hypertension conbinsation therapy 2014

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Antihypertensive drugs combinations Dr. Muhamed Al Rohani, MD, FINS Consultant Nephrologist Head of Nephrology Dep. Dibba hospital MOH UAE

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this lecture looks for the benefits and the evidence of the use of antihypertensive drugs up to date also the disadvantages is mentioned here

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Page 1: Hypertension conbinsation therapy 2014

Antihypertensive drugs combinations

Dr. Muhamed Al Rohani, MD, FINSConsultant Nephrologist

Head of Nephrology Dep. Dibba hospital

MOH UAE

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Hypertension (HTN) is a major public health concern, affecting 26% of adults worldwide1

Number of people with HTN

worldwide in 20001972 million

Increase in the number of adults with HTN globally by 20251

60%

Percent of all global healthcare spending

attributable to high blood pressure2

10%

Annual worldwide cost of hypertension2$370 billion

1. Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK, He J. Global burden of hypertension: analysis of worldwide data. Lancet. 2005 Jan 15-21;365(9455):217-23. Gaziano TA, Asaf B, S Anand, et.al. The global cost of nonoptimal blood pressure. J Hypertens 2009; 27(7): 1472-1477.

1.6 Billion HTN patients estimated

by 2025

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Historical Lessons on the Risks of Hypertension and the Benefits of Treatment

CHD

Inci

denc

e Ra

te/

1000

Per

son

Year

s

0

10

20

30

40

50

Placebo ActiveTreatment

Cum

ulati

ve F

atal

&

Non

fata

l End

poin

ts

The Framingham Study The Vet. Adm. Study II

Ann Intern Med. 1961; 55:33–50. JAMA. 1970; 213:1143–1152.

Hypertension IncreasesMorbidity and Mortality

Treatment DecreasesMorbidity and Mortality

0

20

40

60

80

100

120

140

Men Women

NormotensionHypertension

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Risk Factors for Cardiovascular Disease

• Smoking• Hyperlipidaemia • High salt intake• Lack of exercise• Obesity• Diabetes• Alcohol >4pints of beer/day• Genetic

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CVmortality

risk

SBP/DBP (mm Hg)

0

1

2

3

4

5

6

7

8

115/75 135/85 155/95 175/105

CV Mortality Risk Doubles WithEach 20/10 mm Hg BP Increment*

*Individuals aged 40-69 years, starting at BP 115/75 mm Hg.CV, cardiovascular; DBP, diastolic blood pressure; SBP, systolic blood pressure.Lewington S et al. Lancet. 2002;360:1903-1913.Chobanian AV et al. JAMA. 2003;289:2560-2572.

BP > 140/90 mmHg associated with: 69% of pts in the 1st heart attack 74% of pts with heart failure 77% of pts in the 1st stroke

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0

1

2

3

4

5

6

7

8

9

120/80 140/90 160/100 180/110

HTN leads to an increased risk of death from stroke and heart disease

Systolic BP / Diastolic BP (mmHg)

8x

4x

2x

CV mortality risk doubles for every 20 mmHg increase in systolic blood pressure.1,2

Car

dio

vasc

ula

r M

ort

alit

y R

isk

Chobanian et al. Hypertension 2003;42:1206-1252; 2Lancet 2002;360:1903-1913

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BP Differences of 10 mmHg Are Associated With Up to a 40% Effect on

CV Risk

• Meta-analysis of 61 prospective, observational studies• 1 million adults• 12.7 million person-years

Lewington S et al. Lancet. 2002;360:1903–1913.

10 mmHg decrease in mean SBP 40% reduction in

risk of stroke mortality

30% reduction in risk of IHD mortality

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CV=cardiovascular.Neal B et al. Lancet. 2000;356:1955–1964.

Current Antihypertensive Therapy Reduces CV EventsAv

erag

e Re

ducti

on in

Eve

nts,

%

Major CV Events

20%–30%

Stroke

30%–40%

CV Death

30%–40%

–60

–40

–20

0

–100

–80

Can we do better?

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Target BP (mm Hg)Number of antihypertensive agents

1Trial 2 3 4

AASK MAP <92

UKPDS DBP <85

ABCD DBP <75

MDRD MAP <92

HOT DBP <80

IDNT SBP <135/DBP <85

ALLHAT SBP <140/DBP <90

Multiple Antihypertensive Agents Are Needed to Achieve Target BP

DBP, diastolic blood pressure; MAP, mean arterial pressure; SBP, systolic blood pressure. Bakris GL et al. Am J Kidney Dis. 2000;36:646-661.Lewis EJ et al. N Engl J Med. 2001;345:851-860.Cushman WC et al. J Clin Hypertens. 2002;4:393-405.

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ALLHAT study:

The LIFE Trial

42,418 patients with hypertension SBP >140mmHg and/or DBP >90 mmHg OR Took medication for hypertension and had at least one additional risk factor for CHD Age >55 years Diuretics vs. ACEi Stage 1 and 2 only 26% the BP controlled by single drug 30% required 3 drugs

42,418 patients with hypertension SBP >140mmHg and/or DBP >90 mmHg OR Took medication for hypertension and had at least one additional risk factor for CHD Age >55 years Diuretics vs. ACEi Stage 1 and 2 only 26% the BP controlled by single drug 30% required 3 drugs

9,200 patients with hypertension SBP 160 – 200 mmHg and/or DBP 95- 115 mmHg with LVH ARBs vs. BB Stage 2 90% had 2 drugs 50% BP achieved

9,200 patients with hypertension SBP 160 – 200 mmHg and/or DBP 95- 115 mmHg with LVH ARBs vs. BB Stage 2 90% had 2 drugs 50% BP achieved

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Poor Compliance and Persistence with Antihypertensive Treatment

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The percentage of patients in this category is estimated at approximately 10–15% of the hypertensive population.

Definition of resistant hypertension: uncontrolled BP despite adherence to a regimen with at least three antihypertensive agents including a diuretic.

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Objective To determine the average reduction in BP, prevalence of adverse effects, and reduction in risk of stroke and IHD events produced by the five main categories of antihypertensive drugs, singly and in combination.Design Meta-analysis of 354 randomized double blind placebo controlled trials. 40 000 treated patients and 16 000 patients given placebo

Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomized trials (2003 BMJ)

Results All five categories of drug produced similar reductions in BP. The standard dose average reduction was 9.1 mm Hg systolic and 5.5 mm Hg diastolic .The half standard dose was 7.1 mm Hg systolic and 4.4 mm Hg diastolic (20% lower) The BP lowering effects of different categories of drugs were additive. Symptoms attributable to thiazides, BB, and CCB were strongly dose related; but by ACEi (mainly cough) were not dose related. ARBs caused no excess of symptoms. The prevalence of symptoms with two drugs in combination was less than additive. Adverse metabolic effects (such as changes in cholesterol or potassium) were negligible at half standard dose.

Conclusions Combination low dose drug treatment increases efficacy and reduces adverse effects. From the average blood pressure in people who have strokes (150/90 mm Hg) three drugs at half standard dose are estimated to lower blood pressure by 20 mm Hg systolic and 11 mm Hg diastolic and thereby reduce the risk of stroke by 63% and IHD events by 46% at age 60-69.

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Rational of combination therapy 1. The heterogeneity of the hypertensive population. 2. Initial falls in BP from monotherapy are also opposed by reflex responses in

counter-regulatory mechanisms that are activated following BP reduction.1

3. Combining selected classes of antihypertensive therapy with different modes of action.

4. RAAS blockers tolerability is the best in comparison.5. ARBs or ACEi + duiretics reduce the incidence of hypokalemia6. ARBs or ACEi + CCB reduce the incidence and severity of edema

1. Sever P, Messerli FH. Eur Heart J 2011;32:2499-506.2. Law M et al. BMJ 2003;326:1427-31. 3. Alan Grdman. Current opinion nephrol hyoetens 2012,21:486-491

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Drug combination (AHS)Preferred :

ARBs/diureticsARBs/CCBACEi/diureticsACEi/CCB

Acceptable:BB/diuretics Thiazide/K+ sparing CCB/diuretics CCB/BBBB/diuretics

Less effective:ACEi/BBARB/BBCCB(nondihydropyridine)/BBCentral acting agent/BB

1. Reduces risk of hypokalemia2. Ameliorates diuretic-induced activation of

RAAS 3. Ameliorates CCB edema 4. Reduction of mortality 5. Option for CKD 1. BB ameliorate thiazide-induced activation

of RAAS2. Side effect sexual dysfunction and glucose

intolerance 3. BB less effect as anti-HTN 4. Carvedilol 1. BB with CCB increase the risk of

bradycardia and heart block 2. the combination of ACE inhibitor/CCB

was associated with a 20% reduction in major CV endpoints compared with ACE inhibitor/HCTZ. (ACCOMPLISH)

3. Abrupt discontinuation cause hypertensive crisis

New combinationsValsartan/amlodipine/HCTOlmesartan/amlodipine/HCTAliskiren/amlodipine/HCT

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Date of download: 9/2/2014

Copyright © The American College of Cardiology. All rights reserved.

From: An Effective Approach to High Blood Pressure Control: A Science Advisory From the American Heart Association, the American College of Cardiology, and the Centers for Disease Control and Prevention

J Am Coll Cardiol. 2014;63(12):1230-1238. doi:10.1016/j.jacc.2013.11.007

Appendix

Figure Legend:

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Persistence with antihypertensive therapy regimens; single-pill combination therapy vs free-drug combinations.

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Initial Fixed-Dose Combination TherapyADVANTAGES

• 2 drugs needed for control of Stage 2 BP• Low (therapeutic) dose of 2 drugs

– more effective than higher dose of single drug– usually well tolerated– adverse effects can be reduced

• Simplified treatment regimen: adherence improved by 26% compare to free combination

• and potential for improved outcomes • Economic benefits

– Fewer copayments– health care costs reduced– fewer office visits

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Reduced discontinuation of antihypertensive treatment by two-drug combination as first step. Evidence from daily life practice

OBJECTIVES: To measure persistence with antihypertensive drug therapy in patients initiating treatment with mono or combination therapy.

METHODS: Data were limited to patients aged 40-80 years who received their first antihypertensive drug prescription (n = 433,680 and 41,199, respectively)

CONCLUSION: Initiating treatment with a combination of two drugs is associated with a reduced risk of treatment discontinuation.

Corrao G1, et al, J Hypertens. 2010 Jul;28(7):1584-90.MILANO ITALY

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Strategies for Combination Therapy in HypertensionConclusionCombination therapy is necessary in

approximately 75% of patients with hypertension. Rational combination therapy begins with the selection of two-drug combinations that exhibit additive BP reduction, excellent tolerability and a demonstrated ability to reduce CV endpoints in long-term clinical trials. The latter include ACE inhibitors, ARBs, CCBs and low-dose diuretics. More than 25% of patients need at least three drugs. Strategies for clinical use of combination therapy continue to evolve.

Current guidelines recommend routine initiation of a combination in patients with Stage 2 hypertension. More recent studies suggests a potential for hastening goal attainment and improving long-term outcomes through the use of initial combination therapy in a broader spectrum of patients with hypertension.

• In a meta-analysis of nine studies comparing administration of SPCs or their separate components, the adherence rate was improved by 26% in patients receiving SPCs

• initial combination treatment consistently reduces the time taken to reach target BP compared with initial monotherapy. After 8 weeks, 48% of patients achieved their target compared with 75% begun on a combination.

• Initial combination therapy was associated with a 33% reduction in major CV events compared with patients initiated on monotherapy and later switched to a combination treatment by their treating physician.

• Initial combination treatment should be used sparingly in frail or very elderly patients (the presence of orthostatic hypotension)

Alan H. Gradman, Curr Opin Nephrol Hypertens. 2012;21(5):486-491

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Initial Fixed-Dose Combination TherapyDISADVANTAGES

• BP may be controlled with 1 drug in some patients– However, majority of patients require 2 drugs

• Combination ‘too potent’ causing hypotension– Benefit risk profile for each combination should be assessed in appropriate

patient population– Individualize therapy

• Additive risk for dose independent adverse effects– However, mono components likely to be taken as part of a multi drug regimen – Balance against risk of dose dependent side effects with high dose monotherapy

and risk of inadequate BP control (stroke, heart failure and MI)• If adverse effects

– must discontinue both drugs: – more office visits– more lab tests

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Cost-effectiveness analysis of cardiovascular disease prevention with a multidrug regimen

Sanz G and Fuster V (2008) Fixed-dose combination therapy and secondary cardiovascular prevention: rationale, selection of drugs and target population

Nat Clin Pract Cardiovasc Med doi:10.1038/ncpcardio1419

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Thank you for

Patience and Sacrifice

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1.5 Initiating and monitoring antihypertensive drug treatment, including blood pressure targetsInitiating treatment1.5.1 Offer antihypertensive drug treatment to people aged under 80 years with stage 1 hypertension who have one or more of the following:target organ damage established cardiovascular disease renal disease diabetes a 10-year cardiovascular risk equivalent to 20% or greater. [new 2011]1.5.2 Offer antihypertensive drug treatment to people of any age with stage 2 hypertension. [new 2011]1.5.3 For people aged under 40 years with stage 1 hypertension and no evidence of target organ damage, cardiovascular disease, renal disease or diabetes, consider seeking specialist evaluation of secondary causes of hypertension and a more detailed assessment of potential target organ damage. This is because 10-year cardiovascular risk assessments can underestimate the lifetime risk of cardiovascular events in these people. [new 2011]

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.6 Choosing antihypertensive drug treatment1.6.1 Where possible, recommend treatment with drugs taken only once a day. [2004]1.6.2 Prescribe non-proprietary drugs where these are appropriate and minimise cost. [2004]1.6.3 Offer people with isolated systolic hypertension (systolic blood pressure 160 mmHg or more) the same treatment as people with both raised systolic and diastolic blood pressure. [2004]1.6.4 Offer people aged 80 years and over the same antihypertensive drug treatment as people aged 55–80 years, taking into account any comorbidities. [new 2011]1.6.5 Offer antihypertensive drug treatment to women of child-bearing potential in line with the recommendations on Management of pregnancy with chronic hypertension and Breastfeeding in 'Hypertension in pregnancy' (NICE clinical guideline 107). [2010]Step 1 treatment 1.6.6 Offer people aged under 55 years step 1 antihypertensive treatment with an angiotensin-converting enzyme (ACE) inhibitor or a low-cost angiotensin-II receptor blocker (ARB). If an ACE inhibitor is prescribed and is not tolerated (for example, because of cough), offer a low-cost ARB. [new 2011]1.6.7 Do not combine an ACE inhibitor with an ARB to treat hypertension. [new 2011]1.6.8 Offer step 1 antihypertensive treatment with a calcium-channel blocker (CCB) to people aged over 55 years and to black people of African or Caribbean family origin of any age. If a CCB is not suitable, for example because of oedema or intolerance, or if there is evidence of heart failure or a high risk of heart failure, offer a thiazide-like diuretic. [new 2011]1.6.9 If diuretic treatment is to be initiated or changed, offer a thiazide like diuretic, such as ‑chlortalidone (12.5–25.0 mg once daily) or indapamide (1.5 mg modified-release once daily or 2.5 mg once daily) in preference to a conventional thiazide diuretic such as bendroflumethiazide or hydrochlorothiazide. [new 2011]1.6.10 For people who are already having treatment with bendroflumethiazide or hydrochlorothiazide and whose blood pressure is stable and well controlled, continue treatment with the bendroflumethiazide or hydrochlorothiazide. [new 2011]1.6.11 Beta-blockers are not a preferred initial therapy for hypertension. However, beta-blockers may be considered in younger people, particularly:those with an intolerance or contraindication to ACE inhibitors and angiotensin II receptor antagonists orwomen of child-bearing potential orpeople with evidence of increased sympathetic drive. [2006]1.6.12 If therapy is initiated with a beta-blocker and a second drug is required, add a calcium-channel blocker rather than a thiazide-like diuretic to reduce the person's risk of developing diabetes. [2006]Step 2 treatment1.6.13 If blood pressure is not controlled by step 1 treatment, offer step 2 treatment with a CCB in combination with either an ACE inhibitor or an ARB[6]. [new 2011]1.6.14 If a CCB is not suitable for step 2 treatment, for example because of oedema or intolerance, or if there is evidence of heart failure or a high risk of heart failure, offer a thiazide-like diuretic. [new 2011]1.6.15 For black people of African or Caribbean family origin, consider an ARB[6] in preference to an ACE inhibitor, in combination with a CCB. [new 2011]Step 3 treatment1.6.16 Before considering step 3 treatment, review medication to ensure step 2 treatment is at optimal or best tolerated doses. [new 2011]1.6.17 If treatment with three drugs is required, the combination of ACE inhibitor or angiotensin II receptor blocker, calcium-channel blocker and thiazide-like diuretic should be used. [2006]Step 4 treatment1.6.18 Regard clinic blood pressure that remains higher than 140/90 mmHg after treatment with the optimal or best tolerated doses of an ACE inhibitor or an ARB plus a CCB plus a diuretic as resistant hypertension, and consider adding a fourth antihypertensive drug and/or seeking expert advice. [new 2011]1.6.19 For treatment of resistant hypertension at step 4:Consider further diuretic therapy with low-dose spironolactone (25 mg once daily)[7] if the blood potassium level is 4.5 mmol/l or lower. Use particular caution in people with a reduced estimated glomerular filtration rate because they have an increased risk of hyperkalaemia.Consider higher-dose thiazide-like diuretic treatment if the blood potassium level is higher than 4.5 mmol/l. [new 2011]1.6.20 When using further diuretic therapy for resistant hypertension at step 4, monitor blood sodium and potassium and renal function within 1 month and repeat as required thereafter. [new 2011]1.6.21 If further diuretic therapy for resistant hypertension at step 4 is not tolerated, or is contraindicated or ineffective, consider an alpha- or beta-blocker. [new 2011]1.6.22 If blood pressure remains uncontrolled with the optimal or maximum tolerated doses of four drugs, seek expert advice if it has not yet been obtained. [new 2011]

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Display Settings:•Abstract

J Hypertens. 2010 Jul;28(7):1584-90. doi: 10.1097/HJH.0b013e328339f9fa.Reduced discontinuation of antihypertensive treatment by two-drug combination as first step. Evidence from daily life practice.Corrao G1, Parodi A, Zambon A, Heiman F, Filippi A, Cricelli C, Merlino L, Mancia G.Author information •1Department of Statistics, Unit of Biostatistics and Epidemiology, University of Milano-Bicocca, Milan, Italy. [email protected]

Abstract

OBJECTIVES: To measure persistence with antihypertensive drug therapy in patients initiating treatment with mono or combination therapy.METHODS: Data analysis was based on two cohorts of patients, that is, a cohort derived from the registration of drug prescriptions in all residents of the Lombardy region receiving Public Health Service and a cohort of patients followed by general practitioners throughout the Italian territory. Data were limited to patients aged 40-80 years who received their first antihypertensive drug prescription (n = 433,680 and 41,199, respectively) in whom persistency of treatment was examined over 9 months. A proportional hazards model was fitted to estimate the association between the pattern of initial antihypertensive drug therapy and risk of treatment discontinuation. Data were adjusted for available potential confounders.RESULTS: Taking patients starting with diuretic monotherapy as reference, the adjusted risk of treatment discontinuation was progressively lower in patients starting with monotherapy other than a diuretic, a two-drug combination, including a diuretic and a two-drug combination without a diuretic. No significant difference in the risk of discontinuation was seen between extemporaneous and fixed dose combinations, including a diuretic, that is, the only combination reimbursable by Public Health Service and, thus, available in the database. Data were similar for the two cohorts.CONCLUSION: Initiating treatment with a combination of two drugs is associated with a reduced risk of treatment discontinuation.

Abstract (text)Abstractabstractabstractabstract202020abstract

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There is great concern over the impact of patients not achieving BP goals. Poor BP control is associated with a marked increase in the risk of CV fatal and non-fatal events.1 A meta-analysis of 1 million patients in 61 prospective studies demonstrated that the relationship between BP and cardiovascular disease events is continuous, consistent and age-dependent – each 20 mmHg increase in SBP or 10 mmHg increase in DBP is associated with at least a twofold increase in the risk of death from stroke, ischaemic heart disease or other vascular cause.2

The US study using NHANES III data (Third National Health and Nutrition Examination Survey) highlighted in this slide shows that uncontrolled and untreated hypertension is associated with an increased risk of total and CV mortality in the general hypertensive population.3 Relative to treated controlled hypertensive patients, treated uncontrolled patients had a 57% and 74% increased risk of all-cause and CVD mortality, with untreated hypertensives having a 34% and 37% increased risk, respectively. This association was persistent and remained significant after excluding subjects with hypertension co-morbidities at baseline.3

1. Grassi G et al. Eur Heart J 2011;32:218-25.2. Lewington S et al. Lancet 2002;360:1903-13.3. Gu Q et al. Am J Hypertens 2010;23:38-45.

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69% 1st heart attack 74% Heart failure 77% 1st stroke

Too low BP may leads to cardiac events The J-CurvThe J-curve effect describes an inverse relation

between low blood pressure (BP) and cardiovascular complications. This effect is more pronounced in patients with preexisting coronary artery disease (CAD), hypertension or left ventricular hypertrophy (LVH). e phenomenon The recent large clinical outcomes trials have observed a J-curve effect between a diastolic BP of 70-80 mmHg as well as a systolic BP <130 mmHg. The J-curve phenomenon does not appear in stroke or renal disease. This is because the coronary arteries are perfused during diastole, but the cerebral and renal perfusion mainly occurs in systole. Therefore, caution should be taken to maintain the diastolic blood pressure (DBP) at minimum of 70 mmHg and possibly to maintain the DBP between 80-85 mmHg in patients with severe LVH, CAD or vascular diseases. BP control in high-risk elderly patients should be carefully done as undergoing aggressive therapy to lower the systolic blood pressure below 140 mmHg can cause cardiovascular complications due to the severely reduced DBP and increased pulse pressure.

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