Hypertensive Dyslipidaemics

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  • The answer is C – 27 million. US Dept of Health and Human Services. JNC 7. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure . Bethesda, Md: National Institutes of Health; May 2003. NIH Publication No. 03-5233. US Department of Health and Human Services (DHHS). National Center for Health Statistics. Third National Health and Nutrition Examination Survey, 1988-1994, NHANES III.
  • The answer is C – 27 million. US Dept of Health and Human Services. JNC 7. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure . Bethesda, Md: National Institutes of Health; May 2003. NIH Publication No. 03-5233. US Department of Health and Human Services (DHHS). National Center for Health Statistics. Third National Health and Nutrition Examination Survey, 1988-1994, NHANES III.
  • The answer is B – 33%. According to analysis of data from the National Health and Nutrition Examination Survey, 1988-1994, approximately 27 million Americans have concomitant hypertension and dyslipidemia. Of those, only one third have been diagnosed with both conditions. US Department of Health and Human Services (DHHS). National Center for Health Statistics. Third National Health and Nutrition Examination Survey, 1988-1994, NHANES III.
  • The answer is A – 10%. Further, the same data show that only 3% are being treated to goal for both conditions.
  • Of the 10% of people treated for hypertension and dyslipidemia, only 3% get to goal.
  • Coupled with the findings from clinical trials, results from the M ultiple R isk F actor I ntervention T rial (MRFIT) offer strong support for intensified preventive efforts across all age groups. MRFIT found strong graded relationships between serum cholesterol levels above 180 mg/dL, systolic blood pressure (BP) >110 mm Hg, and diastolic BP >70 mm Hg and mortality due to coronary heart disease (CHD). Systolic BP was a stronger predictor than diastolic BP. Study Description: MRFIT was a randomized, multicenter primary prevention trial that studied the effect of intervention on the incidence of CHD. Between 1973 and 1975, more than 360,000 men aged 35 to 57 years in 18 US cities were screened for entry. Neaton JD, Wentworth D, for the Multiple Risk Factor Intervention Trial Research Group. Serum cholesterol, blood pressure, cigarette smoking, and death from coronary heart disease: overall findings and differences by age for 316 099 white men. Arch Intern Med . 1992;152:56-64.
  • The importance of systolic BP as a risk factor for coronary heart disease (CHD) is highlighted by the results of observational studies. An analysis of the 316,099 white men aged 35 to 57 screened between 1973 and 1975 for the Multiple Risk Factor Intervention Trial (MRFIT) assessed the influence of BP and other risk factors on death from CHD over a mean follow-up of 12 years. These men indicated that they had not been previously hospitalized for a heart attack or were not taking medication for diabetes. A strong risk gradient was evident for systolic BP for each category of diastolic BP category. Systolic BP was a stronger predictor of CHD death than was diastolic BP in all age groups. Neaton JD, Wentworth D, for the Multiple Risk Factor Intervention Trial Research Group. Serum cholesterol, blood pressure, cigarette smoking, and death from coronary heart disease: overall findings and differences by age for 316,099 white men. Arch Intern Med . 1992;152:56-64.
  • It is always a pleasure to present to ISHIB. My charge is to discuss the implications of the AASK trial on the management of hypertension in Blacks. The first implication is that we are beginning to accumulate data on the best way to lessen the toll that this disease extracts from our community.
  • The Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 (PROVE IT–TIMI 22) trial demonstrated that in patients who have recently had an ACS, early and continued lowering of LDL-C to levels substantially below current target levels is of great benefit. Investigators compared 40 mg of pravastatin (standard therapy) daily with 80 mg of atorvastatin daily (intensive therapy) in 4162 patients who had been hospitalized for an ACS within the preceding 10 days The median LDL-C level achieved during treatment was 95 mg/dL in the standard-therapy group and 62 mg/dL in the intensive-therapy group ( P <0.001).
  • In the PROVE-IT trial, Kaplan-Meier estimates of the rates of the primary end point at 2 years were 26.3% and 22.4% for pravastatin and atorvastatin, respectively, indicating a 16% reduction in the hazard ratio in favor of atorvastatin ( P =0.005; 95% confidence interval, 5%-26%).
  • Potential time course of statin effects CHD risk reduction with a statin appears to occur as a result of several related changes, including restoration of endothelial function, reduction in inflammation, and stabilization of vulnerable plaque. The time course for these antiatherosclerotic effects of statins ranges from days to years. Within weeks to months after beginning statin therapy, endothelial function of coronary arteries is restored. Concurrent with this or following by just a few months is a reduction in inflammatory markers, such as high-sensitivity C-reactive protein. These effects appear to coincide with the reduction in ischemic events demonstrated after about 18 months of statin therapy. After several years of therapy (i.e., 1.5 – 2.5 years), fatal and nonfatal myocardial infarction rates begin to decline in statin-treated patients, and after 5 years of therapy, significant reductions have been documented. These changes coincide somewhat with stabilization of vulnerable atherosclerotic plaque during which the lipid-rich core of plaque is replaced with connective tissue and matrix.
  • Potential time course of statin effects CHD risk reduction with a statin appears to occur as a result of several related changes, including restoration of endothelial function, reduction in inflammation, and stabilization of vulnerable plaque. The time course for these antiatherosclerotic effects of statins ranges from days to years. Within weeks to months after beginning statin therapy, endothelial function of coronary arteries is restored. Concurrent with this or following by just a few months is a reduction in inflammatory markers, such as high-sensitivity C-reactive protein. These effects appear to coincide with the reduction in ischemic events demonstrated after about 18 months of statin therapy. After several years of therapy (i.e., 1.5 – 2.5 years), fatal and nonfatal myocardial infarction rates begin to decline in statin-treated patients, and after 5 years of therapy, significant reductions have been documented. These changes coincide somewhat with stabilization of vulnerable atherosclerotic plaque during which the lipid-rich core of plaque is replaced with connective tissue and matrix.
  • It is always a pleasure to present to ISHIB. My charge is to discuss the implications of the AASK trial on the management of hypertension in Blacks. The first implication is that we are beginning to accumulate data on the best way to lessen the toll that this disease extracts from our community.
  • DOES INCREASED IN GLUCOSE IN ALLHAT TRANSLATE INTO INCREASED RISK OF DM SEEN IN EPID STUDIES Points of Emphasis / Key Messages The risk of cardiovascular death is substantially increased in patients with type 2 diabetes and comorbid elevated SBP. For an SBP of 120 to 139 mm Hg, concurrent diabetes is equivalent to adding 40 mm Hg to the systolic pressure. In addition, MRFIT demonstrated that SBP (as well as elevated serum cholesterol levels and cigarette smoking) is a significant predictor of mortality in men with and without diabetes. The Multiple Risk Factor Intervention Trial (MRFIT) enrolled 361,662 men 35 to 37 years of age. A total of 5625 were receiving treatment for diabetes; the remaining 356,037 did not have diabetes. The study did not classify diabetes as insulin-dependent or non-insulin-dependent (NIDDM), but because of the participants’ age, more than 90% were assumed to have NIDDM.   Men whose SBP was  180 mm Hg had nearly twice the risk of CV mortality if they had diabetes. If SBP was 140 to 179 mm Hg, the risk was more than twice that of men with diabetes.   Reference Stamler J, Vaccaro O, Neaton JD, Wentworth D. Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care . 1993;16:434-444.
  • This post-hoc comparison is of lisinopril (n=9054, 3210 Blacks) versus amlodipine (n=9048, 3213 Blacks).
  • It is always a pleasure to present to ISHIB. My charge is to discuss the implications of the AASK trial on the management of hypertension in Blacks. The first implication is that we are beginning to accumulate data on the best way to lessen the toll that this disease extracts from our community.
  • It is always a pleasure to present to ISHIB. My charge is to discuss the implications of the AASK trial on the management of hypertension in Blacks. The first implication is that we are beginning to accumulate data on the best way to lessen the toll that this disease extracts from our community.
  • Visceral adipose tissue is associated with a higher rate of free fatty acid (FFA) flux to the liver via the splanchnic circulation. In contrast, subcutaneous accumulation is not associated with direct effects in the liver, since FFA are released into the systemic circulation. FFA flux to the liver, in turn, is associated with a higher production of glucose, triglycerides, and VLDL; small, dense LDL particles, and lower HDL-C levels. Elevated FFA levels also inhibit glucose uptake by skeletal muscle, thereby contributing to impairment of insulin sensitivity, characteristic of the prediabetic state. Hyperinsulinemia, a result of reduced insulin sensitivity, enhances sodium reabsorption and increases sympathetic nervous system activity, resulting in elevated systolic blood pressure. Elevated FFA contribute to hypertension, dyslipidemia, and insulin resistance
  • It is always a pleasure to present to ISHIB. My charge is to discuss the implications of the AASK trial on the management of hypertension in Blacks. The first implication is that we are beginning to accumulate data on the best way to lessen the toll that this disease extracts from our community.
  • Thus, in the context of emerging evidence of vascular protection, the Goals of Therapy in hypertension need to be not only to control the BP, but also - To improve quality of life (symptoms) To reduce progression of CVD & induce regression, where possible and to reduce mortality & morbidity Thus, there is a change from the standard focus of controlling hypertension to a new, modified approach whereby in addition to BP control, there is the additional need to prevent the hypertension induced structural and functional abnormalities of the vascular endothelium. Correction of such endothelial dysfunction enables prevention of metabolic abnormalities and target organ damage and the restoration of the normal endothelium-dependent vasomotor tone. How can we achieve this? By adopting therapy that will restore the abnormal endothelium to a normal one. But, what is the difference between normal and abnormal endothelium?
  • Hypertensive Dyslipidaemics

    1. 1. Therapy of hypertensives with dyslipidaemia Unlearning towards better learning
    2. 2. The agenda for today <ul><li>Hypertension – the background </li></ul><ul><li>Current status of dyslipidaemia </li></ul><ul><li>The case studies </li></ul><ul><li>The clinical trials & the observations </li></ul><ul><li>The learnings </li></ul><ul><li>The summary </li></ul>
    3. 3. Hypertension The background
    4. 4. Hypertension <ul><li>What we record as B.P. </li></ul><ul><ul><li>It is only a marker of the bigger problem </li></ul></ul><ul><li>The Truth is </li></ul><ul><ul><li>Hypertension is a multi-organ systemic disease </li></ul></ul><ul><li>The Problem is </li></ul><ul><ul><li>Hypertension is asymptomatic in 85% of cases </li></ul></ul>
    5. 5. Hypertension – Be wise <ul><li>It is wrong </li></ul><ul><ul><li>To consider Hypertension as an isolated disease </li></ul></ul><ul><li>The Truth is </li></ul><ul><ul><li>Hypertension, DM, Dyslipidemia, Obesity coexist </li></ul></ul><ul><ul><li>They are the 4 pallbearers to the grave of CHD/CVD </li></ul></ul><ul><li>For all of them </li></ul><ul><ul><li>Primary & secondary prevention by TLC = answer </li></ul></ul><ul><ul><li>Afflicted with one, must be screened for all other thieves </li></ul></ul>
    6. 6. Hypertension – Therapy goal <ul><li>Goal BP </li></ul><ul><ul><li>To Keep B.P. < 140/90 mm Hg in each patient </li></ul></ul><ul><ul><li>This may be revised to 120/80 may be ? 110/70 </li></ul></ul><ul><ul><li>MRFIT’s cut off values are 115/75 mm Hg </li></ul></ul><ul><li>The Truth is </li></ul><ul><ul><li>It is essential to keep the B.P at or below the goal </li></ul></ul><ul><ul><li>But, It also matters how the goal B.P. is achieved ! </li></ul></ul>
    7. 7. Current status Hypertension and dyslipidaemia
    8. 8. Rule of halves in hypertension <ul><li>What is this rule of halves in HT ? </li></ul>JNC 7. May 2003; Third National Health and Nutrition Examination Survey, 1988-1994, NHANES III. <ul><li>For every 800 adults in the community </li></ul><ul><ul><li>400 are HT (either ↑ SBP or ↑ DBP or both) </li></ul></ul><ul><ul><li>Of them only 200 are diagnosed HT </li></ul></ul><ul><ul><li>Of them only 100 are started on treatment </li></ul></ul><ul><ul><li>Of them only 50 are on correct drug </li></ul></ul><ul><ul><li>Of them in only 25 the goal B.P. is attained </li></ul></ul><ul><ul><li>Means 25 ÷ 400 = 6% only have goal BP </li></ul></ul><ul><ul><li>And we have yet to look at HT with other conditions </li></ul></ul>
    9. 9. People with concomitant hypertension & dyslipidemia 90 million with dyslipidemia JNC 7. May 2003; Third National Health and Nutrition Examination Survey, 1988-1994, NHANES III. 27 million with concomitant hypertension, dyslipidemia 50 million with hypertension
    10. 10. People with concomitant hypertension & dyslipidemia 9 million diagnosed (33%) 18 million undiagnosed (67%) Third National Health and Nutrition Examination Survey, 1988-1994, NHANES III.
    11. 11. People with concomitant hypertension & dyslipidemia Source: Unpublished data from the Third National Health and Nutrition Examination Survey (NHANES-III), CDC 1994; data from 1999.
    12. 12. People with concomitant hypertension & dyslipidemia 10% Treated For Hypertension & Dyslipidemia Source: Unpublished data from the Third National Health and Nutrition Examination Survey (NHANES-III), CDC 1994; data from 1999. 3% at Goal
    13. 13. Co-prevalence of dyslipidemia & hypertension in India The prevalence of coexistence of dyslipidemia and hypertension in patients surveyed at Apollo Hospitals (n=501) Indian Heart Journal 1996: 48(4): 371-374 0 10 20 30 40 50 Percent 60 70 80 90 100 0 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)
    14. 14. 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
    15. 15. The approach <ul><li>Global risks assessment and reduction is the best way to reduce CV events. </li></ul><ul><li>Hypertension and Hyperlipidemia are 2 most common risks found in our population. </li></ul><ul><li>New antihypertensive drugs are beneficial in BP control and prevention of CV events. </li></ul><ul><li>Multi-drug combinations should be used to modify risk factors and/or metabolic disturbances but is usually associated with poor compliance. </li></ul>
    16. 16. Whom to Screen for Dyslipidemia? <ul><li>Influenced by cardiac risk factors: </li></ul><ul><li>By age alone: </li></ul><ul><ul><li>Men over age 40 </li></ul></ul><ul><ul><li>Women over age 50 (or post-menopausal) </li></ul></ul><ul><li>Other risk factors (at any age): </li></ul><ul><ul><li>DM, HTN, Smoking, Abdominal Obesity </li></ul></ul><ul><ul><li>Family history of early cardiovascular disease </li></ul></ul><ul><li>Physical signs of hyperlipidemia (at any age): </li></ul><ul><ul><li>Xanthomata, xanthelasmas, arcus corneae, etc </li></ul></ul><ul><li>Evidence of existing atherosclerosis (any age) </li></ul>
    17. 17. Factors Influencing Risk Assessment <ul><li>Metabolic Syndrome </li></ul><ul><li>Abdominal Obesity </li></ul><ul><li>Apolipoprotein B (apoB) </li></ul><ul><li>Lipoprotein(a) </li></ul><ul><li>Homocysteine </li></ul><ul><li>C-Reactive Protein (CRP) </li></ul><ul><li>Genetic Risk </li></ul><ul><li>Hormone Replacement Therapy (HRT) </li></ul>
    18. 18. Factors Influencing Risk Assessment <ul><li>Presence of the Metabolic Syndrome </li></ul><ul><ul><li>A clustering of cardiovascular risk factors, including abdominal obesity, insulin resistance, and hypertension, as well as lipid abnormalities (↑TGs and ↓HDL) </li></ul></ul><ul><li>Presence of Abdominal Obesity </li></ul><ul><ul><li>with waist circumference as a useful estimate </li></ul></ul>
    19. 19. Factors Influencing Risk Assessment <ul><li>Apolipoprotein B (apoB) </li></ul><ul><ul><li>There is 1 molecule of apoB in each atherogenic lipid particle (VLDL, IDL, LDL, lp(a))’ </li></ul></ul><ul><ul><li>↑apoB (for the same lipid levels) = smaller, denser, more atherogenic LDL particles </li></ul></ul><ul><ul><li>Better estimate than LDL of cardiovascular risk </li></ul></ul><ul><ul><li>ApoB levels correlate better than LDL levels to clinical outcomes in statin trials </li></ul></ul><ul><ul><li>For ‘high risk’ patients, target apoB <0.9g/L </li></ul></ul><ul><ul><li>Sample does not need to be fasting </li></ul></ul>
    20. 20. Factors Influencing Risk Assessment <ul><li>Lipoprotein(a) (lp(a)) </li></ul><ul><ul><li>Appears to be an independent risk factor for premature atherosclerosis and CAD </li></ul></ul><ul><ul><li>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 </li></ul></ul><ul><ul><li>Monogenic and not responsive to diet </li></ul></ul><ul><ul><li>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 </li></ul></ul>
    21. 21. Factors Influencing Risk Assessment <ul><li>Homocysteine </li></ul><ul><ul><li>↑homocysteine levels predict adverse outcomes in patients with CAD </li></ul></ul><ul><ul><li>Fixed-dose folate & B12 trials looking at cardiovascular endpoints are ongoing </li></ul></ul><ul><ul><li>No ‘treat-to-target’ trial (to homocysteine <9μmol/L) </li></ul></ul><ul><ul><li>No evidence yet to screen for homocysteine </li></ul></ul>
    22. 22. Factors Influencing Risk Assessment <ul><li>C-Reactive Protein (CRP) </li></ul><ul><ul><li>↑CRP may add prognostic information to Framingham Study data </li></ul></ul><ul><ul><li>↑CRP associated with abdominal obesity and the metabolic syndrome </li></ul></ul><ul><ul><li>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’) </li></ul></ul>
    23. 23. Factors Influencing Risk Assessment <ul><li>C-Reactive Protein (CRP) </li></ul><ul><ul><li>Do not measure during an acute illness or in patients with chronic inflammatory disease </li></ul></ul><ul><ul><li>Measure 2x, two weeks apart, and use the lower value </li></ul></ul><ul><ul><li>Low risk <1 mg/ml & high risk 3-10mg/ml </li></ul></ul><ul><ul><li>If >10mg/ml, look for infection/inflammation </li></ul></ul>
    24. 24. Hypertensive patient with Dyslipidaemia Case study
    25. 25. Patient # 1 <ul><li>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. </li></ul><ul><ul><li>Approximately a year back, he suffered a myocardial infarction, but has since been asymptomatic. He does not have any other significant past medical history. </li></ul></ul><ul><ul><li>His current medications include aspirin 81 mg daily and a beta-blocker. </li></ul></ul><ul><ul><ul><li>His sitting blood pressure is 155/95 mmHg, heart rate 58 beats/min. </li></ul></ul></ul><ul><ul><ul><li>Pertinent laboratory values: glucose 86 mg/dl; total cholesterol 228 mg/dl; HDL-C 37 mg/dl; LDL-C 128 mg/dl. </li></ul></ul></ul><ul><ul><ul><li>An echocardiogram shows concentric LVH and preserved left ventricular systolic function (ejection fraction 56%). </li></ul></ul></ul>
    26. 26. Question # 1 <ul><li>A statin (to reduce LDL-C to ≤ 100 mg/dl), a calcium channel blocker, and a diuretic. </li></ul><ul><li>An angiotensin-receptor blocker and a statin (to reduce LDL-C to ≤ 70 mg/dl). </li></ul><ul><li>An ACE inhibitor and a statin (to reduce LDL-C to ≤ 120 mg/dl). </li></ul><ul><li>Oral nitrates, hydralazyne, and a statin (to reduce LDL-C to ≤ 70 mg/dl). </li></ul><ul><li>Niacin, a calcium channel blocker, and a diuretic. </li></ul>Which of the following should be done? <ul><li>An ACE inhibitor and a statin (to reduce LDL-C to ≤ 120 mg/dl). </li></ul>
    27. 27. MRFIT - Effect of Systolic & Diastolic BP on CHD Mortality *Men aged 35-57 years followed for a mean of 12 years. <120 120-139 140-159 160+ CHD Death Rate per 10,000 Person-Years 48.3 37.4 34.7 43.8 38.1 80.6 31.0 25.5 24.6 25.3 25.2 24.9 Systolic BP (mm Hg) Diastolic BP (mm Hg) Neaton et al. Arch Intern Med . 1992;152:56-64.  100+ 80-89 70-74 <70 75-79 90-99 23.8 16.9 13.9 12.8 12.6 11.8 20.6 10.3 11.8 8.8 8.5 9.2 Patient in Question # 1
    28. 28. Treatment of hypertensive patients with Dyslipidaemia The learning from different studies
    29. 29. Selected major trials <ul><li>PROVE IT – TIMI 22 </li></ul><ul><li>MRC/BHF Heart Protection Study </li></ul><ul><li>ASCOT- LLA </li></ul><ul><li>ALLHAT </li></ul>
    30. 30. Lower is better <ul><li>statin therapy provides benefits even with lower LDL-C </li></ul>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 Patients with CHD Event (%) 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-P CARE-S LIPID-P 4S-P LIPID-S CARE-P 4S-S AFCAPS-P ASCOT-S ASCOT-P Simvastatin Pravastatin Lovastatin HPS-S HPS-S HPS-P HPS-P S=statin treated P=placebo treated
    31. 31. 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. No. at Risk Pravastatin Atorvastatin 2063 2099 1688 1736 1536 1591 1423 1485 810 842 138 133 106 106 95 62 0 20 40 60 80 100 120 Pravastatin 40 mg/day (n=2063) Atorvastatin 80 mg/day (n=2099) Median LDL-C (mg/dL) Baseline Final (Mean, 24 mo) P <0.001
    32. 32. PROVE IT: Intensive Statin Therapy ↓ All-Cause Mortality and Risk of MACE No. at Risk Pravastatin Atorvastatin 2063 2099 1688 1736 1536 1591 1423 1485 810 842 138 133 Cannon CP, et al. N Engl J Med. 2004;350:1-10. Months of Follow-up
    33. 33. MRC/BHF Heart Protection Study <ul><li>HPS: Lancet 360(9326):7-22, 6 July 2002 </li></ul><ul><ul><li>20,556 men & women aged 40-80 with TC >3.5 </li></ul></ul><ul><ul><li>All at ‘high risk’ of CAD </li></ul></ul><ul><ul><ul><li>Known CAD/MI/PVD/CVS </li></ul></ul></ul><ul><ul><ul><li>DM, HTN, or both </li></ul></ul></ul><ul><ul><li>RCT: Simvastatin 40mg vs. placebo </li></ul></ul><ul><ul><ul><li>Decreased death rate by 13% </li></ul></ul></ul><ul><ul><ul><li>Decreased combined cardiovascular end points by 24% </li></ul></ul></ul><ul><ul><li>Benefits in all subgroups, including baseline LDL <2.6 </li></ul></ul><ul><ul><li>Very compelling, well done trial </li></ul></ul><ul><ul><li>Ultimate LDL target still unclear, other studies now looking at LDL targets of <1.8 </li></ul></ul>
    34. 34. ASCOT – LLA - Rationale <ul><li>Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm </li></ul><ul><li>Premise </li></ul><ul><ul><li>High prevalence of dyslipidemia in hypertensive patients </li></ul></ul><ul><ul><li>Most CV disease events occur in patients with BP and lipid concentrations deemed normal </li></ul></ul><ul><li>Hypothesis </li></ul><ul><ul><li>Lipid lowering will benefit hypertensive patients, not conventionally deemed dyslipidemic </li></ul></ul>
    35. 35. ASCOT – LLA - Findings <ul><li>In patients with hypertension and additional CV risk factors, addition of atorvastatin </li></ul><ul><ul><li>Had significant effects on nonfatal CVD and fatal MI </li></ul></ul><ul><ul><li>Benefits even in absence of traditional dyslipidaemia </li></ul></ul><ul><li>Identification of the at-risk patient with hypertension and other CV risk factors enables appropriate treatment for CV event prevention </li></ul><ul><li>Study was stopped after 3 years because of significant benefit in the treatment group </li></ul>
    36. 36. Diet control & dyslipidaemia reduction
    37. 37. Time course of Statin effects * Time course established Days Years LDL-C lowered* Inflammation reduced Vulnerableplaques stabilized Endothelial function restored Ischemic episodes reduced Cardiac events reduced*
    38. 38. Therapy <ul><li>In ‘high risk’ patients: </li></ul><ul><ul><li>Start drug treatment immediately, concurrently with diet and lifestyle modification </li></ul></ul><ul><ul><li>Priority is to get LDL <2.5 and TC/HDL <4 </li></ul></ul><ul><ul><li>Given HPS data, treat with Simvastatin 40mg or equivalent statin for LDL target. </li></ul></ul><ul><ul><li>If can’t reach LDL target: </li></ul></ul><ul><ul><ul><li>Bile acid sequestrants (cholestyramine, colestipol), or </li></ul></ul></ul><ul><ul><ul><li>Ezetimibe - better tolerated </li></ul></ul></ul><ul><ul><ul><li>Either can decrease LDL by another 10-20% compared with statin alone </li></ul></ul></ul>
    39. 39. Treatment of hypertensive patients with Dyslipidaemia Different antihypertensive perspectives
    40. 40. Elevated SBP in Type 2 Diabetes Increases Cardiovascular Risk Stamler J et al. Diabetes Care . 1993;16:434-444. Elevated SBP increases risk of CV death almost twofold in diabetic vs nondiabetic patients 20 Cardiovascular Mortality Rate per 10,000 Patient-Years SBP (mm Hg) Nondiabetic patients Diabetic patients 250 200 150 100 50 0 <120 120–139 140–159 160–179 180–199  200 MRFIT
    41. 41. Hypertension Optimal Treatment (HOT) Study Lancet 1998; 351: 1755–62 p=0.005 (DM) 0 5 10 15 20 25 Events/1000 pt-years <90 <85 <80 Target diastolic BP DM non-DM Reduction in CV events
    42. 42. Questions on antihypertensives <ul><li>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. </li></ul><ul><li>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? </li></ul>
    43. 43. Questions on antihypertensives <ul><li>Is there synergy between certain anti-hypertensive medication combinations that outweigh benefits of the individual medications? </li></ul><ul><li>The adverse effects of thiazide-type diuretics on blood cholesterol, glucose, potassium, uric acid have been known for more than 40 years </li></ul>
    44. 44. Approaches to hypertension therapy
    45. 45. Lifestyle Modification approach in hypertension therapy 5–20 mm/10 kg wt loss Weight reduction All put together reduce BP by 20 to 55 mmHg 2–4 mmHg Abstinence from alcohol 4–9 mmHg Physical activity 2–8 mmHg Dietary sodium reduction 8–14 mmHg Adopt DASH [Dietary Approaches to Stop Hypertension] eating plan Approximate BP reduction [range] Modification
    46. 46. ALLHAT <ul><li>ALLHAT is the first study to report on the effect of antihypertensive regimens on clinical outcomes in hypertensives with the MetS. </li></ul><ul><li>ALLHAT was designed to evaluate the effect of diuretics on clinical outcomes compared to agents without these adverse metabolic effects </li></ul>ALLHAT
    47. 47. ALLHAT - Definition of MetS (DS) participants <ul><li>Any 3 or more of the following: </li></ul><ul><ul><li>Hypertension (present in all as a condition of enrollment into ALLHAT) </li></ul></ul><ul><ul><li>Fasting glucose >100 mg/dl or 100-125 mg/dl in non-diabetics with MetS </li></ul></ul><ul><ul><li>BMI ≥ 30 kg/m2 </li></ul></ul><ul><ul><li>Fasting triglycerides ≥ 150 mg/dL </li></ul></ul><ul><ul><li>HDL cholesterol <40 mg/dl in men, <50 mg/dl in women </li></ul></ul>ALLHAT
    48. 48. ALLHAT <ul><li>How large is the difference in metabolic effects, esp the effect on glucose? </li></ul><ul><li>Does the effect associate with an increase in adverse clinical outcomes compared to drugs with a more favorable metabolic profile? </li></ul><ul><li>Are patients at higher risk (e.g. patients with diabetes or the metabolic syndrome) more vulnerable to the adverse effects of available antihypertensive agents? </li></ul>ALLHAT
    49. 49. Hypertension Trial 42,418 high-risk hypertensive patients 90% previously treated, 10% untreated STEP 1 AGENTS Chlorthalidone 12.5-25 mg Amlodipine 2.5-10 mg Lisinopril 10-40 mg Doxazosin 1-8 mg N=15,255 N=9,048 N=9,054 N=9,061 STEP 2 AND 3 AGENTS (5 years)* Atenolol 28.0% Clonidine 10.6% Reserpine 4.3% Hydralazine 10.9% * Of participants with data available for determination. ALLHAT
    50. 50. Outcomes in ALLHAT participants with the metabolic syndrome <ul><li>Patients with metabolic syndrome (MetS) are at very high risk for complications of hypertension </li></ul><ul><li>Use of agents with favorable metabolic effects esp recommended in hypertensives with MetS </li></ul><ul><li>Alpha-blockers and RAS inhibitors demonstrate the most favorable effect on blood glucose and lipids, </li></ul><ul><li>CCBs are intermediate, followed by THZ-diuretics. </li></ul>ALLHAT
    51. 51. Summary & conclusions <ul><li>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. </li></ul><ul><li>ALLHAT fails to support an increase in CVD risk associated with diuretic-induced glucose elevation or incident diabetes in hypertensive patients. </li></ul>ALLHAT
    52. 52. Summary & conclusions <ul><li>ALLHAT provides further evidence against the consideration of intermediate outcomes in the selection of antihypertensive agents. </li></ul><ul><li>Findings apply equally to Black and non-Black populations </li></ul>ALLHAT
    53. 53. Effect of various antihypertensives on coexisting disorders
    54. 54. Effect of various antihypertensives on coexisting disorders Parameter Diuretic ACEi, ARB β blocker 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
    55. 55. Treatment of hypertensive patients with Dyslipidaemia Learning on alpha blockade
    56. 56. Effect of various drugs on CHD risk Drugs 1995 14%  – 25%  Atenolol 19%  Captopril 18%  Enalapril 15-45%  Doxazosin Effect on CHD risk Drug
    57. 57. Change in Lipid Levels with Doxazosin Treatment: HALT Study Total-C LDL-C Triglycerides HDL-C Change in Lipid Levels (mg/dl) Am Heart J 1996;131: 966-973
    58. 58. Changes in Lipid Parameters after 24 weeks Total Chol. HDL Chol. HDL Total Chol. Triglyc Am J Card 1987;59:103G Average ( + S.E.)
    59. 59. How does doxazosin reduce lipids <ul><li>Upregulation of LDL receptors </li></ul><ul><li>Decreased cholesterol synthesis </li></ul><ul><li>Decreased absorption of cholesterol from GIT </li></ul><ul><li>Decrease in lipoprotein lipase activity </li></ul><ul><li>Inhibition of VLDL synthesis </li></ul>
    60. 60. Doxazosin and CHD risk reduction <ul><li>Beneficial effect on lipids </li></ul><ul><li>Beneficial effect on insulin resistance </li></ul><ul><li>Improved fibrinolytic activity </li></ul><ul><li>Reduces left ventricular hypertrophy </li></ul><ul><ul><li>All these should effectively reduce the risk of CHD </li></ul></ul>
    61. 61. Summary for all studies <ul><li>Lower pill burden was associated with better Adherence to AHT [antihypertensive treatment] and LLT [lipid lowering treatment] </li></ul><ul><ul><li>Patients who initiated AHT and LLT concurrently were significantly more likely to be adherent to both regimens </li></ul></ul><ul><li>Single-pill regimens were associated with significantly better persistence to ACE inhibitors, diuretics, and antidiabetic agents </li></ul>
    62. 62. Concomitant Hypertension/Dyslipidemia: Key Management Principles <ul><li>Individualize but avoid unduly prioritizing treatment of 1 condition over the other </li></ul><ul><li>Educate patients about CVD risk reduction </li></ul><ul><ul><li>Simultaneous blood pressure control and lipid-lowering through TLC </li></ul></ul><ul><li>Employ treatment approaches that facilitate long-term adherence by considering real-world issues </li></ul><ul><ul><li>Drug cost </li></ul></ul><ul><ul><li>Dosing schedules / Number of pills taken per day </li></ul></ul><ul><ul><li>Adverse effects </li></ul></ul>
    63. 63. Concomitant Hypertension/Dyslipidemia: Key Management Principles <ul><li>Regularly update patients on current numbers and goals for both blood pressure and lipids </li></ul><ul><ul><li>Explain significance of numbers </li></ul></ul><ul><ul><li>Record goal in chart to prompt follow-up at each visit </li></ul></ul>
    64. 64. Recording Chart
    65. 65. Treatment of hypertensive patients with Syndrome X The approach
    66. 66. Remember <ul><li>The deadly trio to manage, whenever you see any one- </li></ul><ul><ul><li>Hypertension </li></ul></ul><ul><ul><li>Dyslipdeamia </li></ul></ul><ul><ul><li>Insulin resistance </li></ul></ul><ul><li>Why is this so? </li></ul><ul><ul><li>FFAs </li></ul></ul>
    67. 67. 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 FFA FFA Glucose VLDL  HDL-C  Small dense LDL FFA Insulin Triglyceride C-II C-III B-100 and CO 2
    68. 68. The cardiovascular dysmetabolic syndrome Am. J. Med., 1998; 105(1A): 1S-3S Hypertension Obesity Hyperinsulinaemia Diabetes Hypertriglyceridaemia Small, dense LDL Low HDL Hypercoagulability Insulin resistance Atherosclerosis Endothelial dysfunction
    69. 69. Participants with Diabetes in ANTI-HYPERTENSIVE drug trials <ul><li>ALLHAT </li></ul>15,297 <ul><li>ASCOT </li></ul>5,145 <ul><li>VALUE </li></ul>4,891 <ul><li>HOPE </li></ul>3,577 (43.6% hypertensive) <ul><li>CONVINCE </li></ul>3,266 <ul><li>HOT </li></ul>1,501 <ul><li>LIFE </li></ul>1,195 <ul><li>UKPDS </li></ul>1,148 <ul><li>SHEP </li></ul>583 <ul><li>Syst-Eur </li></ul>492 <ul><li>ABCD </li></ul>470 <ul><li>ANBP-2 </li></ul>426
    70. 70. Treatment of hypertensive patients with Dyslipidaemia Summary of Learning
    71. 71. Key Challenges Overview: Summary <ul><li>Obesity is significant risk factor for several interrelated conditions </li></ul><ul><ul><li>Hypertension </li></ul></ul><ul><ul><li>Dyslipidemia </li></ul></ul><ul><ul><li>Diabetes </li></ul></ul><ul><ul><li>Atherosclerosis </li></ul></ul><ul><li>Even relatively low levels of elevated blood pressure and lipids impart significant increased CVD risk </li></ul><ul><li>Hypertension and dyslipidemia often occur concomitantly </li></ul><ul><li>Concomitant hypertension and dyslipidemia increase CVD risk exponentially </li></ul>
    72. 72. Paradigm shift in anti-hypertensive therapy <ul><li>It is not just ↓B.P., but today we must strive to </li></ul><ul><li>Alter the modifiable risk factors </li></ul><ul><li>Keep the SBP < 140 and DBP < 90 </li></ul><ul><li>Prevent or halt or reduce Target Organ Damage – </li></ul><ul><ul><li>LVH, CHD, CHF, CVA, CRF, PVD & Retina. </li></ul></ul><ul><li>Prevent or control DM (as HT + DM is hazardous) </li></ul><ul><li>Prevent or control Dyslipidemia (Endothelial Dysf.) </li></ul><ul><li>Reduce morbidity and mortality </li></ul><ul><li>Improve QUALY – Quality Adjusted Life Years </li></ul>
    73. 73. What is the essential approach in hypertension treatment?
    74. 74. What is MOST essential in hypertension treatment? <ul><li>Not that ‘my drug is superior to yours’ </li></ul><ul><li>Not that ‘this trial is better than that’ </li></ul><ul><li>Nor ‘this combination is better than that’ </li></ul><ul><li>But to get AS MANY PEOPLE as we can to goal SBP < 140 & DBP < 90 </li></ul><ul><li>And prevent or halt TOD. </li></ul><ul><li>Of course, tailor the treatment as per individual patient’s co-morbidities. </li></ul>
    75. 75. What is new in hypertension treatment? <ul><li>HT is a multi-organ disease, and so not to consider in isolation but to look for ‘Co-Thieves’ </li></ul><ul><li>Today’s goal BP is 140/90 – It will sure be less tomorrow </li></ul><ul><li>It matters to attain goal; matters more how it is attained. Monotherapy is gone; Combined Rx replaces </li></ul><ul><li>In DM, CKD, IHD the cut off values are 10 mm less </li></ul>
    76. 76. What is new in hypertension treatment? <ul><li>↑ SBP is more important than ↑ DBP; Often ignored! </li></ul><ul><li>Wide pulse pressure (SBP-DBP) signifies arterial damage </li></ul><ul><li>Target organ damage (TOD) must be investigated and treated. </li></ul><ul><li>LVH = single imp. predictor of mortality and morbidity </li></ul><ul><li>ABI, MAU, ABPM, PWV etc., identify high risk cases early </li></ul>

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