No significant difference was observed between amlodipine (the red line) and chlorthalidone (the blue line) for the primary outcome. The relative risk for amlodipine compared to chlorthalidone was 0.98, with a 95% confidence interval of 0.90-1.07. Also, no significant difference was observed between lisinopril (the green line) and chlorthalidone for the primary outcome. The relative risk was 0.99, with a 95% confidence interval of 0.91-1.08.
The three core messages for the ALLHAT antihypertensive trial are: Diuretics should be the drug of choice for first step therapy of hypertension For the patient who cannot take a diuretic (which should be an unusual circumstance), CCB’s and ACEI’s may be considered. Most hypertensive patients require more than one drug. Diuretics should generally be part of the antihypertensive regimen. Lifestyle advice should also be provided.
Combination therapy reduced blood pressure by 12/5 mm Hg and reduced stroke risk by 43% - the benefit was similar in hypertensive patients as well as normotensives. By contrast, single-drug therapy reduced blood pressure by 5/3 mm Hg with no statistically significant reduction in stroke risk, although the confidence interval is wide a risk reduction of up to 23% for stroke cannot be ruled out. It is important to remember that patients were randomized between active agent and placebo - active agent could have been single or combination therapy as determined by the patients physician. Therefore, the study was powered to detect reductions in stroke risk in the active treatment group. There was not a sufficient patient base receiving single agent to detect a statistically significant risk reduction in stroke.
C:\Cema\HipertensióN Arterial Curso 2008 2
Hipertensión Arterial 2008
Enfermedad cardiovascular <ul><li>HTA es el principal factor que contribuye al riesgo de enfermedad cardiovascular. </li></ul><ul><li>El segundo contribuyente al mayor riesgo es que la población llega a mayor edad y tiene mayor obesidad </li></ul>
White-Coat Effect with Age Mansoor et al. J Hum Hypertens 1996;10:87
Enfermedad Cardiovascular <ul><li>Tercer factor que contribuye es el inadecuado control de la Hipertensión: </li></ul><ul><li>EEUU : 29 % </li></ul><ul><li>Canadá : 17 % </li></ul><ul><li>Europa : < 10 % (Inglaterra, Alemania Italia ,España y suecia ) </li></ul>
Definición operacional Hipertensión Arterial <ul><li>Hipertension es ... “el nivel de Presion sanguinea en donde los beneficios de la accion (i.e. intervencion terapeutica) exceden a los de la inaction.” </li></ul><ul><ul><li>Evans and Rose Brit Med Bull 1971;27:37-42 </li></ul></ul>
Treatment Strategies and Risk Stratification JNC 6
Classification and Management of BP for adults *Treatment determined by highest BP category. † Initial combined therapy should be used cautiously in those at risk for orthostatic hypotension. ‡ Treat patients with chronic kidney disease or diabetes to BP goal of <130/80 mmHg. JNC 7 slideset Two-drug combination for most † (usually thiazide-type diuretic and ACEI or ARB or BB or CCB). Yes or > 100 > 160 Stage 2 Hypertension Drug(s) for the compelling indications. ‡ Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) as needed. Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination. Yes or 90–99 140–159 Stage 1 Hypertension Drug(s) for compelling indications. ‡ No antihypertensive drug indicated. Yes or 80–89 120–139 Prehypertension Encourage and <80 <120 Normal With compelling indications Without compelling indication Initial drug therapy Lifestyle modification DBP* mmHg SBP* mmHg BP classification
Sudden Deaths by Time of Day Peckova et al. Circulation 1998;98:31
Low Dose Diuretics vs. Others From Psaty BM et al. JAMA 2003;289:2534
The Reasons Why Low-Dose Diuretics Should be Initial Therapy 1. They reduce cardiovascular morbidity and mortality. 2. They lower blood pressure, particularly in patients consuming excessive sodium. 3. They enhance the antihypertensive efficacy of all other antihypertensive drugs. 4. They rarely cause side effects. 5. They reduce calcium loss and osteoporosis. 6. They are relatively inexpensive.
Results of Different Levels of Blood Pressure Control in Hypertensive Patients with Type 2 Diabetes : B-Blocker compared with ACE Inhibitor-Based Treatment Program <ul><li>8.4-year follow-up of 1148 subjects (achieved blood pressure of 144/82 mm Hg compared with 154/87 mm Hg) </li></ul><ul><li>Reduced risk of: </li></ul><ul><ul><li>Stroke (44%) </li></ul></ul><ul><ul><li>Fatal strokes (58%) </li></ul></ul><ul><ul><li>Death related to diabetes (32%) </li></ul></ul><ul><ul><li>Heart failure (56%) </li></ul></ul><ul><ul><li>Fatal and nonfatal coronary heart disease events (21%) (trend but not significant) </li></ul></ul><ul><li>No difference in outcome between a captopril-based and </li></ul><ul><li>an atenolol based treatment program </li></ul>UKPDS . BMJ 1998;317:703-713
CV Events in Swedish Trial in Old Persons (Stop-2) Conventional Rx (diuretics and B-blockers) compared to ACE-Is and CCBs No difference in BP outcomes No overall difference in EVENTS Lancet 1999;354:751
Results of An ARB-Based (Losartan Compared to a B-Blocker Based (Atenolol) Treatment Program in Hypertensive Patients with LVH (LIFE Study) <ul><li> Losartan Atenolol Goal BPs </li></ul><ul><li>Achieved BP (mm Hg) 144/82 145/82 45-50% SBP <140 </li></ul><ul><li> 89% DBP <90 </li></ul><ul><li>% Difference Losartan vs Atenolol </li></ul><ul><li>Primary endpoint P Value </li></ul><ul><li>(CV death, MI, Stroke) -13* .02 </li></ul><ul><li>Stroke -25* .001 </li></ul><ul><li>MI +07 NS </li></ul><ul><li>CV mortality -11 NS </li></ul><ul><li>Total mortality -10 NS </li></ul><ul><li>New onset diabetes -25* .001 </li></ul><ul><li>Lancet 2002;359:1004 *Statistically significant </li></ul>
Percentage of Type 2 Diabetic Patients with End-Stage Renal Disease in the RENAAL Study <ul><li>Losartan – therapy with ARB plus other medications; placebo – therapy with medications other than an ARB or ACE inhibitor. (Risk reduction, 28%; P = 0.002) </li></ul><ul><li>Brenner BM, et al. N Engl J Med 2001;345:865 </li></ul>Months of Study End-Stage Renal Disease (%) 0 12 24 36 48 30 20 10 0 Placebo Losartan
Heart Outcomes Preventions Evaluation (HOPE) Study Events ACE-1 (Ramipril)* Regimen that did not include an ACE-1 No. Randomized 4645 4652 % Reduction in Risk - Ramipril:Other therapy MI, Stroke, CVD 22 CV death 25 MI 20 Stroke 31 Non-CV death +3 (NS) All cause mortality 16 *10 mg/day - 62.5% remained on Rx at 4.5 years New Engl J Med 11/10/99
Relative Risk of Cardiovascular Mortality and Morbidity for ACEIs vs Calcium Antagonists ( STOP-2 Study ) <ul><li>* Significant difference. </li></ul><ul><li>Hansson L et al. Lancet. 1999;354:1751-1756 </li></ul>
En pacientes de alto riesgo (HOPE, IRMA, IDNT, RENAAL, and LIFE), el uso de un IECA (o un ARA) usualmente con un diuretico) reducen eventos CV mas que un regimen que no incluye estas medicaciones.
2003 The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT),
Cumulative Event Rates for the Primary Outcome (Fatal CHD or Nonfatal MI) by ALLHAT Treatment Group Chlorthalidone Amlodipine Lisinopril Years to CHD Event 0 1 2 3 4 5 6 7 Cumulative CHD Event Rate 0 .04 .08 .12 .16 .2 0.81 0.99 (0.91-1.08) L / C 0.65 0.98 (0.90-1.07) A / C p value RR (95% CI)
Implications of ALLHAT <ul><li>Diuretics should be the drug of choice for first </li></ul><ul><li>step therapy of hypertension in most patients* </li></ul><ul><li>Most hypertensive patients require more than one drug. Diuretics should generally be part of the antihypertensive regimen. </li></ul><ul><li>*[BP levels were lower in diuretic treated patients ] </li></ul>
Possible Advantages of Low-Dose Combination Therapy Compared to High-Dose Monotherapy <ul><li>Blood pressure response is greater </li></ul><ul><li>Percentage of responders is higher </li></ul><ul><li>Side effects may be less </li></ul><ul><li>Titration to effective dose is simplified- Goal BP achieved sooner </li></ul><ul><li>Adherence is improved </li></ul>
<ul><li>Stroke </li></ul><ul><li>Combination 43% </li></ul><ul><li>Single Drug 5% (-19 to 23) </li></ul><ul><li>Total Stroke 28% </li></ul>Combination versus Monotherapy Favors active Favors placebo Risk Reduction ( 95%CI ) 0.4 1.0 2.0 Hazard Ratio PROGESS Study
Combination Therapy <ul><li>In the LIFE trial treatment to goal was aggressively pursued </li></ul><ul><li>90% of patients required multiple medications </li></ul>
Benefits of Lowering BP by Average Percent Reduction Stroke incidence 35–40% Myocardial infarction 20–25% Heart failure 50% -12 -4-5 About mmHg