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Meeting Reports

62nd Annual Scientific Sessions of the American College of Cardiology (ACC)
March 9 - 11, 2013
San Francisco, CA

NOVEL THERAPEUTICS MAY LOWER LDL IN FAMILIAL HYPERCHOLESTEROLEMIA


Familial combined hyperlipidemia is a highly atherogenic disorder that affects 1% to 2% of the Western world [Shoulders CC et al. Hum Mol Genet 2004]. It occurs in approximately 20% of patients who develop coronary heart disease before age 60 [Aouizerat BE et al. Am J Hum Genet 1999].


Patrick M. Moriarty, MD, University of Kansas Medical Center, Lawrence, Kansas, USA, explained that treatment of familial hypercholesterolemia (FH) represents an unmet medical need. Statins have been shown to improve survival and reduce the risk of myocardial infarction (MI) in heterozygous familial hypercholesterolemia (HeFH) [Versmissen J et al. BMJ 2008] and prolong survival in homozygous familial hypercholesterolemia (HoFH) [Raal FJ et al. Circulation 2011]. Emerging therapies include apolipoprotein B (ApoB) inhibitors, microsomal triglyceride transfer protein (MTP) inhibitors, and proprotein convertase subtilism kexin 9 (PCSK9) inhibitors [Alonso R et al. Expert Rev Cardiovasc Ther 2013].


Mipomersen, an Injectable Apolipoprotein B-100 Inhibitor

 John J.P. Kastelein, MD, PhD, University of Amsterdam, Amsterdam, The Netherlands, spoke about the benefits of mipomersen, a 20-mer phosphorothioate antisense oligonucleotide that is complementary in sequence to a segment of the human ApoB mRNA [Kastelein JJ et al. Circulation 2006]. Mipomersen is administered as a subcutaneous injection and has been shown to reduce low-density lipoprotein cholesterol (LDL-C), apoB, total cholesterol, and non-high-density lipoprotein cholesterol (non-HDL-C) levels in patients with HoFH, heterozygous FH as well as high-risk hypercholesterolemic patients. It has been developed as an adjunct to standard therapies including a statin; however, its indication was limited by regulatory authorities due to its many side effects, including liver enzyme abnormalities and accumulation of fat in the liver [Raal FJ et al. Lancet 2010; Stein EA et al. Circulation 2012].


In a randomized, double-blind, multicenter, placebo controlled, Phase 3 study in which 34 HoFH patients who were already receiving the maximum tolerated dose of a lipid-lowering drug were randomly assigned to mipomersen 200 mg subcutaneously every week or placebo for 26 weeks, the mean percent change in LDL-C concentration was significantly greater with the addition of mipomersen (−24.7%; 95% CI, −31.6 to −17.7) compared with placebo (−3.3%; 95% CI, −12.1 to 5.5; p=0.0003) [Raal FJ et al. Lancet 2010].


Lomitapide , an Oral MicrosomalTransfer Protein Inhibitor

 Michael Davidson, MD, University of Chicago, Chicago, Illinois, USA, discussed the oral MTP inhibitor, lomitapide. MTP, an intracellular lipid-transfer protein found in the lumen of the endoplasmic reticulum, is responsible for binding and shuttling individual lipid molecules between membranes [Hussain MM et al. J Lipid Res 2003]. Normal concentrations and function of MTP are necessary for the proper assembly and secretion of apoB-containing lipoproteins in the liver and intestines [Liao W et al. J Lipid Res 2003].


A dose-escalation study to examine the safety, tolerability, and effects on lipid levels of lomitapide (BMS-201038), an inhibitor of the miscrosomal triglyceride transfer protein, showed that all patients tolerated titration to the highest dose of 1.0 mg/kg/day. Treatment at this dose decreased LDL-C levels by 51% and apoB levels by 56% from baseline (p<0.001 for both comparisons) [Cuchel M et al. N Engl J Med 2007]. Serious adverse effects associated with lomitapide included hepatic fat accumulation and elevated liver aminotransferase levels. Thus as with mipomersen, lomitapide has received FDA approval for use only in patients with HoFH due to adverse events which include elevations in serum transaminase and hepatic steatosis and gastrointestinal side effects [Robinson JG. J Manag Care Pharm 2013].


Cholesteryl Ester Transfer Protein Inhibitors

 Christopher Cannon, MD, Harvard Medical School, Boston, Massachusetts, USA, discussed the oral CETP inhibitors. The ILLUMINATE trial studied torcetrapib, and, in spite of favorable effects on lipids including a 72% increase in HDL and a 25% reduction in LDL-C, was stopped early due to increased major cardiovascular (CV) events and higher blood pressure ILLUMINATE; Barter PJ et al. N Engl J Med 2007]. Later studies suggested that the adverse effects of torcetrapib came from molecule-specific off-target effects on the adrenal gland, and were not related to the direct effect of CETP inhibition [Krishna R et al. Lancet 2007].


Dalcetrapib, the second CETP inhibitor developed, was evaluated in the dal-OUTCOMES trial in patients (n=15,871) with a recent acute coronary syndrome. A substantial increase in HDL levels was seen with dalcetrapib compared with placebo (31% to 40% vs 4% to 11%), and no off-target effects on the adrenal gland or hypertension were observed. However, dalcetrapib did not reduce the primary composite outcome of death from coronary heart disease, a major nonfatal coronary event or ischemic stroke (8.3% with dalcetrapib vs 8.0% with placebo; HR, 1.04; 95% CI, 0.93 to 1.16; p=0.52) [Schwartz GG et al. N Engl J Med 2012].


Anacetrapib is the third CETP inhibitor. It increases HDL-C by over 100% and lowers LDL-C by 30% to 40% as monotherapy and when coadministered with statins [Cannon CP et al. N Engl J Med 2010]. In a recent 1.5-year safety study in ~1600 patients with CV disease [Cannon CP et al. N Engl J Med 2010], anacetrapib treatment had no effect on blood pressure, electrolytes, or aldosterone, and the distribution of CV events suggested that anacetrapib treatment would not be associated with an increase of CV risk as was seen with torcetrapib.


A randomized controlled trial in 398 patients with elevated LDL-C or low HDL-C of a fourth CETP inhibitor, evacetrapib, showed that evacetrapib monotherapy produced dose-dependent increases in HDL-C of 54% to 129% and decreases in LDL-C of −14% to −36% (both p<0.001 compared with placebo) [Nicholls SJ et al. JAMA 2011].

 

Both anacetrapib and evacetrapib are currently involved in ongoing Phase 3 trials.


Proprotein Convertase Subtilism Kexin 9 Inhibitors

James M. McKenney, PharmD, Virginia Commonwealth University, Richmond, Virginia, USA, discussed PCSK9 inhibitors, a novel therapy for lowering LDL-C. PCSK9 regulates cholesterol and/or lipid homeostasis via cleavage at nonbasic residues or through induced degeneration of receptors. Reduction in LDL-C levels with PCSK9 is associated with a substantial reduction in the incidence of coronary events, even in populations with a high prevalence of non–lipid-related CV risk factors [Cohen JC et al. N Engl J Med 2006].


In the LAPLACE-TIMI 57 Phase 2, multicenter, dose-ranging study, 631 stable patients with hypercholesterolemia on a statin, were randomly assignedto AMG 145, a fully human monoclonal IgG2 antibody against PCSK9, administered subcutaneously every 2 (70, 105, or 150 mg) or 4 weeks (280, 350, or 420 mg) or matching placebo injections [Giugliano RP et al. Lancet 2012]. At the end of the 12-week period, largely dosedependent reductions in the mean LDL-C concentrations for the every 2-week regimens ranged from 42% to 66% and from 42% to 50% for the every 4-week regimens (p<0.0001 for each dose vs placebo). These results suggest that PCSK9 inhibition could be a new model in lipid management and is being evaluated in ongoing Phase 3 clinical trials.


SAR236553/REGN727, another injectable monoclonal antibody to PCSK9, also showed promising results in a multicenter, randomized, placebo-controlled Phase 2 trial in adults with HeFH and LDL-C concentrations of 100 mg/dL or higher on stable diet and statin dose, with or without ezetimibe. Patients were randomized to receive subcutaneous REGN727 150, 200, or 300 mg every 4 weeks, or 150 mg every 2 weeks, or matching placebo every 2 weeks (ratio 1:1:1:1:1). The primary endpoint of LDL-C reduction from baseline to Week 12 was 29% for 150 mg every 4 weeks (p=0.0113), 32% for 200 g every 4 weeks (p=0.0035), 43% for 300 mg every 4 weeks (p<0.0001), and 68% for 150 mg every 2 weeks (p<0.0001), compared with 11% with placebo. [Stein EA et al. Lancet 2012]. A Phase 3 trial is underway to evaluate the CV effects and long-term safety of this compound on a background of statin therapy.


Until recently, many patients with HeFH and HoFH had difficultly achieving adequate reduction in LDL-C. Mipomersen and lomitapide have recently received FDA approval for the treatment of HoFH and offer new options as adjuncts to high-dose statins and secondline treatments. As emerging therapies such as CETP inhibitors and PCSK9 inhibitors continue development, options will increase for patients with HoFH, HeFH, and other patients with severe dyslipidemia.



2013 CANADIAN HYPERTENSION EDUCATION PROGRAM RECOMMENDATIONS


With the 2013 Joint National Committee Guidelines for the Management of High Blood Pressure (BP) in adults still under revision and not available for discussion, Suzanne Oparil, MD, University of Alabama at Birmingham, Birmingham, Alabama, USA, discussed new and important recommendations from the Canadian Hypertension Education Program (CHEP) [Daskalopoulou SS et al. Can J Cardiol 2012].


In the last few years, out-of-office (home) BP measurement has assumed a more prominent role in the diagnosis and follow-up of hypertensive patients, in part because it may help to identify "white coat” or "masked” hypertension. Differentiation is important because those with masked hypertension have a higher rate of cardiovascular events compared with patients who are normotensive or have white coat hypertension. Previously, patients who were found to have normal BP at home (ie, <135/85 mm Hg) but elevated readings in the office were recommended for 24-hour ambulatory monitoring to confirm white coat hypertension. The Task Force has now added repeat home BP monitoring as another method to confirm white coat hypertension in such patients.


The Task Force also made an important modification to the management recommendations for patients with hypertension associated with nondiabetic chronic kidney disease. After a comprehensive reassessment of the evidence examining BP targets in this patient population, it concluded that there was insufficient evidence to support a target of 130/80 mm Hg. Therefore, the target BP in this patient population was changed to <140/90 mm Hg, similar to the general population.

 

The summary of evidence from CHEP for patients with diabetes and hypertension suggest lowering systolic BP to <140 mm Hg to reduce all-cause mortality and stroke, with systolic BPs <135-130 mm Hg appearing to confer significant additional benefits with respect to stroke.


Although the risk of serious adverse events increases with BPs <140 mm Hg, the absolute number of these risk events is low, and therefore, the <130/80 mm Hg BP target in patients with diabetes remained unchanged in the current CHEP recommendations.


Monotherapy is often not enough [Cushman WC et al. J Clin Hypertens (Greenwich) 2002], especially for patients with diabetes, and therefore, many hypertensive patients now receive ≥2 antihypertensive agents. According to the Task Force, using single pill combinations may help to achieve BP control by improving medication compliance. Another way to improve patient compliance with BP treatment is to start an ongoing counseling to discuss and assess coronary risk (Figure 1) [Grover SA et al. J Gen Intern Med 2009].


Figure 1. Impact of Discussing Coronary Risk With Hypertensive Patients


 

The American Diabetes Association’s (ADA) 2013 edition of Standards of Medical Care in Diabetes recommends that individuals with diabetes and hypertension be treated to a systolic BP goal of <140 mm Hg consistent with the CHEP guidelines [ADA Diabetes Care2013]. In contrast, however, they note that some lower targets for specific patients and for diastolic BP including a systolic BP target of <130 mm Hg may for certain individuals (eg, younger patients) if it can be achieved without unnecessary treatment burden and target diastolic BP for diabetic patients of <80 mm Hg. Patients with BP >120/80 mm Hg should be persuaded to make lifestyle changes, while those with BP ≥140/80 mm Hg should begin treatment with ³1 pharmacological agents (either an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker) plus lifestyle therapy to achieve BP goals. Finally, for pregnant patient with diabetes and chronic hypertension, the ADA suggests BP target goals of 110/65 to 129/79 mm Hg in the interest of long-term maternal health and to minimize impaired fetal growth.



CHRONIC CORONARY ARTERY DISEASE: GUIDELINE UPDATE


Stephan D. Fihn, MD, MPH, University of Washington, Seattle, Washington, USA, discussed the current management of patients with chronic coronary artery disease (CAD) by highlighting key concepts from the 2012 Guidelines for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease [Fihn SD et al. J Am Coll Cardiol 2012]. The guidelines include detailed algorithms for diagnosis, risk assessment, guideline-directed medical therapy (GDMT), and revascularization to improve symptoms.


The key concepts from the guideline include the following:

 

  • Management of stable ischemic heart disease (SIHD) should be based on strong scientific evidence and patient preference.
  • Patients presenting with angina should be categorized as stable versus unstable. Those at moderate or high risk should be treated emergently for acute coronary syndrome.
  • A standard exercise test is the first choice to diagnose IHD for patients with an interpretable electrocardiogram (ECG) and the ability to exercise, especially if the likelihood is intermediate (10% to 90%).
  • Those who have an uninterpretable ECG and are able to exercise should undergo an exercise stress test with nuclear myocardial perfusion imaging (MPI) or echocardiography, particularly if likelihood of IHD is >10%. If unable to exercise, MPI or echocardiography with pharmacologic stress is recommended.
  • Patients diagnosed with SIHD should undergo assessment of risk for death or complications.
  • For patients with an interpretable ECG and who the ability to exercise, a standard exercise test is also the preferred choice for risk assessment. Those who have an uninterpretable ECG and are able to exercise should undergo an exercise stress with nuclear MPI or echocardiography, while for those patients unable to exercise, a nuclear MPI or echocardiography with pharmacologic stress is recommended.
  • Patients with SIHD should generally receive a "package” of GDMT that includes lifestyle interventions and medications shown to improve outcomes. This includes the following (as appropriate): Diet, weight loss, and regular physical activity; if a smoker, smoking cessation; aspirin 75 to 162 mg daily; a statin medication in moderate dosage; if hypertensive, antihypertensive medication to achieve a blood pressure (BP) <140/90 mm Hg; and »» if diabetic, appropriate glycemic control.
  • Patients with angina should receive sublingual nitroglycerin and a b-blocker. When these are not tolerated or are ineffective, a calcium-channel blocker or long-acting nitrate may be substituted or added.
  • Coronary arteriography should be considered for patients with SIHD whose clinical characteristics and results of noninvasive testing indicate a high likelihood of severe IHD and when the benefits are deemed to exceed risk.
  • The relatively small proportion of patients who have "high-risk” anatomy (eg, >50% stenosis of the left main coronary artery), revascularization with coronary artery bypass grafting should be considered to potentially improve survival. Most data showing improved survival with surgery compared with medical therapy are several decades old and based on surgical techniques and medical therapies that have advanced considerably. There are no conclusive data demonstrating improved survival following percutaneous coronary intervention.
  • Most patients should have a trial of GDMT before considering revascularization to improve symptoms. Deferring revascularization is not associated with worse outcomes.
  • Prior to revascularization to improve symptoms, coronary anatomy should be correlated with functional studies to ensure lesions responsible for symptoms are targeted.
  • Patients with SIHD should be carefully followed to monitor progression of disease, complications, and adherence (Table 1). Exercise and imaging studies should generally be repeated only when there is a change in clinical status (not annually).

Table 1. Noninvasive Testing in Known SIHD

 

CABG=coronary artery bypass grafting; CCTA=cardiac computed tomography angiography; CMR=cardiovascular magnetic resonance; ECG=electrocardiogram; PCI=percutaneous coronary intervention; SIHD=stable ischemic heart disease.

 

The Scientific Statement from the American Heart Association (AHA), the American College of Cardiology Foundation (ACCF), and the American Society of Hypertension (ASH) on the Treatment of Hypertension in the Prevention and Management of Ischemic Heart Disease is expected for publication later this year (2013). A prepublication embargo prevented discussion at this year’s annual ACC meeting. Suzanne Oparil, MD, University of Alabama at Birmingham, Birmingham, Alabama, USA, suggested that the 2011 Performance Measures for Adults With Coronary Artery Disease and Hypertension [Drozda J Jr et al. J Am Coll Cardiol 2011] could provide some insight into the direction of the new guidelines. Specifically, she noted that the 2011 measures go beyond targeting established BP goals. The goal of antihypertensive treatment in patients with CAD or at high cardiovascular disease (CVD) risk was defined as <140/90 mm Hg. The rationale behind this change from a prior goal of <130/80 mm Hg was that some clinical trials in which specific antihypertensive drug therapies were given to individuals with CAD or high CVD risk who had BP <140/90 mm Hg showed benefit, but others had negative or equivocal findings. This heterogeneity in the published literature was used to justify a less strict (<140/90 mm Hg) BP goal in the performance measures. While the authors acknowledge that lower BP targets may be appropriate for some patients with CAD or other conditions, it is unclear how such patients could be reliably identified for purposes of performance measurement. In Dr. Oparil’s opinion, the strongest evidence in support of the concept that "lower is not better” is the ACCORD trial, which showed no benefit from intensive (<120 mm Hg) versus standard (<140 mm Hg) BP control in terms of fatal and nonfatal major CV events in patients with type 2 diabetes at high risk for CV events [ACCORD Study Group. N Engl J Med 2010]. Subanalyses and post hoc reports from the INVEST [Cooper-DeHoff RM et al. JAMA2010] and ONTARGET trials [Mancia G et al. Circulation 2011] provide similar findings. Although the Systolic Blood Pressure Intervention Trial [SPRINT; NCT01206062] will likely not end until 2016 or later. Dr. Oparil said the results are highly anticipated as it is designed to assess the effects of intensive BP lowering (<120 vs <140 mm Hg) on major CV events in patients without diabetes but with CVD risk factors, including chronic kidney disease, clinical CVD (excluding stroke), and age >75 years.

 

As with the 8th report on the Joint National Committee on Prevention, Detection, Evaluation and Treatment of Hypertension (JNC8), the Guidelines for the Management of High Blood Pressure in Adults – JNC 2013, the new guidelines for treating lipids in patients at risk for CVD (Adult Treatment Panel; ATP IV) are also still in development. In lieu of a discussion of the guidelines, Jennifer G. Robinson, MD, MPH, University of Iowa, Iowa City, Iowa, USA, discussed new evidence published since the committee completed their work and some of the evidence considered in the development of the guidelines. Of recent interest are the results of a meta-analysis of 27 primary and secondary prevention trials (n=134,537 participants) that evaluated the effects of using statins to lower low-density lipoprotein cholesterol (LDL-C) in individuals at low risk of CVD [Cholesterol Treatment Trialists’ Collaborators.Lancet 2012]. A key finding of the study was that for individuals with a 5-year risk of major vascular events of <10% (a population of patients not typically considered suitable for statin therapy), each 1-mmol/L reduction in LDL-C produced an absolute reduction in major vascular events of approximately 1.1%. In particular, those patients without a history of vascular disease and a 5% to <10% 5-year major CVD risk experienced a significant reduction (34%; p=0.003 for trend) in the relative risk of major CVD and a borderline significant 17% reduction in total mortality compared with those in the higher risk groups (Figure 1).


Figure 1. Reduction in Major CVD Risk Among Primary Prevention Patients With a 5% to 10% 5-Year Major CVD Risk per 1 mmol Reduction in LDL-C With a Statin



CVD=cardiovascular disease; LDL-C=low-density lipoprotein cholesterol; MVE=major vascular events.

Adapted from Mihaylova B et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: Meta-analysis of individual data from 27 randomised trials. The Lancet Aug 2012;380(9841):581-590.


The AHA recently issued a statement on triglycerides and CVD [Miller M et al. Circulation 2011]. Dr. Robinson briefly summarized that statement noting that the focus in patients with triglyceride levels <500 mg/dL should be on decreasing the risk for CVD through improved diet, increased physical activity, and weight loss, and by getting the patient on a statin. These patients should also be assessed for diabetes. Treatment is the same for patients whose triglyceride level is >500 mg/dL, but with the additional focus of preventing pancreatitis.

 

This session offered some early insights into the long-awaited and eagerly anticipated release of the JNC-8 and ATP IV guidelines.



HIGH-DOSE ROSUVASTATIN REDUCES CONTRAST-INDUCED NEPHROPATHY


Among statin-naïve patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS) managed with an early invasive strategy, pretreatment with high-dose rosuvastatin was associated with a significant reduction in the incidence of contrast-induced acute kidney injury (CI-AKI). In addition, pretreatment with rosuvastatin was also associated with a reduction in adverse clinical events at 30 days compared with placebo. Anna Toso, MD, Misericordia e Dolce Hospital, Prato, Italy, presented the results of the Protective Effect of Rosuvastatin and Antiplatelet Therapy on Contrast-Induced Acute Kidney Injury and Myocardial Damage in Patients With Acute Coronary Syndrome study [PRATOACS; NCT01185938] on behalf of the trial investigators.


Statins, due to their lipid-lowering and pleiotropic properties, may have a renal-protective effect after contrast medium administration for patients undergoing an angiographic procedure. However, the dose, type, timing and target population for statin use is uncertain. This study tested the hypothesis that high doses of rosuvastatin given before an angiographic procedure would protect against the development of CI-AKI.


In the PRATO-ACS trial, statin-naïve NSTE-ACS patients admitted to the cardiac care unit (CCU) between July 2010 and August 2012 managed with an early invasive strategy were eligible for the study. Exclusion criteria were: emergent angiography, acute renal failure or early-stage renal disease requiring dialysis, a baseline serum creatinine ≥3 mg/dL, contraindications to statin treatment, or exposure to contrast medium within the last 10 days. After admission to the CCU, 271 patients were randomized to receive rosuvastatin (loading dose of 40 mg, then 20 mg/day) or a placebo. The primary endpoint was the development of CI-AKI defined as a rise in serum creatinine ≥0.5 mg/dL absolute or ≥25% increase relative to baseline that occurred within 72 hours of contrast exposure.


Serum creatinine increases ≥25%, ≥0.5 mg/dL, and ≥0.3 mg/dL within 48 and 72 hours, as well as a decrease in estimated glomerular filtration rate ≥25% within 72 hours were additional biomarker endpoints. Other clinical endpoints included acute renal failure requiring dialysis, persistent renal damage, all-cause mortality, myocardial infarction, and stroke through 30 days.


All patients were treated with dual antiplatelet therapy (aspirin+clopidogrel) prior to coronary angiography (±percutaneous coronary intervention) and after discharge. In addition, all patients received oral N-acetylcysteine and hydration both pre- and 24 hours post contrast medium (nonionic, dimeric isoosmolar) administration. CI-AKI analysis was performed in 252 patients in each group after 72 hours. At discharge patients in the rosuvastatin pretreatment group continued rosuvastatin 20 mg, while those in control group received atorvastatin 40 mg daily.


There were no significant differences in baseline clinical, biochemical, or demographic characteristic, time from randomization to angiography, procedural success, or CI-AKI Mehran risk score, a validated risk prediction model for the development of CI-AKI, between the 2 groups.


CI-AKI was significantly less frequent in patients pretreated with rosuvastatin compared with placebo (6.7% vs 15.1%; adjusted OR, 0.38; 95% CI, 0.20 to 0.71; p=0.001; Figure 1). Compared with placebo, pretreatment with rosuvastatin was associated with significant reductions in all of the CI-AKI endpoints and the effect was consistent across all prespecified subgroups.


Figure 1. Primary Endpoint: CI-AKI



Reproduced with permission from A Tosso, MD.


In addition, rosuvastatin pretreatment reduced the rate of acute renal failure requiring dialysis, persistent renal damage, all-cause mortality, myocardial infarction, and stroke at 30 days (3.6% vs 7.9%; p=0.036) compared with placebo (Figure 2).


Figure 2. Adverse Clinical Events (30 Days)



Reproduced with permission from A Tosso, MD.


To date, there have been few effective strategies to protect patients from developing CI-AKI. The findings from the PRATO-ACS trial are notable and further studies are needed to both corroborate these results and potentially evaluate whether this is a class-effect of statins or unique to rosuvastatin.



RANOLAZINE PROVIDES BENEFIT OVER PLACEBO FOR T2DM PATIENTS WITH ANGINA


In a trial focused on the treatment of stable angina in patients with type 2 diabetes (T2DM), ranolazine significantly reduced the frequency of angina episodes compared with placebo. Mikhail Kosiborod, MD, St. Luke’s Mid America Heart Institute, Kansas City, Missouri, USA, presented the results of the Type 2 Diabetes Evaluation of Ranolazine in Subjects With Chronic Stable Angina study [TERISA; Kosiborod M et al. J Am Coll Cardiol 2013].


The primary objective of the randomized double-blind TERISA study was to evaluate the efficacy of ranolazine versus placebo on angina frequency in T2DM patients with coronary artery disease and chronic stable angina who were also taking 1 or 2 antianginal medications (eg, b-blockers). The primary endpoint was the average weekly number of angina episodes from Week 2 to Week 8 of treatment, while secondary endpoints included the average weekly number of sublingual nitroglycerin (SL NTG) doses from Week 2 to Week 8.


The trial enrolled 949 patients at 104 sites in Europe, Asia, and North America. Following a 4-week single-blind baseline-setting placebo period, patients (mean age 64 years) were randomized to receive ranolazine 1000 mg BID (n=473) or placebo (n=476) for 8 weeks. Eleven patients in each arm that either initiated or discontinued the study drug during the first 2 weeks were excluded from the final analysis. Researchers received daily data transmissions from patients who recorded angina episodes and SL NTG use in handheld electronic device diaries (98% compliance). Researchers followed-up with a phone call 2 weeks after the end of the 8-week period. Randomized patients were mostly male (61%) and had a mean diabetes duration of 7.5 years and a mean baseline HbA1C of 7.3%.


For the primary endpoint, patients in the ranolazine group experienced significantly fewer average weekly angina episodes from Week 2 to Week 8 than patients in the placebo group (3.8 vs 4.3,; p=0.008; Figure 1). Furthermore, patients in the ranolazine group took fewer average weekly SL NTG doses from Week 2 to Week 8 than those in the placebo group (1.7 vs 2.1, respectively; p=0.003; Figure 2). There were few serious adverse events, with no significant difference between the 2 groups.


Figure 1. Angina Frequency With Ranolazine Versus Placebo


 

 

Reproduced from Kosiborod M et al. Evaluation of Ranolazine in Patients with Type 2 Diabetes Mellitus and Chronic Stable Angina. Results from the TERISA randomized clinical trial. Journal of the American College of Cardiology Jan 2013; 10.1016/J.JACC.2013.02.011. With permission from Elsevier.


Figure 2. Average SL NTG Doses With Ranolazine Versus Placebo



SL NTG=sublingual nitroglycerin.

Reproduced from Kosiborod M et al. Evaluation of Ranolazine in Patients with Type 2 Diabetes Mellitus and Chronic Stable Angina. Results from the TERISA randomized clinical trial. Journal of the American College of Cardiology Jan 2013; 10.1016/J.JACC.2013.02.011. With permission from Elsevier.


It should be noted that generalizability of these results may be limited due to the lack of racial diversity of the study population. In addition, the short follow-up limits conclusions about the durability of therapy. Significant geographic heterogeneity was seen in treatment effect (p for interaction=0.016) with an apparent attenuation of benefit in selected Eastern European countries. Dr. Kosiborod said that an investigation is currently ongoing to determine the reason for this lack of an effect in these patients. In another subgroup analysis, the overall benefit with ranolazine versus placebo was more pronounced in patients with higher baseline HbA1C levels (p for interaction=0.027); however, measurement was not taken on follow-up for possible comparison.


In conclusion, TERISA showed that ranolazine was more effective than placebo in reducing angina frequency in T2DM patients with coronary artery disease and chronic stable angina. Future studies may shed light on potential dual effects of ranolazine on angina and glucose control in T2DM patients.



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