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Conflict of Interest

Conflict of Interest. This presentation by Franz H. Messerli is sponsored by Boehringer Ingelheim . Therefore any mentioning of a Boehringer Ingelheim product should be considered as biased information and automatically be treated as suspicious.

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Conflict of Interest

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  1. Conflict of Interest This presentation by Franz H. Messerli is sponsored by Boehringer Ingelheim. Therefore any mentioning of a Boehringer Ingelheim product should be considered as biased information and automatically be treated as suspicious.

  2. “In the past 100 years, only during the 1918 flu pandemic was cardiovascular disease not the number-one cause of death”. AHA Year End Statistics 2005

  3. What is the residual lifetime risk of becoming hypertensive in a normotensive person at age 55? • 10 – 30 % • 30 – 50 % • 50 – 70 % • 70 – 90 % • >90 % ?

  4. Residual Lifetime Risk for Hypertension From Age 55 100 80 60 40 10 15 20 25 20 0 93 91 Women 88 83 Men 78 72 56 52 Risk for Hypertension (%) Time (Years) Individuals who are normotensive at age 55 have a > 90% lifetime risk of developing hypertension Vasan RS et al. JAMA. 2002;287:1003-1010 Framingham.

  5. McCord C, Freeman HP. N Engl J Med. 1990 Jan 18;322(3):173-7.

  6. National Vital Statistics System, United States, 2002

  7. Arterial Pressure of Franklin D. Roosevelt from 1935 until his death on April 12, 1945 350 D-Day Election Yalta ? 300 250 200 Arterial Blood Pressure (mmHg) 150 100 EKG: LVH 50 Proteinuria: + + + 0 M A M J J A S O N D J F M A 1935 1937 1939 1941 1944 1945 Month and Year Messerli, FH, NEJM, 332:1038-1039, 1995

  8. “The treatment of the hypertension itself is a difficult and almost hopeless task in the present state of our knowledge and in fact, for aught we know … ”

  9. “… the hypertension may be an important compensatorymechanism which should not be tampered with, even were it certain that we could control it.” Paul Dudley White, MD, Heart Disease, First Edition 1931

  10. Syst-Eur: Fatal and Nonfatal Stroke (in 4695 Randomized Patients) 6 – 5 – Placebo • 42% • P < 0.003 4 – Events per 100 Patients 3 – 2 – Active Treatment 1 – 0 – I 0 I 1 I 2 I 3 I 4 Time Since Randomization (Years) Staessen J et al. 1997

  11. “Systolic hypertension in the presence of a normal or reduced diastolic pressure is rarely considered responsible for target organ damage.” Engelman K, Braunwald E. Ch.37, “Elevation of Arterial Blood Pressure,” Harrison’s Principles of Internal Medicine. 6th Ed. 1970.

  12. Syst-Eur: Fatal and Nonfatal Stroke (in 4695 Randomized Patients) - 32% P < 0.001 All Endpoints - 42% Stroke P = 0.003 - 26% Cardiac P= 0.03 - 29% CHF P = 0.12 - 30% P= 0.12 MI -100 -50 0 50% Active Better Placebo Better Staessen J, et al. 1997.

  13. Data Selection: • Randomized trials lasting at least one year, which used as first line agents diuretics and/or beta-blockers and reported morbidity and mortality outcomes in elderly hypertensive patients.

  14. All Cause Mortality Diuretics 7 681/5838 907/6618 ß-blockers 2 227/1521 384/2678 Meta-Analysis of Prospective Clinical Trials in Hypertension in the Elderly Active Treatment Control Outcome Events/ Events/ Odds Ratio and First Drug # Trials Patient Patients 95% Confidence Interval 0.4 0.6 0.8 1.0 1.2 1.4

  15. Active Treatment Control Outcome Events/ Events/ Odds Ratio and First Drug # Trials Patient Patients 95% Confidence Interval Coronary Heart Disease Diuretics 8 365/5876 531/6661 ß-blockers 2 115/1521 197/2678 Cardio-Vascular Disease Diuretics 7 332/5838 510/6618 ß-blockers 2 130/1521 230/2678 0.4 0.6 0.8 1.0 1.2 1.4 Meta-Analysis of Prospective Clinical Trials in Hypertension in the Elderly

  16. Relative risk of major events with atenolol vs placebo (n = 6825) Carlberg B et al. Lancet 2004; 364:1684–1689.

  17. Cochrane review: Beta blockers should not be first line for hypertensionFebruary 2, 2007 Sue Hughes • The available evidence does not support the use of beta blockers as first-line drugs in the treatment of hypertension [1]. • The review bases this conclusion on "the relatively weak effect of beta blockers to reduce stroke and the absence of an effect on coronary heart disease when compared with placebo "

  18. Analysis 01.01. Comparison 01 Beta-blocker vs Placebo or No treatment, Outcome 01 Total mortality Cochrane Database of Systematic ReviewsPublished by John Wiley & Sons, Ltd : 24 January 2007

  19. Antihypertensive Therapy and Cardioprotection Beta Blockers Diuretics Primary Prevention no yes Secondary Prevention yes ?

  20. Myths and Misperceptions… "Which of the following class of drugs have been proven to reduce mortality in hypertensive patients?" • Beta-blockers 78% • ACE inhibitors 65% • Diuretics 53% • CCBs 17% Kaboli PJ, et al. J Clin Hypertens 2007;9:416-423.

  21. SYST EUR: Effect of Calcium Antagonist Treatment on Dementia 10 Placebo 8 6 -55% P=0.0008 Cases per 100 Patients 4 Active Treatment 2 0 0 2 4 6 8 Time since Randomization (Years) Forette F., et al. Arch Intern Med In Press 2002

  22. Effect of Antihypertensive Therapy on Cognitive Dysfunction/Dementia Forette F, et al. Lancet. 1998;352(9137):1347-51.

  23. Outcome Evidence for Betablockers in CV Disease None Some Strong Hypertension Heart Failure ACS Post MI Stable Angina HOCM Perioperative Bangalore S, Messerli FH et al. JACC in press 2007

  24. Percentage of Patients Continuing Prescribed Drug Regimen after 1 Year 100 80 60 40 20 0 Percent ARB ACEI CA BB D Mancia G, et al. AJH 2003;16:1066–73

  25. Placebo(n = 58) Telmisartan(40–120 mg)(n = 62) Amlodipine(5–10 mg)(n = 65) SBP 160 140 120 BP (mm Hg) DBP 100 80 0 Time of Day 0800 1200 1600 2000 2400 0400 0800 Telmisartan vs Amlodipine Using 24-h ABPM1 Baseline ABPM 1. Lacourcière Y, Lenis J, Orchard R, et al. A comparison of the efficacy and duration of action of theangiotensin II receptor blocker telmisartan to amlodipine. Blood Press Monit. 1998;3:295–302.

  26. 160 Placebo(n = 58) Telmisartan(40–120 mg)(n = 62) Amlodipine(5–10 mg)(n = 65) 150 140 BP (mm Hg) 130 120 0800 1200 1600 2000 2400 0400 0800 Time of Day Effects of Telmisartan vs AmlodipineDerived from 24-h ABPM1 End of Therapy (Week 12) – Systolic BP 1. Lacourcière Y, Lenis J, Orchard R, et al. A comparison of the efficacy and duration of action of theangiotensin II receptor blocker telmisartan to amlodipine. Blood Press Monit. 1998;3:295–302.

  27. End of Therapy (Week 12) – Diastolic BP 110 Placebo(n = 58) Telmisartan(40–120 mg)(n = 62) Amlodipine(5–10 mg)(n = 65) 100 90 BP (mm Hg) 80 70 60 0800 1200 1600 2000 2400 0400 0800 Time Effects of Telmisartan vs AmlodipineDerived from 24-h ABPM1 1. Lacourcière Y, Lenis J, Orchard R, et al. A comparison of the efficacy and duration of action of theangiotensin II receptor blocker telmisartan to amlodipine. Blood Press Monit. 1998;3:295–302.

  28. Effect of ARBs on BP at Trough ( placebo subtracted ) 46 studies, 13451 pts The Cochrane Collaboration, Heran BS et al. October 2008

  29. Effect of ACE-Is on BP at Trough ( placebo subtracted ) 92 studies, 12954 pts The Cochrane Collaboration, Heran BS et al. October 2008

  30. Blood Pressure Reduction at Trough mm Hg # of Studies 92 46 6 # of Patients 12954 13451 3694 # of Drugs 14 9 11 Messerli FH, Bangalore S. Circulation. 2009;119(3):371-3

  31. Dose Response of ARB Withdrawal Rate 46 studies, 13451 pts The Cochrane Collaboration, Heran BS et al. October 2008

  32. Dose Response of ARB Withdrawal Rate 46 studies, 13451 pts The Cochrane Collaboration, Heran BS et al. October 2008

  33. Dose Response of ACE-I Withdrawal Rate RR 92 studies, 12954 pts The Cochrane Collaboration, Heran BS et al. October 2008

  34. ACE-Inhibitor Related Angioedema –How Uncommon? Incidence: 0. 1% 0. 2% 0. 5% First week incidence 1/2,500 pts. Subsequent incidence 1/500 pts/year • Messerli FH, Nussberger. Lancet 2000;356:608–9

  35. The Risk of Angioedema (AE) Among angioedema thatare life-threatening(larynx, respiratory tract): 20 – 22% Among life-threateningangioedema thatare fatal: 1 – 16– 24% • Messerli FH, Nussberger. Lancet 2000;356:608–9

  36. ACE-Inhibitors and Angioedema (AE) Worldwide ACE-I use > 30,000,000 Episodes of Angioedema/year 60,000 Episodes of life-threatening Angioedema/year 12,000 Episodes of fatal Angioedema/year >1,000 Number of patients • Messerli FH, Nussberger. Lancet 2000;356:608–9

  37. Asphyxia Due to ACE Inhibitor Mediated Angioedema Dean DE, et al. J Forensic Science 2001;46:1239–43

  38. Angioedema with ACE-Inhibitors n = 85 Rx for hypertension n = 82 Rx for heart failure n = 3 Median duration of ACE-I Rx: 12 months Range: 1 day – 13 years Median time between 1st attack and ACE-I Rx withdrawal: 12 months Range: 1 day – 12 years Lorenza et al. CMJ, 2006;175:1065

  39. Losartan (%) Atenolol (%) p-value Angioedema 6 (0∙1%) 11 (0∙2%) 0∙237 Bradycardia 66 (1%) 391 (9%) <0∙0001 Cancer 356 (8%) 315 (7%) 0∙118 Cold extremities 178 (4%) 269 (6%) <0∙0001 Cough 133 (3%) 113 (2%) 0∙220 Dizziness 771 (17%) 727 (16%) 0∙247 Hypotension 121 (3%) 75 (2%) 0∙001 Sexual dysfunction 164 (4%) 214 (5%) 0∙009 Sleep disturbance 30 (0∙7%) 38 (0∙8%) 0∙333 LIFE: Prespecified Adverse Events of Special Interest B Dahlof et al. Lancet 2002;359:995-1003

  40. VALUE:Incidence of angioedema and facial edema

  41. Kaplan-Meier Curves for the Primary Outcome in the Three Study Groups The ONTARGET Investigators. N Engl J Med 2008;10.1056/NEJMoa0801317

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