Upload
balasubramaniam-iyer
View
3.756
Download
5
Embed Size (px)
DESCRIPTION
Citation preview
Therapy of hypertensives with dyslipidaemia
Unlearning towards better learning
The agenda for today
• Hypertension – the background
• Current status of dyslipidaemia
• The case studies
• The clinical trials & the observations
• The learnings
• The summary
Hypertension
The background
Hypertension
• What we record as B.P.– It is only a marker of the bigger problem
• The Truth is–Hypertension is a multi-organ systemic disease
• The Problem is–Hypertension is asymptomatic in 85% of cases
Hypertension – Be wise
• It is wrong– To consider Hypertension as an isolated disease
• The Truth is–Hypertension, DM, Dyslipidemia, Obesity coexist–They are the 4 pallbearers to the grave of CHD/CVD
• For all of them–Primary & secondary prevention by TLC = answer–Afflicted with one, must be screened for all other thieves
Hypertension – Therapy goal
• Goal BP– To Keep B.P. < 140/90 mm Hg in each patient– This may be revised to 120/80 may be ? 110/70 – MRFIT’s cut off values are 115/75 mm Hg
• The Truth is–It is essential to keep the B.P at or below the goal–But, It also matters how the goal B.P. is achieved !
Current status
Hypertension and dyslipidaemia
Rule of halves in hypertension
• What is this rule of halves in HT ?
JNC 7. May 2003; Third National Health and Nutrition Examination Survey, 1988-1994, NHANES III.
• For every 800 adults in the community–400 are HT (either ↑ SBP or ↑ DBP or both)–Of them only 200 are diagnosed HT–Of them only 100 are started on treatment–Of them only 50 are on correct drug–Of them in only 25 the goal B.P. is attained–Means 25 ÷ 400 = 6% only have goal BP–And we have yet to look at HT with other conditions
90 million with dyslipidemia
People with concomitant hypertension & dyslipidemia
JNC 7. May 2003; Third National Health and Nutrition Examination Survey, 1988-1994, NHANES III.
27 million with concomitant hypertension, dyslipidemia
50 millionwith
hypertension
People with concomitant hypertension & dyslipidemia
9 million diagnosed
(33%) 18 million undiagnosed
(67%)
Third National Health and Nutrition Examination Survey, 1988-1994, NHANES III.
Source: Unpublished data from the Third National Health and Nutrition Examination Survey (NHANES-III), CDC 1994; data from 1999.
People with concomitant hypertension & dyslipidemia
Treated for neither43%
Treated for 1
47%
Treated for both10%
Treated for neither Treated for 1 Treated for both
People with concomitant hypertension & dyslipidemia
10% Treated 10% Treated For Hypertension For Hypertension & Dyslipidemia& Dyslipidemia
3% at Goal
Source: Unpublished data from the Third National Health and Nutrition Examination Survey (NHANES-III), CDC 1994; data from 1999.
The prevalence of coexistence of dyslipidemia
andhypertension
in patients surveyed at
Apollo Hospitals (n=501)
Indian Heart Journal 1996: 48(4): 371-374
0 10 20 30 40 50Percent
60 70 80 90 1000
TC>200 mg/dl(n=501)
LDL>130 mg/dl(n=486)
HDL<35 mg/dl(n=501)
TG>200 mg/dl(n=496)
TC/HDL ratio>4.5(n=500)
Co-prevalence of dyslipidemia & hypertension in India
MRFIT - Hypertension and Dyslipidemia and CAD Risk
Adapted from Neaton JD, et al. Arch Intern Med. 1992;152:56-64.
Age-adjusted CAD death rates
The approach
• Global risks assessment and reduction is the best way to reduce CV events.
• Hypertension and Hyperlipidemia are 2 most common risks found in our population.
• New antihypertensive drugs are beneficial in BP control and prevention of CV events.
• Multi-drug combinations should be used to modify risk factors and/or metabolic disturbances but is usually associated with poor compliance.
Whom to Screen for Dyslipidemia?Influenced by cardiac risk factors:• By age alone:
–Men over age 40–Women over age 50 (or post-menopausal)
• Other risk factors (at any age):–DM, HTN, Smoking, Abdominal Obesity–Family history of early cardiovascular disease
• Physical signs of hyperlipidemia (at any age):–Xanthomata, xanthelasmas, arcus corneae, etc
• Evidence of existing atherosclerosis (any age)
Factors Influencing Risk Assessment
• Metabolic Syndrome• Abdominal Obesity• Apolipoprotein B (apoB)• Lipoprotein(a)• Homocysteine• C-Reactive Protein (CRP)• Genetic Risk• Hormone Replacement Therapy (HRT)
Factors Influencing Risk Assessment
• Presence of the Metabolic Syndrome–A clustering of cardiovascular risk factors,
including abdominal obesity, insulin resistance, and hypertension, as well as lipid abnormalities (↑TGs and ↓HDL)
• Presence of Abdominal Obesity– with waist circumference
as a useful estimate
Factors Influencing Risk Assessment
• Apolipoprotein B (apoB)–There is 1 molecule of apoB in each atherogenic
lipid particle (VLDL, IDL, LDL, lp(a))’–↑apoB (for the same lipid levels) = smaller,
denser, more atherogenic LDL particles–Better estimate than LDL of cardiovascular risk–ApoB levels correlate better than LDL levels to
clinical outcomes in statin trials–For ‘high risk’ patients, target apoB <0.9g/L–Sample does not need to be fasting
Factors Influencing Risk Assessment
• Lipoprotein(a) (lp(a))–Appears to be an independent risk factor for
premature atherosclerosis and CAD–Its atherogenicity seems to depend on the presence
of other factors, and its utility as a risk factor seems to disappear if the LDL is markedly lowered
–Monogenic and not responsive to diet–Lp(a) >30mg/dL in patients with TC/HDL ratio >5.5
or other major risk factors may indicate need for earlier and more intensive LDL-lowering therapy
Factors Influencing Risk Assessment
• Homocysteine–↑homocysteine levels predict adverse outcomes
in patients with CAD–Fixed-dose folate & B12 trials looking at
cardiovascular endpoints are ongoing–No ‘treat-to-target’ trial (to homocysteine
<9μmol/L)–No evidence yet to screen for homocysteine
Factors Influencing Risk Assessment
• C-Reactive Protein (CRP)–↑CRP may add prognostic information to Framingham
Study data–↑CRP associated with abdominal obesity and the
metabolic syndrome–May be clinically useful in identifying people who are at
higher risk than their Global Risk Assessment would indicate (especially for people with a calculated 10-year risk of 11-19%, so calculated to be at ‘moderate risk’)
Factors Influencing Risk Assessment
• C-Reactive Protein (CRP)–Do not measure during an acute illness or in
patients with chronic inflammatory disease–Measure 2x, two weeks apart, and use the lower
value–Low risk <1 mg/ml & high risk 3-10mg/ml–If >10mg/ml, look for infection/inflammation
Hypertensive patient with Dyslipidaemia
Case study
Patient # 1• A 57-year old man, who staying in a small town,
comes to see his son in the big city and the son gets him to you for opinion. – Approximately a year back, he suffered a myocardial
infarction, but has since been asymptomatic. He does not have any other significant past medical history.
– His current medications include aspirin 81 mg daily and a beta-blocker. • His sitting blood pressure is 155/95 mmHg, heart rate 58 beats/min. • Pertinent laboratory values: glucose 86 mg/dl; total cholesterol 228
mg/dl; HDL-C 37 mg/dl; LDL-C 128 mg/dl. • An echocardiogram shows concentric LVH and preserved left
ventricular systolic function (ejection fraction 56%).
Question # 1
1. A statin (to reduce LDL-C to ≤ 100 mg/dl), a calcium channel blocker, and a diuretic.
2. An angiotensin-receptor blocker and a statin (to reduce LDL-C to ≤ 70 mg/dl).
3. An ACE inhibitor and a statin (to reduce LDL-C to ≤ 120 mg/dl).
4. Oral nitrates, hydralazyne, and a statin (to reduce LDL-C to ≤ 70 mg/dl).
5. Niacin, a calcium channel blocker, and a diuretic.
Which of the following should be done?
• An ACE inhibitor and a statin (to reduce LDL-C to ≤ 120 mg/dl).
*Men aged 35-57 years followed for a mean of 12 years.*Men aged 35-57 years followed for a mean of 12 years.
<120<120120-139120-139
140-159140-159160+160+
CHD Death Rate per 10,000 Person-Years
100+100+
80-8980-89
70-7470-74<70<70
75-7975-79
90-9990-99
MRFIT - Effect of Systolic & Diastolic BP on CHD Mortality
48.348.3
37.437.434.734.7 43.843.8
38.138.1
80.680.631.031.0
25.525.524.624.6
25.325.325.225.2
24.924.9
23.823.8
16.916.913.913.9
12.812.812.612.6
11.811.8
20.620.6
10.310.311.811.8
8.88.88.58.5
9.29.2
Systolic BPSystolic BP(mm Hg)(mm Hg)
Diastolic BPDiastolic BP(mm Hg)(mm Hg)
Patient in Question # 1
Neaton et al. Arch Intern Med. 1992;152:56-64.
Treatment of hypertensive patients with Dyslipidaemia
The learning from different studies
Selected major trials
• PROVE IT – TIMI 22
• MRC/BHF Heart Protection Study
• ASCOT- LLA
• ALLHAT
Lower is better• statin therapy provides benefits even with
lower LDL-C
Adapted from Kastelein JJP. Atherosclerosis. 1999;143(suppl 1):S17-S21., Sever PS, et al. Lancet. 2003;361:1149-1158., Heart Protection Study Collaborative Group. Lancet. 2003;361:2005-2016
0
210
Pat
ient
s w
ith C
HD
Eve
nt (%
)
Mean LDL-C Level at Follow-up (mg/dL)
Secondary prevention
Primary prevention
Atorvastatin
90 110 130 150 170 190
5
10
15
20
25
AFCAPS-S
WOSCOPS-S
WOSCOPS-PCARE-S
LIPID-P
4S-P
LIPID-S
CARE-P
4S-S
AFCAPS-PASCOT-SASCOT-P
Simvastatin
Pravastatin
Lovastatin
HPS-S
HPS-S
HPS-P
HPS-P
S=statin treatedP=placebo treated
PROVE IT – TIMI 22: moderate vs intensive statin therapy in pts. with ACS
Cannon CP, et al. N Engl J Med. 2004;350:1-10.
106 10695
62
0
20
40
60
80
100
120
Pravastatin 40 mg/day(n=2063)
Atorvastatin 80 mg/day(n=2099)
Med
ian
LDL-
C (m
g/dL
)BaselineFinal (Mean, 24 mo) P <0.001
No. at Risk
PravastatinAtorvastatin
20632099
16881736
15361591
14231485
810842
138133
PROVE IT: Intensive Statin Therapy ↓ All-Cause Mortality and Risk of MACE
No. at Risk
PravastatinAtorvastatin
20632099
16881736
15361591
14231485
810842
138133
Cannon CP, et al. N Engl J Med. 2004;350:1-10.
Months of Follow-up
MRC/BHF Heart Protection Study
• HPS: Lancet 360(9326):7-22, 6 July 2002– 20,556 men & women aged 40-80 with TC >3.5– All at ‘high risk’ of CAD
• Known CAD/MI/PVD/CVS• DM, HTN, or both
– RCT: Simvastatin 40mg vs. placebo• Decreased death rate by 13%• Decreased combined cardiovascular end points by 24%
– Benefits in all subgroups, including baseline LDL <2.6– Very compelling, well done trial– Ultimate LDL target still unclear, other studies now
looking at LDL targets of <1.8
ASCOT – LLA - Rationale
• Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm
• Premise– High prevalence of dyslipidemia in
hypertensive patients– Most CV disease events occur in patients with
BP and lipid concentrations deemed normal
• Hypothesis– Lipid lowering will benefit hypertensive
patients, not conventionally deemed dyslipidemic
ASCOT – LLA - Findings
• In patients with hypertension and additional CV risk factors, addition of atorvastatin
– Had significant effects on nonfatal CVD and fatal MI– Benefits even in absence of traditional dyslipidaemia
• Identification of the at-risk patient with hypertension and other CV risk factors enables appropriate treatment for CV event prevention
• Study was stopped after 3 years because of significant benefit in the treatment group
Diet control & dyslipidaemia reduction
Time course of Statin effects
* Time course establishedDaysDays YearsYears
LDL-C LDL-C lowered*lowered*
InflammationInflammationreducedreduced
VulnerableplaquesVulnerableplaquesstabilizedstabilized
EndothelialEndothelialfunctionfunctionrestoredrestored
IschemicIschemicepisodesepisodesreducedreduced
Cardiac eventsCardiac eventsreduced*reduced*
Therapy
• In ‘high risk’ patients:– Start drug treatment immediately, concurrently
with diet and lifestyle modification– Priority is to get LDL <2.5 and TC/HDL <4– Given HPS data, treat with Simvastatin 40mg
or equivalent statin for LDL target.– If can’t reach LDL target:
• Bile acid sequestrants (cholestyramine, colestipol), or
• Ezetimibe - better tolerated• Either can decrease LDL by another 10-20%
compared with statin alone
Treatment of hypertensive patients with Dyslipidaemia
Different antihypertensive perspectives
Stamler J et al. Diabetes Care. 1993;16:434-444.
Elevated SBP increases risk of CV death almost twofold in diabetic vs nondiabetic patients
Car
diov
ascu
lar M
orta
lity
Rat
e pe
r 10,
000
Patie
nt-Y
ears
SBP (mm Hg)
Nondiabetic patientsDiabetic patients
250
200
150
100
50
0<120 120–139 140–159 160–179 180–199 200
MRFIT20
Elevated SBP in Type 2 Diabetes Increases Cardiovascular Risk
Hypertension Optimal Treatment (HOT) Study
Lancet 1998; 351: 1755–62
p=0.005 (DM)
0
5
10
15
20
25
Even
ts/1
000
pt-y
ears
<90 <85 <80Target diastolic BP
DMnon-DM
Reduction in CV events
Questions on antihypertensives
• Antihypertensives are very effective in reducing clinical outcomes. But the adverse metabolic effects of these agents significantly reduce their benefit, in comorbid hypertension especially in hypertension with dyslipidaemia and in Syndrome-X cases.
• Is the “how to” of hypertension control as important as the “how well” of hypertension control in patients requiring more than one anti-hypertensive agent?
Questions on antihypertensives
• Is there synergy between certain anti-hypertensive medication combinations that outweigh benefits of the individual medications?
• The adverse effects of thiazide-type diuretics on blood cholesterol, glucose, potassium, uric acid have been known for more than 40 years
Approaches to hypertension therapy
Lifestyle Modification approach in hypertension therapy
Modification Approximate BP reduction [range]
Weight reduction 5–20 mm/10 kg wt lossAdopt DASH [Dietary Approaches to Stop Hypertension] eating plan
8–14 mmHg
Dietary sodium reduction 2–8 mmHgPhysical activity 4–9 mmHgAbstinence from alcohol 2–4 mmHg
All put together reduce BP by 20 to 55 mmHg
ALLHAT
• ALLHAT is the first study to report on the effect of antihypertensive regimens on clinical outcomes in hypertensives with the MetS.
• ALLHAT was designed to evaluate the effect of diuretics on clinical outcomes compared to agents without these adverse metabolic effects
ALLHATALLHAT
ALLHAT - Definition of MetS (DS) participants
• Any 3 or more of the following:–Hypertension (present in all as a condition of
enrollment into ALLHAT)–Fasting glucose >100 mg/dl or 100-125 mg/dl in
non-diabetics with MetS –BMI ≥ 30 kg/m2–Fasting triglycerides ≥ 150 mg/dL–HDL cholesterol <40 mg/dl in men, <50 mg/dl in
women
ALLHATALLHAT
ALLHAT
• How large is the difference in metabolic effects, esp the effect on glucose?
• Does the effect associate with an increase in adverse clinical outcomes compared to drugs with a more favorable metabolic profile?
• Are patients at higher risk (e.g. patients with diabetes or the metabolic syndrome) more vulnerable to the adverse effects of available antihypertensive agents?
ALLHATALLHAT
42,418 high-riskhypertensive patients
90% previously treated, 10% untreated
STEP 1 AGENTSSTEP 1 AGENTS
Chlorthalidone12.5-25 mg
Amlodipine2.5-10 mg
Lisinopril10-40 mg
Doxazosin1-8 mg
N=15,255 N=9,048 N=9,054 N=9,061
STEP 2 AND 3 AGENTS (5 years)*STEP 2 AND 3 AGENTS (5 years)*
Atenolol28.0%
Clonidine10.6%
Reserpine4.3%
Hydralazine10.9%
* Of participants with data available for determination.
Hypertension Trial ALLHATALLHAT
Outcomes in ALLHAT participants with the metabolic syndrome
• Patients with metabolic syndrome (MetS) are at very high risk for complications of hypertension
• Use of agents with favorable metabolic effects esp recommended in hypertensives with MetS
• Alpha-blockers and RAS inhibitors demonstrate the most favorable effect on blood glucose and lipids,
• CCBs are intermediate, followed by THZ-diuretics.
ALLHAT
Summary & conclusions
• Despite a more favorable metabolic profile, antihypertensive therapy initiated with an - blocker, an ACEI, or a CCB was NOT superior to one initiated with a thiazide-type diuretic, including in those with MetS.
• ALLHAT fails to support an increase in CVD risk associated with diuretic-induced glucose elevation or incident diabetes in hypertensive patients.
ALLHATALLHAT
Summary & conclusions
• ALLHAT provides further evidence against the consideration of intermediate outcomes in the selection of antihypertensive agents.
• Findings apply equally to Black and non-Black populations
ALLHATALLHAT
Effect of various antihypertensives on coexisting disorders
Effect of various antihypertensives on coexisting disorders
Parameter Diuretic ACEi, ARB βblocker Ca+ Blocker
Ischemia No effect Improves Improves Negative
LVH, LVF Improves Improves Improves* Negative
CV Mortality Improves Improves Improves Increases
Heart rate No effect No effect Bradycardia Tachycardia
Use in DM Negative Excellent Negative Negative
Lipid effects Negative Excellent Negative Neutral
Fluid & Na Enhances No effect Vasoconstr. Vasodilatory
K ex / bronchi Enhances No effect Bronchospa No effect
UA / Conduct. ↑ Uric acid No effect ↓conduction No effect
Treatment of hypertensive patients with Dyslipidaemia
Learning on alpha blockade
Effect of various drugs on CHD riskDrug Effect on CHD risk
Doxazosin 15-45%
Enalapril 18%
Captopril 19%
Atenolol 14% – 25%
Drugs 1995
Change in Lipid Levels with Doxazosin Treatment: HALT Study
-8.3
-6.9
-8.9
0.4
-10
-8
-6
-4
-2
0
2Total-C LDL-C Triglycerides
HDL-C
Cha
nge
in L
ipid
Lev
els
(mg/
dl)
Am Heart J 1996;131: 966-973
Changes in Lipid Parameters after 24 weeks
-25-20-15-10-505
1015202530
DoxazosinHydrochlorothiazide
Total Chol.HDL Chol.
HDLTotal Chol.
Triglyc
Am J Card 1987;59:103G
Ave
rage
(+S
.E.)
How does doxazosin reduce lipids
• Upregulation of LDL receptors
• Decreased cholesterol synthesis
• Decreased absorption of cholesterol from GIT
• Decrease in lipoprotein lipase activity
• Inhibition of VLDL synthesis
Doxazosin and CHD risk reduction
1. Beneficial effect on lipids
2. Beneficial effect on insulin resistance
3. Improved fibrinolytic activity
4. Reduces left ventricular hypertrophy– All these should effectively reduce the risk of CHD
Summary for all studies
• Lower pill burden was associated with better Adherence to AHT [antihypertensive treatment] and LLT [lipid lowering treatment]–Patients who initiated AHT and LLT concurrently
were significantly more likely to be adherent to both regimens
• Single-pill regimens were associated with significantly better persistence to ACE inhibitors, diuretics, and antidiabetic agents
Concomitant Hypertension/Dyslipidemia: Key Management Principles
• Individualize but avoid unduly prioritizing treatment of 1 condition over the other
• Educate patients about CVD risk reduction– Simultaneous blood pressure control and lipid-lowering
through TLC
• Employ treatment approaches that facilitate long-term adherence by considering real-world issues– Drug cost– Dosing schedules / Number of pills taken per day– Adverse effects
Concomitant Hypertension/Dyslipidemia: Key Management Principles
• Regularly update patients on current numbers and goals for both blood pressure and lipids–Explain significance of numbers–Record goal in chart to prompt follow-up at each
visit
Recording Chart
Treatment of hypertensive patients with Syndrome X
The approach
Remember
• The deadly trio to manage, whenever you see any one-
1. Hypertension2. Dyslipdeamia3. Insulin resistance
• Why is this so?1. FFAs
Elevated FFAP: contribute to hypertension, dyslipidemia, and insulin resistance
Eckel RH et al. Lancet. 2005;365:1415-28.VLDL = very low density lipoproteins
Hypertension
Triglyceride (intramuscular droplet)
Sympathetic nervous system
Glycogen
Insulin
FFAFFA
GlucoseVLDL
HDL-CSmall dense LDL
FFA InsulinTriglyceride
C-IIC-IIIB-100 and
CO2
Am. J. Med., 1998; 105(1A): 1S-3S
HypertensionObesityHyperinsulinaemiaDiabetesHypertriglyceridaemiaSmall, dense LDLLow HDLHypercoagulability
Insulinresistance
Atherosclerosis
Endothelialdysfunction
The cardiovascular dysmetabolic syndrome
Participants with Diabetes in ANTI-HYPERTENSIVE drug trials
•ALLHAT 15,297•ASCOT 5,145•VALUE 4,891•HOPE 3,577 (43.6% hypertensive)•CONVINCE 3,266•HOT 1,501•LIFE 1,195•UKPDS 1,148•SHEP 583•Syst-Eur 492•ABCD 470•ANBP-2 426
Treatment of hypertensive patients with Dyslipidaemia
Summary of Learning
Key Challenges Overview: Summary
• Obesity is significant risk factor for several interrelated conditions– Hypertension– Dyslipidemia– Diabetes– Atherosclerosis
• Even relatively low levels of elevated blood pressure and lipids impart significant increased CVD risk
• Hypertension and dyslipidemia often occur concomitantly
• Concomitant hypertension and dyslipidemia increase CVD risk exponentially
72
Paradigm shift in anti-hypertensive therapy
• It is not just ↓B.P., but today we must strive to1. Alter the modifiable risk factors
2. Keep the SBP < 140 and DBP < 90
3. Prevent or halt or reduce Target Organ Damage – • LVH, CHD, CHF, CVA, CRF, PVD & Retina.
4. Prevent or control DM (as HT + DM is hazardous)
5. Prevent or control Dyslipidemia (Endothelial Dysf.)
6. Reduce morbidity and mortality
7. Improve QUALY – Quality Adjusted Life Years
73
What is the essential approach in hypertension treatment?
74
What is MOST essential in hypertension treatment?
• Not that ‘my drug is superior to yours’
• Not that ‘this trial is better than that’
• Nor ‘this combination is better than that’
• But to get AS MANY PEOPLE as we can to goal SBP < 140 & DBP < 90
• And prevent or halt TOD.
• Of course, tailor the treatment as per individual patient’s co-morbidities.
What is new in hypertension treatment?
• HT is a multi-organ disease, and so not to consider in isolation but to look for ‘Co-Thieves’
• Today’s goal BP is 140/90 – It will sure be less tomorrow
• It matters to attain goal; matters more how it is attained. Monotherapy is gone; Combined Rx replaces
• In DM, CKD, IHD the cut off values are 10 mm less
76
What is new in hypertension treatment?
• ↑ SBP is more important than ↑ DBP; Often ignored!
• Wide pulse pressure (SBP-DBP) signifies arterial damage
• Target organ damage (TOD) must be investigated and treated.
• LVH = single imp. predictor of mortality and morbidity
• ABI, MAU, ABPM, PWV etc., identify high risk cases early