L. She also pointed out that a large proportion of patients will have previously unknown diabetes and impaired glucose intolerance, about 60% of myocardial infarction patients. This is only determined by performing an oral glucose tolerance test before discharge [Norhammer A et al. Lancet 2002].



DIABETES AND HEART FAILURE: WHAT ARE THE MANAGEMENT OPTIONS?


Some 5.7 million people in the United States have heart failure (HF) [Roger VL et al. Circulation 2012]. HF causes >55,000 deaths each year [Kochanek KD et al. Natl Vital Stat Rep 2011], with significant associated costs related to healthcare services, medications, and lost productivity [Heidenriech PA et al. Circulation2011]. David Aguilar, MD, Baylor College of Medicine, Houston, Texas, USA, discussed the management options for DM and HF.


According to Dr. Aguilar, management of diabetes in patients with HF is generally is similar to those without HF, but there are diabetes-specific issues. These include the appropriate glycemic targets in patients with HF, and the appropriate options for hyperglycemic therapy.


Recommendations for glycemic control from the American Diabetes Association [Diabetes Care 2013] call for:

 

  • HbA1C goal below or around 7%, which is considered reasonable due to microvascular benefits and potential long-term macrovascular benefits if glucose lowering regimen implemented soon after DM diagnosis
  • More stringent HbA1C goals (<6.5%) for selected patients (eg, those with short diabetes duration, less risk of hypoglycemia, long life expectancy, and no significant CVD)
  • Less stringent HbA1C goals (<8%) for those with advanced microvascular or macrovascular complications, extensive comorbid conditions, or a history of hypoglycemia or difficult to treat, longstanding DM

 

According to Dr. Aguilar, optimal hyperglycemic therapy in HF patients is not clear. He noted that metformin can be used with caution, and that prospective outcome data are needed for other agents, including glucagon-like peptide-1 agonists and dipeptidyl peptidase-4 inhibitors given unexpected results from the SAVOR-TIMI 53 trial in high-risk CV patients.


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