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Hypertension

HYPERTENSION:
 
  • Stage 1 /2 / 3 - Goal - Controlled / Uncontrolled - cause, if uncontrolled - treatment plan if uncontrolled




Pseudohypertension
  • In elderly patient 

Malignant Hypertension
  • Pathology:
    • Endothelial proliferation (not smooth as in benign HTN)
    • More inflammatoy cells 
Essential Hypertension:
    • NNT: to prevent 1 CVA
      • = 13 with diastolic BP of 115 mmHg 
      • = 167 with diastolic BP < 110
      • Lancet 1990
      • VA Cooperative Study, JAMA, 1967
    • Pathology
      • Lumen open
      • Less inflammatory cells
      • Hyelonosis
    • Pathophysiology
      • Na if enters the endothelial cells will decrease the production of NO. Thus, decreased vasodilator effect on smooth muscles on vessels. That leads to HTN. 
      • On the other hand, if Na does not enter endothelial cells, then there is an increase in NO production leading to vasodilation. That leads to good BP control. 
      • Na intake of note has J-curve (more relevant in benign essential HTN)
      • High potassium diet is vasodilatory
    • Additional concepts:
      • HTN trial do not look into MI, they look into Stroke, and CHF 
      • Synergy of added BP medication
        • Diuretic with ACEI or ARB or Direct Renin Inhibitor 
        • Diuretic with BB
          • Synergy is due to inbibition of RAAS pathway than the direct affect on the rate control or its ionotropic effect
      • Added value of BP medication
Secondary HTN or Difficult to control HTN :
 
  • Pathophysiology
    •  "Pressure Naturesis" is impaired
    • Even though Renin is low, RAAS is high ?? 
  • Etiology
    • Endocrinological and Hormonal Causes
      • Pheochromocytoma
      • Cushings
      • OCP
    • Nephrological Causes
      • Renal artery stenosis (Fibromuscular Dysplasia, or Atherosclearotic Renal Art. Stenosis)
      • Primary Kidney Disesase (GN etc)
    • Increased sympathetic outflow 
      • OSA
    • Others.
      • Coarctation of Aorta
Hyperaldosetoronism :
  • Most patients have normal K, however, many have either hypokalemia or easily inducible hypokalemia Guideline 2008
  • 3 rules of Endocrinology
    • First test is always a Screening Test
    • Second: Confirmation test is done only if Screening Test is done
    • Finally, Imaging studies are done always done at the last for anatomical localization once the diagnosis is confirmed in second stage 
 
Tests: 
  • Initial: 
    • Plasma Aldo Conc (PAC or Plasma Renin Activity - PRA) and Plasma Renin Concentration (PRC)
      • Both are required for diagnosis 
        • elevated Plasma Aldo to Renin Ratio
        • elevated Plamsa Aldosterone Concentration
    • 3 situations can arise: Case 4-2012
      • Elevated PAC, Suppressed PRC: Primary Hyperaldo (i.e Aldo production is not regulated by its regulator Renin)
      • Elevated PAC, Elevated PRC: Secondary Hyperaldo (i.e Aldo production is dependent on its regulator Renin)
      • Supressed PAC, Supressed PRC: 
        • Hypercortosolism 
          • Mechanism Case 4-2012Cortisol has a high affinity for the mineralocorticoid receptor but is normally prevented from binding because of rapid metabolism by 11β-hydroxysteroid dehydrogenase (11β-HSD). Alternatively, very high cortisol levels can exceed the metabolic capacity of 11β-HSD, allowing cortisol to exert aldosterone-like effects on potassium balance and blood pressure. 
        • Chronic Liqorice Intoxication
          • Mechanism Case 4-2012: Chronic licorice intoxication can mimic hyperaldosteronism, because glycyrrhetoric acid, a component of licorice, inhibits 11β-HSD, allowing endogenous cortisol to activate mineralocorticoid receptors.
    • Details of Tests:


Appreciate the medications can affect the test results 
Also, appreciate how will such results be affected 
An Endocrine Society Clinical Practice Guideline 2008

Appreciate the Medications that can be used for BP control during the test.

  • Pheochromocytoma
  • Cushings
  • OCP
Nephrolgical Causes
  • Renal artery stenosis (Fibromuscular Dysplasia, or Atherosclearotic Renal Art. Stenosis)
  • Primary Kidney Disesase (GN etc)
Increased sympathetic outflow 
  • OSA
Others.. 
  • Coarctation of Aorta
Newer studies
  • Assessing the Na compliance
    • Ur K / Ur Na  > 1 (mEq/L) or > 2 (mg / dL as done in DASH study) 
    • 24 hr urine collection
      • 2000 mg / 23 (atomic weight of Na) = around 88. Hence, 24 hr Urine Na is < 100 mEq that also shows patient compliance 
      • We could also recommend 2000 mg of K per day and likewise check the Urine excretion
  • 4 Strategies for treatment (Dr. Wilkowski's Noon Conf presentation)
    • Strategy I—significant increase in diuretics.
      • Change HCTZ to Chlorthalidone
        • use half the dose due to twice the half life
        • Risk of Hyponatremia and Hypokalemia is higher in older patient (>75 yr). Be careful in the elderly patient population
      • Change from thiazide to loop diuretic. 
      • Furosemide 40 mg daily becomes 80 mg BID.
      • Consider torsemide, more bioavailable, longer half-life than furosemide. 
      • Consider combination of thiazide plus loop diuretic.
        • Usually Chlorthialidone for weeks, and Metalozone for days
      • MOVE one of your agent to Night time 
    • Strategy II—combination drug preparations, if insurance will cover them, can increase compliance.
      • Calcium channel blocker/ARB and ACEI/diuretic another possibility.
      • ARB with ACEI does have additional effect on blood pressure lowering; but be aware of loss of significant GFR or hyperkalemia
        • ACEI/DIURETC: many such combinations are present
        • CCB/ACEI
          • Lotrel (amlodipine/benaz)
          • Tarka (verapamil/trando)
          • Lexxel (felodipine/enal)
        • ARB/DIURETIC
          • Every ARB  has such combinations
        • CCB/ARB
          • Exforge (amlodipine/valsartan)
          • Azor (amlodipine/olmesartan)
    • Strategy III—add an aldosterone antagonist, spironolactone or epleronone
      • Mainly to improve the pressure natureses is effect, and less so for direct diuretics effect.
          • K+ increased by 1 meq/L in patients with K+ > 4.5 and GFR < 45 ml / min when used for HTN 
      • A number of studies by M. Epstein at U of Miami and Calhoun/Oparil at UAB demonstrate improved control with this addition to any three drug regimen
      • Review renal function, check serum or plasma potassium, discontinue the patient’s potassium supplements and be aware spironolactone causes gynecomastia
      • Note, Aldactazide (spironolactone with HCTZ)
      • PATHWAY 2 study
        • Suitable for: Overweight with Stage 1 and 2 CKD 
        • Criticism of PATHWAY 2:
          • Not sure on the effect on AA
          • Not sure on its effect on Obese 
          • Advanced CKD and risk of Hyperkalemia
          • What if Sodium intake is low

    • Strategy IV—go to the three vitamin L’s: Loniten (load and consolidate), Lasix and Lopressor
      • Minoxidil (Loniten) 2.5 mg po q 4 hours, but hold if BP      sys < 145 or dia < 75, then consolidate to 2.5-20 mg bid
      • Furosemide (Lasix) 40-80 mg bid-tid to prevent reflex sodium retention and edema from minoxidil
      • Metoprolol (Lopressor) 50-100 mg bid to achieve beta-blockade and prevent reflex tachycardia from minoxidil

  

 

 

    

Accelerated Hypertension
  • Treatment: 
    • Renal Failure: Fenoldipin is preferred (D1 agonist). Is 6 times more potent than Dopamine for renal vasodilatation. 
    • ACS: NTG / Esmolol / Nicardipine / Clevidipine (Cleviprex)
  • Pathogenesis: 
    • Severe HTN (critical level or rate of rise) causes  vascular damage by 
      • Musculomucoid intimal hyperplasia
      • Fibrinoid necrosis
        • These two process leads to lumen narrowing
          • This causes Ischemia of vessels in
            • Retina
            • CNS
            • Heart
            • Kidney
            • GI / Pancrease
Additional new studies 
  • ASTRAL (NEJM ) 
    • Severity of the stenosis was not clearly defined as an inclusion criteria.
    • 40% of patient had 50-70 % of the stenosis 
  • SIMPLICITY 3 (NEJM 2014)
    • Ablation of sympathetic nerve to the kidney 
    • No true benefit of sympathectomy i.e no role of renal denervation
  • CORAL (NEJM 2014)
Additional Misc References


The Story of Hypertension


Primary Prevention Trial
  • High Risk Patient: 
    • HOPE NEJM 2000
    • SPRINT NEJM 2015
  • Intermediate Risk Patient (Note: Majority of CV event occurs in patient with average risks with no previous CV disease)
    • HOPE -3 NEJM 2016 (Blood Pressure Control Only Arm)
    • HOPE -3 NEJM 2016 (Blood Pressure and Cholesterol Control Arm) (No: BP or Cholesterol Target was used, treatment was instituted based on the risks of patient) 
Secondary Prevention Trial 
  • Stroke Patients: Progress Trial
  • Life Trial 


ACEI reduce CV event and mortality in patients with PAD, CAD, Stroke or DM with additional CV risks (HTN, HLD, Smoking, Microalbuminuria) but without LV dysfunction or LV failure (HOPE Study). Note: Patient did not have to have HTN to be included in the study . Also, contrast the outcome of ACCORD BP trial NEJM 2010 (see below) among the patient with DM 2 and high risk for CV events where no benefit of intensive blood pressure control was seen.


HOPE 2000

  • Inclusion Criteria: High CV risk or established CV events. 
    • Men and women who were at least 55 years old with history of coronary artery disease, stroke, peripheral vascular disease, or diabetes plus at least one other cardiovascular risk factor (hypertension, elevated total cholesterol levels, low high-density lipoprotein cholesterol levels, cigarette smoking, or documented microalbuminuria). 
  • Exclusion Criteria: 
    • Patients were excluded if they had heart failure, were known to have a low ejection fraction (<0.40), were taking an angiotensin-converting–enzyme inhibitor or vitamin E, had uncontrolled hypertension or overt nephropathy, or had had a myocardial infarction or stroke within four weeks before the study began

HOPE NEJM 2000


HOPE NEJM 2000


HOPE NEJM 2000


ACE inhibitors (ACEi) seem to reduce secondary stroke in patients 'not classically' hypertensive (PROGRESS: Perindopril + Indapamide vs Perindopril alone; patients enrolled in the study did not necessarily have HTN ) and angiotensin receptor blockers (ARB) appear superior to beta-blockers for reducing mortality, even with similar blood pressure reductions (LIFE: Losartan vs Atenolol). Note: 



Major Limitation of PROGRESS Trial: Did not include the data of Indapamide alone, which perhaps may have been better than Perindopril itself. 
Indapamide alone may have reduced stroke by as much as 38% (43% for the combined therapy minus 5% for perindopril alone), which would be consistent with the 34% risk reduction seen with low dose diuretics in the primary prevention setting and the 29% risk reduction seen with indapamide alone in the post-stroke antihypertensive treatment study (PATS).


So, LIFE study showed, ARB better than BB for CV mortality and morbidity benefit. 


However, Calcium channel blockers (CCB) may give better control than angiotensin receptor blockers (VALUE: Valsartan vs Amlodipine) though this could be off-set by a class benefit from ARBs. May be the agent of choice when adding to an ACEI in high risk patients (ACCOMPLISH)


  




 

The trial was terminated early after a mean follow-up of 36 months, when the boundary of the prespecified stopping rule was exceeded.
 

Thiazides seem to give particularly good blood pressure control (ALLHAT) though end-points were similar for ACEi and CCB. Also, when added as a second agent to an ACEi, a calcium channel blocker may be a better choice (ACCOMPLISH)


Note: It is best to start ACEI + CCB in patient with HTN vs ACEI + HCTZ (ACCOMPLISH; 13 % of patient had previous stroke); however, secondary stroke prevention for non-HTN patients, probably one should still stick with ACEI + Thiazide (PROGRESS) as no other study had looked into the patient with relatively normal BP treatment goal with better outcome. 


Alpha-blockers appear less attractive and in ALLHAT this arm was stopped early for increased cardiovascular events and heart failure


ALLHAT JAMA 2000


 

Early trials of Renal denervation appeared to offer substantial blood pressure reductions in patients with resistant hypertension (Symplicity HTN -2) but blinded trials failed to show a benefit above placebo (Symplicity HTN-3)


HTN Goal for > 50 yrs; with increased risk of CV events, but without DM (studied in ACCORD BP) or prior history of stroke (studied in PROGRESS trial). (SPRINT). This study was stopped before the end date due to significantly positive outcomes. 


  




Limitation of ACCORD BP Trial ACCORD BP Editorial NEJM 2010
i) Statistical power may be less due to study design
ii) Diuretics and either ACEI or BB were used for intensive blood pressure control. CCB instead of BB was not used. Who knows if that may have played the role. 26.2 % patient used BB in Intensive regimen, whereas 24.8 % patient used BB in standard treatment group. 

Difference between ACCORD and SPRINT
All results have almost the same trend. Only difference is the POWER was different. Look at the trend for CV outcome from the chart above. 

Primary Prevention Trial
  • High Risk Patient : (high cardiovascular risk is defined as a 5-year risk of cardiovascular events of ≥6.5% Lancet 2014 
    • HOPE NEJM 2000
    • SPRINT NEJM 2015
  • Intermediate Risk Patient (Note: Majority of CV event occurs in patient with average risks with no previous CV disease)
    • HOPE -3 NEJM 2016 (Blood Pressure Control Only Arm)
    • HOPE -3 NEJM 2016 (Blood Pressure and Cholesterol Control Arm) (No: BP or Cholesterol Target was used, treatment was instituted based on the risks of patient) 
How is Intermediate Risk Patient defined in HOPE-3 Trial? defined as an annual risk of major cardiovascular events of approximately 1%; i.e 5 yr risk < 5)
Inclusion criteria: 
  • men 55 years of age or older and women 65 years of age or older who had at least one of the following cardiovascular risk factors:
    • elevated waist-to-hip ratio, 
    • history of low concentration of high-density lipoprotein cholesterol, 
    • current or recent tobacco use, 
    • dysglycemia, 
    • family history of premature coronary disease, and 
    • mild renal dysfunction.
  • women 60 years of age or older who had at least two such risk factors mentioned above. 
  • Fasting lipid, glucose, and creatinine levels and blood pressure were measured before enrollment. However, participants were not selected on the basis of history of either hypertension or hyperlipidemia, and the trial did not mandate strict blood-pressure or lipid levels for entry. Persons with a history of hypertension could be enrolled if the blood pressure was adequately controlled (in the assessment of the recruiting physician) with lifestyle or drugs other than an ARB, ACE inhibitor, or thiazides

  



 


Conclusion: 

If BP> 144: Both BP lowering medications, and Statin are of useful. 
If BP< 144: Only Statin may be of use irrespective of Cholesterol level. Bottom Line Statin are of useful in Primary Prevention of CV risks. 
  • Neither of the drugs for blood-pressure lowering that were used in the trial have been shown to reduce the risk of cardiovascular events at such low doses 
  • Hydrochlorothiazide, even at a dose of 25 mg per day, has been less effective in reducing the risk of cardiovascular events than has a full dose of amlodipine (ACCOMPLISH Trial, NEJM 2008), whereas chlorthalidone at a dose of 25 mg per day has been effective in reducing the risk of cardiovascular events in a placebo-controlled trial (SHEP, JAMA 1991) and has been at least as effective as amlodipine (ALLHAT, JAMA 2002)
  • Comparison to SPRINT Trial: 
    • Inclusion criteria was > 130/80 BP. But, the goal of BP control was more intensive than in HOPE -3, and that may have been the reason for observed benefit of intensive blood pressure control in SPRINT NEJM 2015. BP Control in SPRINT was twice as seen in HOPE 3.
    • Patient in SPRINT Trial were included irrespective of CV risks. Some had CV risks, and others did not have. Among the participants who did not have clinical cardiovascular disease at baseline were required to have subclinical cardiovascular disease (definition???) or a high 10-year cardiovascular risk (on the basis of the Framingham risk score) that was higher than 15% 


Among patients with eGFR < 60, ACEI may confer additional cardiovascular protection and provide mortality benefit (PEACE). 

  

For > 80 yr, BP target of < 150/80 is better (HYVET)


Reference for above: http://cardiologytrials.org


HTN Urgency

  • Best medicine to use is Captopril. 
  • Onset of Action: 15 - 30 min
  • Max BP drop at 30 - 90 min
  • Given as 25 mg dose , followed by 90 - 120 min later by incremental doses of 50 g to 100 mg 
  • Continue Captropril until restarting home medication and BP is normal or converted to long acting ACEI 


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