The
American College of Cardiology (ACC) and the American Heart association (AHA)
established new guidelines for the treatment of blood
cholesterol to reduce atherosclerotic cardiovascular risk in adults. Atherosclerotic
Cardiovascular Disease (ASCVD) includes coronary heart disease (CHD), stroke,
and peripheral arterial disease. These recommendations are based on careful
consideration of higher quality randomized controlled trials (RCTs), and
systematic reviews and meta-analyses of RCTs.
Important Points
The expert panel acknowledged the
absence of clinical trial data that support treatment to specific low-density
lipoprotein cholesterol (LDL-C) and non-HDL-C goals. The guideline identifies four major groups of patients for whom
cholesterol-lowering HMG-CoA reductase inhibitors, or statins, have the
greatest chance of preventing stroke and heart attacks. The guideline also
emphasizes the importance of adopting a heart-healthy lifestyle to prevent and
control high blood cholesterol.
Four major populations identified by these guidelines that benefit from statins
are as follows:
1.
Adults with clinical ASCVD: high-intensity
statin therapy (Table1) should be used to achieve at least a 50% reduction in
LDL - C unless otherwise contraindicated. For those age > 75 yrs., moderate
dose statin may be used.
2.
Adults
with primary elevations of LDL–C ≥190 mg/dL: high-intensity statin therapy
should be used to achieve at least a 50% reduction in LDL -C unless otherwise
contraindicated.
3.
Adults
40 to 75 years of age with diabetes & without clinical ASCVD with
LDL-C 70-189 mg/dL: A moderate-intensity statin- that lowers LDL-C 30%
to 49%. High-intensity statin is a reasonable choice if the patient also has a
10-year risk of atherosclerotic cardiovascular disease exceeding 7.5%. In
adults with diabetes mellitus, who are <40 or >75 years of age, it is
reasonable to evaluate the potential for ASCVD benefits and for adverse
effects, for drug-drug interactions, and to consider patient preferences when
deciding to initiate, continue, or intensify statin therapy.
4.
Adults
without clinical ASCVD or diabetes who are 40 to 75 years of age with LDL-C
70-189 mg/dL and an estimated 10-year ASCVD risk of 7.5% or higher: a moderate- or
high-intensity statin therapy should be used.
|
High-Intensity Statin Therapy
|
Moderate-Intensity Statin
Therapy
|
Low-Intensity Statin Therapy
|
|
Daily dose lowers LDl-C on
average, by approximately≥50%
|
Daily dose lowers LDl-C on
average, by approximately 30% to < 50%
|
Daily dose lowers LDl-C on
average, by < 30%
|
|
Atorvastatin(40†)-80mg
Rosuvastatin
20 (40) mg
|
Atorvastatin 10(20)mg
Rosuvastatin (5) 10 mg
Simvastatin 20-40 mg‡
Pravastatin 40(80) mg
Fluvastatin XL 80 mg
Fluvastatin 40 mg bid
Pitavastatin 2-4 mg
|
Simvastatin 10 mg
Pravastatin 10-20 mg
Lovastatin 20 mg
Fluvastatin 40 mg bid
Pitavastatin 1 mg
|
Table 1: High, Moderate and Low
intensity statin therapy (adapted from ACC/AHA Guidelines)
• Treating to LDL -C
targets and lower the better is no longer recommended
• With few exceptions,
use of lipid-modifying drugs other than statins is discouraged. Only statins
have data of CV protection. Non-statin lipid lowering drugs have no evidence of
CV protection
• The
guideline offers a new approach to risk assessment- Ten-year
ASCVD risk
— which includes both coronary events & stroke — is determined using online
calculators that can be accessed through the AHA and ACC websites. It contain
modifiable and non modifiable risk factors like sex, age, race, total
cholesterol, HDL- cholesterol, systolic blood pressure and its treatment,
diabetes and smoking.
• Adherence to a healthy
diet and lifestyle is the keystone of cardiovascular health and it is recommended
for all patients, regardless of cholesterol-lowering drug therapy.
• No
evidence of statin benefit if NYHA Class II-IV heart failure, or if on
haemodialysis.
• Individuals Not in a
Statin Benefit Group:
No recommendations are made to inform treatment decisions in selected
individuals who are not included in the four statin benefit groups. In these
individuals whose 10-year risk is <7.5% or when the decision is unclear,
other factors including family history of premature ASCVD, LDL-C >160 mg/dl,
high-sensitivity C-reactive protein ≥2 mg/dl, coronary calcium score ≥300 Au or
≥75th percentile for age, sex, ethnicity, and ankle-brachial index <0.9, or
elevated lifetime risk of ASCVD may be used to enhance the treatment decision
making.
• Potential for ASCVD
risk reduction benefit, potential for adverse effects, drug-drug interactions,
and patient preferences should be discussed.
Limitations of Guidelines
The new
guideline has caused much controversy by changing the fundamentals of
cholesterol treatment from an approach that treats to specific LDL-C and
non-HDL-C targets to one that treats specific patient populations regardless of
their lipid profile. Guideline focus on patient groups who are well represented
in RCTs. So the recommendations are designed to inform clinical judgment, not
to replace it.
Clinician judgment is important for
several patient groups for whom the RCT evidence is insufficient like in
younger adults (<40 years of age) who have a low estimated 10-year ASCVD
risk, but a high lifetime ASCVD risk and those with serious co morbidities and
increased ASCVD risk e.g.,
individuals with HIV, rheumatologic or inflammatory diseases, or who have
undergone a solid organ transplant.
Indian
perspective
Relevance
to India
•
Under-representation
of Indian Population: Guidelines
for dyslipidemia management and treatment have largely been derived from
clinical trials comprised of mostly Non Hispanic World populations, which have
often under-represented Asian population.
•
Need
for Non Statin Drugs: Atherogenic
triad comprises
of high triglycerides, Low HDL and increased small dense LDL particles is
common in Indian and associated with high CVD risk, so statins alone may not be enough.
•
Unfortunate
Young Indians: Indians get DM and
CVD at an early age, around ten years earlier then the western population,
probably because of high prevalence of Metabolic Syndrome. The new guideline
recommendations for using statins in primary prevention are limited to patients
40-75 years old unless their LDL-C is ≥ 190 mg/dL. However, the process of
atherosclerosis starts at very young age and therefore failure to start
lipid-lowering medications in the younger dyslipidemic population is a failure
of primary prevention. Despite the absence of RCTs that address statin therapy
in the young age group, a moderate or high dose statin may be considered in
certain high-risk individuals.
•
Underutilization of
Statins:
New ASCVD risk calculator underestimate the cardiovascular risk, hence sratins
may remain underutilized.
•
High Vs moderate Dose
of Statins: Possibly,
Asian population respond well with moderate dose of statins to decrease LDL-C
level <50% as compare to high dose of statins in western population possibly
because of low BMI. Therefore lesser side effects and lesser chances of getting
new onset DM
•
Statin Induced Risk of
Diabetes mellitus: Indians are having high incidence and prevalence
of Diabetes Mellitus and IGT and statins are increasingly being linked for
diabetes.
Atherogenic
Dyslipidemia
A combination of hypertriglyceridemia, low levels of
HDL-cholesterol and high levels of small dense low density lipoprotein, termed
as “atherogenic dyslipidemia” is particularly seen in Asian Indians. Diet(
increased carbohydrate food intake, increased dairy products consumption and
low Omega 3 polyunsaturated fatty acids), lack of Physical activity and abnormal
body composition like large adipocytes and it’s abnormal regional distribution
are responsible for development of Atherogenic dyslipidemia. Diabetic patients are
known to have high levels of serum triglyceride (TG) and low levels of
high-density lipoproteins (HDL).
Role
of Non Statins
The new guideline makes it clear that statins are a
must, but it does not strongly recommend the use of non-statin lipid lowering
medications because of the lack of definitive data that proves its efficacy. As
previously stated that the combination of a lower dose statin and another
lipid-lowering medication is more effective at lowering LDL-C than a high dose
statin alone.2 Non-statin lipid lowering medications are very
effective at lowering LDL-C and most experts would add one or more when the
LDL-C level remains elevated or when patients have recurrent ASCVD despite high
dose statin therapy.
Fibrates are more effective than statins in reducing
serum triglyceride levels and increasing HDL-cholesterol levels.3Atherogenic
dyslipidemia in Asian Indians may be well managed by the use of fibrates,
although the combination may have more adverse effects BUT recent evidence indicates
that combination is well tolerated by Indian population.4,5
Niacin is more effective than either statins or
fibrates in increasing HDL- cholesterol levels (~35%), however it may not be tolerated?
And has failed in clinical trials ( AIM HIGH and HPS2 THRIVE )
When to add
Fibrates
In a major systematic review and meta-analysis6
including 45058 participants, fibrates can reduce the risk of major
cardiovascular events predominantly by prevention of coronary events, and might
have a role in individuals at high risk of cardiovascular events and in those
with combined dyslipidaemia. According to this review fibrates therapy produced
a 10% RR reduction (95% CI 0—18) for major cardiovascular events (p=0·048) and
a 13% RR reduction (95% CI7—19) for coronary events (p<0·0001), but had no
benefit on stroke (−3%, −16 to 9; p=0·69). No effect of fibrate therapy was
noted on the risk of all-cause mortality (0%, −8 to 7; p=0·92), cardiovascular
mortality (3%, −7 to 12; p=0·59), sudden death (11%, −6 to 26; p=0·19), or
non-vascular mortality (−10%, −21 to 0·5; p=0·063). Fibrates reduced the risk
of albuminuria progression by 14% (2—25; p=0·028). Improvement in microvascular
complications like retinopathy was also observed. Serious drug-related adverse
events were not significantly increased by fibrates (17 413 participants,
225 events; RR 1·21, 0·91—1·61; p=0·19), although increases in serum creatinine
concentrations were common (1·99, 1·46—2·70; p<0·0001) (Fig 1).
|
Fig 1: Adopted from Jun et al lancet 2010
|
Underestimation
of CV Risk
ACC/AHA
provided a CV Risk calculator for estimation of 10-year risk for ASCVD in men
and women 40 through 79 years of age. But the guidelines also state that, ‘These
estimates may underestimate the risk for persons from some race/ethnic groups,
especially American Indians, some Asian Americans (e.g., of south Asian
ancestry), and some Hispanics (e.g., Puerto Ricans)’ Therefore, usage of same
CV Risk calculator may underestimate ASCVD risk in Indian population. This
could be understood in the following case example:
40 years old Indian male, who was smoker with
positive family history and no h/o diabetes mellitus and hypertension with
dyslipidemia (TC- 180, HDL- 36 and LDL- 115). His 10 year risk calculated on
new risk calculator was 4.9%, hence no
statin was prescribed. After 3 months, patient presented with chest discomfort
with bilateral arm pain, his ECG was suggestive of anterior wall MI. Coronary
angiography revealed 99% thrombus containing lesion in proximal left anterior
descending (LAD) artery, subsequently PCI to LAD was done.
Once
you underestimate the ASCVD risk in any patient, following the guidelines,
based on the ASCVD risk will lead to underutilization of Statin therapy as in
above case. The high prevalence of CHD in early age in Indian population further
necessitates the usage of statin therapy earlier & more aggressively.
Statin
and Risk of Dysglycaemia
In a meta-analysis7
Statin therapy was associated with a 9% increased risk for incident diabetes
(odds ratio [OR] 1.09; 95% CI 1.02-1.17), but the risk is low both in absolute
terms and when compared with the reduction in coronary events. Clinical
practice in patients with moderate or high cardiovascular risk or existing
cardiovascular disease should not change (Fig: 2)
|
Fig 2: Adopted from Sattar
N, Preiss D Ray, KK et al. Lancet 2010; 375: 735-42
|
Results
from three large randomized clinical trials (TNT, IDEAL, SPARCL) were compared8. High dose of
atorvastatin in SPARCL trial is associated with a slightly increased risk of
new-onset T2DM (8.71% vs. 6.06%, adjusted HR: 1.37, 95% CI: 1.08 to 1.75, p =
0.011). While no significant difference was found with Atorvastatin 80 mg Vs
Atorvastatin 10 mg in TNT trial (9.24%
vs. 8.11%, adjusted hazard ratio [HR]: 1.10, 95% confidence interval [CI]: 0.94
to 1.29, p = 0.226) and atorvastatin 80 mg Vs Simvastatin 20 mg in IDEAL trial (6.40%
vs. 5.59%, adjusted HR: 1.19, 95% CI: 0.98 to 1.43, p = 0.072). Baseline
fasting glucose level and features of the metabolic syndrome are predictive of
new-onset T2DM across the 3 trials.
Prognosis
of Patients with New-Onset T2DM
In multivariate analysis of three trials (TNT,
IDEAL, SPARCL) major cardiovascular events occurred in 11.3% of patients with
and 10.8% of patients without new-onset T2DM (adjusted HR: 1.02, 95% CI: 0.77
to 1.35, p = 0.69).8
The landmark Heart Protection Study clearly establishes
that statins are safe and effective as cardioprotective therapy. In this study
(mostly secondary prevention), for every 1 person newly diagnosed with diabetes
due to statin use, 5 deaths, 6 nonfatal myocardial infarctions, and 4 strokes
were prevented in 5 years.9
The
expert panel emphasizes that the occurrence of major CVD event (MI or stroke)
represent a much greater harm to health status than does an increase in blood
glucose leading to a diagnosis of diabetes. The net absolute benefit of statin
therapy may be considered as a comparison of the absolute risk reduction for
CVD compared with the absolute excess risk including that for diabetes. Benefit
also could be understood as a comparison of the number of statin treated
patients that would result in prevention of 1 case of major ASCVD with number
of statin – treated patients that would result in 1 extra case of diabetes.
Prognosis or MACE for long term new onset diabetes
is not known and no data for Indian population.
Intensity of Statin
High
Vs. Moderate dose - Statins use is associated with a very modest excess risk of new onset
diabetes and also the myelgia and transaminitis. These side effects are dose dependent and
higher with higher doses of statins. This has been proved in RCTs and meta-analyses
of RCTs (i.e., 0.1 excess case per 100 individuals treated 1 year with
moderate-intensity statin therapy and 0.3 excess cases per 100 individuals
treated for 1 year with high-intensity statin therapy). But, this should not
change statin prescribing, as statins reduce cardiovascular events and
all-cause mortality.
In a meta-analysis10 of 5 statin trials
with 32 752 participants without diabetes at baseline, 2749 developed
diabetes (1449 assigned intensive-dose therapy, 1300 assigned moderate-dose therapy,
representing 2.0 additional cases in the intensive-dose group per 1000
patient-years) 6684 experienced cardiovascular events (3134 and 3550,
respectively, representing 6.5 fewer cases in the intensive-dose group per 1000
patient-years) over a weighted mean follow-up of 4.9 +/- 1.9 years. Odds ratios
were 1.12 (95% confidence interval [CI], 1.04-1.22) for new-onset diabetes and
0.84 (95% CI, 0.75-0.94) for cardiovascular events for participants receiving
intensive therapy compared with moderate-dose therapy. As compared with
moderate-dose statin therapy, the number needed to harm per year for
intensive-dose statin therapy was 498 for new-onset diabetes while the number
needed to treat per year for intensive-dose statin therapy was 155 for cardiovascular
events (Fig 3).
|
Fig: 3
|
In a large randomized trial11 of statin
therapy in patients of South-Asian origin with hypercholesterolemia (from the IRIS Trial), statin therapy was
well tolerated and effective in decreasing LDL cholesterol in patients of
South-Asian origin, with the 10- and 20-mg doses of rosuvastatin and
atorvastatin allowing most patients to reach recommended LDL cholesterol goals.
Even
guideline stated that the history of hemorrhagic stroke and asian ancestry may
modify the decision to use higher statin intensities1. Therefore in
Indian population with higher prevalence of atherogenic dyslipidemia, adding
fibrates to a moderate intensity statins may be suitable to reduce >50% of LDL as
desired by guidelines and it is better tolerated with lesser degree of myalgia
and transaminitis and also the fewer incidences of new onset diabetes mellitus
(0.1/100 vs. 0.3/100).
Should
we have our own guidelines?
We
need evidence based data for our population looking at the epidemiology and
prevalence of dyslipidemia in India, the efficacy and clinical outcome of
antilipidemic drugs . This data should provide us with answers for our
population with regard to statin dosage, role of non statin drugs, age factor
<40 years (atherosclerosis not uncommon) and whether we are more prone for new onset
diabetes.
Conclusions
The
new ACC/AHA guidelines for dyslipidemia has focused on risk of ASCVD based on
RCT and included 4 statin groups one for secondary prevention and three for
primary prevention utilizing the global risk assessment chart. ASCVD risk
calculator is not validated in large population including Indians and it may
underestimate or overestimate the risk of ASCVD so the under/over utilization
of statins. Intensity of statin therapy rather than LDL/non HDL targets is
recommended for clinicians. The higher prevalence of atherogenic dyslipidemia
and metabolic syndrome in Indians at a younger age, low to moderate intensity
statin therapy along with or without non-statin drugs may be useful to reduce
the cardiovascular events and at the same time prevent the onset of new DM.
Statins may also be initiated at early age in certain high risk group.
1.
Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA
Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic
Cardiovascular Risk in Adults: A Report of the American College of
Cardiology/American Heart Association Task Force on Practice Guidelines. J
Am Coll Cardiol 2013.
2.
Gudzune KA, Monroe AK, Sharma R, Ranasinghe PD, Chelladurai
Y, Robinson KA. Effectiveness of Combination Therapy With Statin and Another
Lipid-Modifying Agent Compared With Intensified Statin Monotherapy: A Systematic
Review. Ann Intern Med 2014.
3.
Jonkers IJ, Mohrschladt MF, Westendorp RG.et. al. Severe
hypertriglyceridemia with insulin resistance is associated with systemic
inflammation: reversal with bezafibrate therapy in a randomized controlled
trial. Am J Med 2002; 112:275-80.
4.
Liamis G, Kakafika A, Bairaktari E, et al. Combined treatment
with fibrates and small doses of atorvastatin in patients with mixed
hyperlipidemia. Curr Med Res Opin 2002; 18:125-8.
5.
Taher TH, Dzavik V, Reteff EM. et al. Tolerability of
statin-fibrate and statin-niacin combination therapy in dyslipidemic patients
at high risk for cardiovascular events. Am J Cardiol 2002; 89:390-394.
Sattar N, Preiss D, Murray HM, et al. Statins and risk of
incident diabetes: a collaborative meta-analysis of randomized statins trials.
Lancet 2010; 375:735-42.
8.
Waters DD, Ho JE, DeMicco DA, Breazna A, Arsenault BJ, Wun
CC, et al. Predictors of new-onset diabetes in patients treated with
atorvastatin: results from 3 large randomized clinical trials. J Am Coll
Cardiol2011; 57:1535-45.
9. Heart Protection Study Collaborative Group. MRC/BHF
Heart Protection Study of cholesterol lowering with simvastatin in 20,536
high-risk individuals: a randomised placebo-controlled trial. Lancet 2002;
360:7–22.
10. Preiss
D, Seshasai SR, Welsh P, Murphy SA, Ho JE, Waters DD, et al. Risk of incident
diabetes with intensive-dose compared with moderate-dose statin therapy: a
meta-analysis. JAMA2011; 305:2556-64.
11. Deedwania
PC; Gupta M; Stein M et. al. Comparison
of rosuvastatin versus atorvastatin in South-Asian patients at risk of coronary
heart disease (from the IRIS Trial). Am J Cardiol 2007; 99(11):
1538-43.
Comments
Post a Comment