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].
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
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].
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
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].
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
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].
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].
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.
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].
anacetrapib and evacetrapib are currently involved in ongoing Phase 3 trials.
Proprotein Convertase Subtilism Kexin 9 Inhibitors
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].
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.
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.
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
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
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
- 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.
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.
patients should have a trial of GDMT before considering revascularization to
improve symptoms. Deferring revascularization is not associated with worse
to revascularization to improve symptoms, coronary anatomy should be correlated
with functional studies to ensure lesions responsible for symptoms are
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
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
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
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
This session offered some early
insights into the long-awaited and eagerly anticipated release of the JNC-8 and
ATP IV guidelines.
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
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
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
permission from A Tosso, MD.
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)
permission from A Tosso, MD.
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
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
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
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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