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Does the Pattern of Blood Pressure Effects During the Day Matter?

Does the Pattern of Blood Pressure Effects During the Day Matter?. Thomas Pickering MD, DPhil Behavioral Cardiovascular Health and Hypertension Program Division of General Medicine Columbia Presbyterian Medical Center New York. Issues. Diurnal rhythm of blood pressure

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Does the Pattern of Blood Pressure Effects During the Day Matter?

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  1. Does the Pattern of Blood Pressure Effects During the Day Matter? Thomas Pickering MD, DPhil Behavioral Cardiovascular Health and Hypertension Program Division of General Medicine Columbia Presbyterian Medical Center New York

  2. Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs

  3. Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs

  4. What is the True Blood Pressure? Daytime BP? Dipping Pattern? Nighttime BP? Morning Surge? 24 Hr Average BP? Clinic BP? Variability of BP? Home BP?

  5. Ambulatory BP Differences for Normotensives, and Mild and Established HTN Patients 120- 110- 100- 90- 80- 70- 60- 0- Diastolic Blood Pressure (mm Hg) Established hypertensives Mild hypertensives Normotensives Clinic Work Home Sleep

  6. Clinical situations in which the normal diurnal rhythm of BP may be lost Autonomic Dysfunction Syndromes Diabetes Mellitus Renal Failure Secondary forms of hypertension e.g. Cushing’s disease Drugs, e.g. cyclosporine African-American ethnicity

  7. Nocturnal BP Changes and CV Mortality: Ohasama study (Ohkubo et al; AJH 1997; 10: 1201) Risk of CV Mortality Non-dippers Dippers Risers Extreme dippers

  8. Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs

  9. Morning Peak of VT Detected by Implanted Cardioverter/Defibrillator (Tofler Circ 1995;92: 1203) Episodes of VT

  10. Circadian Rhythm of Ischemic & Hemorrhagic StrokesGallerani et al, Acta Neurol Scand 1993; 87: 482) Ischemic % of strokes Hemorrhagic 1-6 6 -12 12-18 18-24 Hour of day

  11. Analysis of The Influence of the Morning Surge of BP on Stroke Incidence (Kario, Pickering et al, Circ 2003; 107:1401)) Cox regression analysis for clinical stroke events Covariates RR P value Age (10 yrs) 1.80 (1.21-2.69) 0.004 Male gender 1.42 (0.76-2.67) 0.266 BMI 0.98 (0.90-1.07) 0.663 24 hr SBP 1.37 (1.16-1.63 0.003 SCI 4.40 (1.95-10.1) 0.001 Morning BP surge* 1.29 (1.10-1.51) 0.001 Nocturnal BP fall* 0.88 (0.73-1.06) 0.167 Lowest sleep BP 1.05 (0.65-1.71) 0.837 * per 10 mmHg

  12. Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs

  13. Efficacy: telmisartan vs amlodipineusing 24-h ABPM Placebo (n=58) Week 12, SBP Telmisartan (40-120 mg) (n=62) Amlodipine (5-10 mg) (n=65) BP (mm Hg) 160 140 120 100 0 0800 1200 1600 2000 2400 0400 0800 Time Lacourcière Y et al, in press

  14. Effects of Two ARBs Approved for Once Daily Dosing on 24 Hour Blood Pressure(Mancia et al AJC 1999: 84; 28S) Missed Dose

  15. Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs

  16. Do different drug classes have different effects on Daytime vs. Nighttime BP?

  17. Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BPWeiner, Rieckmann, & Pickering, 2005 Medline search of trials in which effects of antihypertensive drugs on daytime, nighttime, and 24 hr BP were described 55 trials satisfied criteria, & were grouped into 3 classes: ACEI, ARBs, Beta blockers (n=10), CCBs & Diuretics (n=35), and combinations (n=10). Across all studies, the absolute change of daytime BP (14/8 mmHg) was significantly greater than the change of nighttime BP (12.5/4.5 mmHg, p<0.01). The magnitude of the difference between the daytime & nighttime changes did not differ between the groups (p>0.7).

  18. Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BPWeiner, Rieckmann, & Pickering, 2005 Change of SBP with Treatment mmHg

  19. Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005 ACEI, ARBs CCBs, Diuretics Day: B=.07 (p=0.53) Night: B=.04 (p=0.63) Day: B=.55 (p<0.001) Night: B=.55 (p<0.001) BP Change mmHg DAY NIGHT Baseline Systolic BP mmHg

  20. Are there class differences in thresholds for lowering BP?(Sekino et al, J Hum Hypertens 1998: 12: 719) Drug Average Effect Threshold BP* on BP Level CBP ABP Daytime Nighttime Nilvadipine -26 -12.5 127 110 Amlodipine -20 -15 127 106 Bisoprolol -19 -12 124 110 Lisinopril -20 -19 97 108 * Estimated from regression line of baseline BP versus change

  21. Are there class differences in thresholds for lowering BP?(Sekino et al, J Hum Hypertens 1998: 12: 719) Drug Average Effect Threshold BP* on BP Level CBP ABP Daytime Nighttime Nilvadipine -26 -12.5 127 110 Amlodipine -20 -15 127 106 Bisoprolol -19 -12 124 110 Lisinopril -20 -19 97 108 Combination1 -20 -14 128 106 * Estimated from regression line of baseline BP versus change 1- ACEI + CCB- Fagard et al Am J Hypertens 1993: 6: 648

  22. Diuretics Convert Non-Dippers to Dippers (Uzu & Kimura Circ 1999; 100:1635) Day Night Systolic pressure mmHg No Rx HCTZ No Rx HCTZ Dippers Non-Dippers

  23. Diuretics Convert Non-Dippers to Dippers (Uzu & Kimura Circ 1999; 100:1635) Day Night Systolic pressure mmHg No Rx HCTZ No Rx HCTZ Dippers Non-Dippers

  24. Regression of Carotid Atherosclerosis by Controlling Morning BP(Marfella et al, Am J Hypertens 2005: 18: 308) Clinic DayNight Morning Carotid IMT 0 SBP mmHg IMT mm NS -0.02 NS NS <0.02 <0.001 -0.04

  25. Regression of Carotid Atherosclerosis by Controlling Morning BP(Marfella et al, Am J Hypertens 2005: 18: 308) Clinic DayNight Morning Carotid IMT 0 SBP mmHg IMT mm ? NS -0.02 NS NS <0.02 <0.001 -0.04

  26. Effects of Alpha-Blockade on the Morning Surge of Blood Pressure (Kario, Pickering, et al Am J Hypertens 2004;17; 668) No Rx Doxazosin

  27. Effects of graded release Diltiazem vs. Enalapril on Morning BP(White et al, Am Heart J 2004: 148: 628) Ramipril Diltiazem ER

  28. Issues Diurnal rhythm of blood pressure Diurnal rhythm of CV events Duration of action of drugs Effects of drugs on diurnal rhythm of blood pressure Effects of timing of administration of drugs

  29. Effects of Time of Administration of Valsartan on Diurnal Changes of BP (Hermida et al Hypertens 2003: 42:283) Change of SBP mmHg P=0.041 P=0.402 P=0.174

  30. Effects of Time of Administration of Valsartan on Diurnal Changes of BP (Hermida et al Hypertens 2003: 42:283) Change of SBP mmHg “Diovan may be used over a dose range of 80 mg to 320 mg daily, administered once-a-day.” P=0.041 P=0.402 P=0.174

  31. Conclusions: Does the Pattern of Blood Pressure Effects During the Day Matter? There is a pronounced diurnal rhythm of BP and cardiovascular events, with a peak of both in the morning hours, and a decrease during the night. In some categories of patients the normal dipping pattern of BP is lost or reversed; this may be associated with increased risk. Drugs approved for once daily dose may have different durations of action, particularly after missed doses. Most classes of antihypertensive drugs lower daytime BP more than nighttime BP. The effects of CCBs may be more closely related to baseline BP than ARBs/ACEI.

  32. Conclusions: Does the Pattern of Blood Pressure Effects During the Day Matter? 6. Different antihypertensive drugs may have different effects on the morning surge of BP. 7. With some antihypertensive drugs the time of dosing may have significant effects on the diurnal pattern of BP. 8. The implications of these time-dependent differences of antihypertensive drugs for CV morbidity are largely unknown, and need to be more fully investigated. 9. Implications of BP-independent effects of antihypertensive drugs based on small differences of clinic BP may be unwarranted.

  33. Duration of Action by Trough:Peak Ratio Placebo Blood Pressure Change mmHg Trough Peak Drug 0 Hours after dosing 24

  34. Trough:Peak Ratio vs Smoothness Index for defining drug effects on 24 hour BP(Omboni et al BPM, 1998; 3:201) Trough Trough:peak ratio Change of systolic pressure mmHg Peak Smoothness Index: mean change/SD Hours since drug dosing

  35. Prognostic Significance of Non-Dipping (Verdecchia et al, BPM 1996; 1 (Suppl 2) ;S81) 1522 subjects followed for 4.2 years after ABPM Covariate Relative Risk Men Women Age>60 7.39 2.44 Diabetes 2.23 2.30 24 hr SBP>median - 3.90 Non-dipper 1.96 1.70

  36. Effects of ACEI and CCB on Low and High Ambulatory BP in 3 Studies Study Effect of Drug on Systolic ABP mmHg ACEI CCB ABP Lo ABP Hi ABP Lo ABP Hi Ashida -7.6 -8.9 -3.8 -12.7 Herpin -7 -9 -1 -7 Kristensen -14.5 -16.6 -2.7 -10.1 Ashida et al AJC 1990: 66: 498. N=41; ACEI = Enalapril; CCB= Nifedipine SR Herpin et al AJC 1992: 69: 923. N=236; ACEI = Various; CCB = Various. Kristensen et al BPM; 1998; 3: 116. N=96; ACEI = Benazepril; CCB = Felodipine ER

  37. Effects of ACEI and CCB on Clinic SBP in Low and High Ambulatory BP Groups in 3 Studies Study Effect of Drug on Systolic CBP mmHg ACEI CCB ABP Lo ABP Hi ABP Lo ABP Hi Ashida -6.5 -9.5 -11 -16 Herpin -13 -9 -13 -7 Kristensen NA NA NA NA Ashida et al AJC 1990: 66: 498. N=41; ACEI = Enalapril; CCB= Nifedipine SR Herpin et al AJC 1992: 69: 923. N=236; ACEI = Various; CCB = Various. Kristensen et al BPM; 1998; 3: 116. N=96; ACEI = Benazepril; CCB = Felodipine ER

  38. p<0.001 p<0.001 p<0.001 Daytime BP Reduction mmHg N.S. 160 150 140 130 Blood pressure level 8 /7 7 /7 10 /8 11 /8 120 110 100 90 n = 18 n = 6 n = 46 n = 48 80 Extreme dippers Dippers Non-dippers Risers

  39. 160 N.S. 150 140 130 120 110 100 90 80 70 60 Nighttime BP Reduction mmHg p<0.01 p<0.001 N.S. Blood pressure level 18 /12 12 /9 1 /2 4 /2 n = 6 n = 46 n = 48 n = 18 Extreme dippers Dippers Non-dippers Reverse dippers

  40. 50 40 30 20 10 0 -10 -20 -30 -40 -50 90 100 110 120 130 140 150 160 170 180 190 200 Effect of Doxazosin on Daytime and Nighttime BPs Nighttime BP Daytime BP Y = 51 - .42 X r = .45, p<.0001 Y = 46 - .36 X r = .44, p<.0001 n=118 SBP change (mmHg) Baseline SBP (mmHg) Kario, Schwartz, Pickering, Hypertension 2000; 35: 787-94.

  41. Effects of Time of Administration of CCBs on Diurnal Changes of BP (Lemmer BPM 1996: 1;169) Drug Dose Effect on BP Time Day Night 24 hr Pattern Amlodipine (1) AM Unchanged PM Unchanged Isradipine (2) AM Unchanged PM Unchanged Nifedipine GITS (3) AM Unchanged PM Unchanged Nitrendipine (4) AM Unchanged PM Unchanged 1. Mengden J Hypertens 1992:10 (supp 4); S136 2. Fogari Br J Clin Pharm 1993: 35:51 3. Lemmer Naunyn- Schmiederberg Arch Pharm 1994; 349(supp); R141 4. Meilhac Therapie 1992: 47: 205

  42. Effects of Time of Administration of ACEIs on Diurnal Changes of BP (Lemmer BPM 1996: 1;169) Drug Dose Effect on BP Time Day Night 24 hr Pattern Benazepril (1) AM Nearly UnchangedPM Changed Enalapril (2) AM Nearly UnchangedPM Changed Quinapril (3) AM Nearly UnchangedPM Changed 1. Palatini Int J Clin Pharm Ther Toxicol 1993:31:295 2. Witte Clin Pharm Ther 1993: 54:177 3. Paltini Clin Pharm Ther 1992; 52: 378

  43. Effects of Time of Administration of Trandolapril on Diurnal Changes of BP (Poirier J Clin Pharm 1993: 33:832) Change of SBP mmHg

  44. Question: If you were allowed just one reading over 24 hours to predict CV morbidity, which would you choose? Going to bed Arising Awake Sleep Awake Morning BP Evening BP Preawake BP Lowest BP Gosse et al, J Hum Hypertens 2001; 15: 413

  45. Factors Influencing Dipping Status Physical activity during day Sleep duration and quality Ethnicity Sympathetic nervous system Glucocorticoids Sodium/volume factors Renal disease Diabetes

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