various treatment options for resistant hypertension

1. RESISTANT HYPERTENSION
Dr Siva Subramaniyan
PGIMER &Dr.RML Hospital
New Delhi

2. RESISTANT HYPERTENSION
• Resistant hypertension is defined as blood pressure that remains
above goal in spite of the concurrent use of 3 antihypertensive agents
of different classes. Ideally, one of the 3 agents should be a diuretic
and all agents should be prescribed at optimal dose amounts.
• What constitutes an “optimal dose” of medication is presumably at
least a moderate dose but not necessarily a maximum dose
• Patients requiring 4 antihypertensive medications (even if controlled)
are classified as having resistant hypertension

3. PREVALENCE
• The prevalence of resistant hypertension is unknown
• Approximately 10% of patients with diagnosed hypertension have
true resistant hypertension
• Although this prevalence is lower than initially thought, it is
nonetheless quite high and likely will get worse.

4. In General Population - Low
In Specialized Clinics -15%
In Clinical Trials* - 30%

5. why hypertension is important
• there is increasing CV risk from SBP 115mmHg
• CV mortality doubles for every 10/5 increase in BP > 120/70mmHg
• High BP causes
- 35% of all cardiovascular deaths
- 50% of all stroke deaths
- 25% of all CAD deaths
- 50% of all congestive heart failure
- 25% of all premature deaths
- commonest cause of CKD overall and commonest cause of ESRD in older
individuals

6. CAUSES
apparent cause true resistant hypertension
Pseudoresistance
High risk patents
Life style
Drug related cause
Secondary causes
Poor adherence
Improper technique
White coat effect

7. PSEUDORESISTANCE
1) Poor Blood Pressure Technique
Two of the most common mistakes normally we make is
- measuring the blood pressure before letting the patient
sit quietly and
- use of too small a cuff - will result in falsely high blood
pressure readings

8. 2) Poor Adherence
• Poor adherence to antihypertensive therapy is a major cause of lack
of blood pressure control.
• Retrospective analyses indicate that approximately 40% of patients
with newly diagnosed hypertension will discontinue their
antihypertensive medications during the first year of treatment.
• During 5 to 10 years of follow-up, less than 40% of patients may
persist with their prescribed antihypertensive treatment

9. 3) White-Coat Effect
• Studies indicate that a significant white-coat effect is as common in
patients with resistant hypertension as in the more general
hypertensive population.
• with a prevalence in the range of 20% to 30%.
• individuals with a white coat effect had fewer cardiovascular events
than those with resistant hypertension and similar rates of
cardiovascular events compared with patients with well controlled
hypertension.
• However, the prognosis of hypertensive patients with white coat
syndrome is worse than that of the general normotensive population

10. HIGH RISK PATIENTS

11. LIFESTYLE FACTORS
Obesity
• Obesity is associated with more severe hypertension, a need for an
increased number of antihypertensive medications, and an increased
likelihood of never achieving blood pressure control.
• As a consequence, obesity is a common feature of patients with
resistant hypertension.
• Obesity is associated with many other condition which can cause
hypertension like OSA, diabetes etc.

12. OBESITY
Obese pt
OSA
Inflammation/ oxidative stress
SNS activation
Na/ volume retention
Endothelial dysfunction
Insulin + leptin resistance
Renal dysfunction
Other drugs causing hypertension

13. Dietary Salt
• Excessive dietary sodium intake
- directly increasing blood pressure and
- by blunting the blood pressure– lowering effect of most classes
of antihypertensive agents
• more pronounced in typical salt-sensitive patients, including the elderly,
African Americans, and patients with CKD
Alcohol
• Heavy alcohol intake is associated with both an increased risk of
hypertension, as well as treatment-resistant hypertension

14. DRUG-RELATED CAUSES

15. SECONDARY CAUSES

17. OBSTRUCTIVE SLEEP APNEA
• Untreated obstructive sleep apnea is strongly associated with
hypertension and in normotensive persons predicts development of
hypertension
• Sleep apnea is particularly common in patients with resistant
hypertension. In an observational study evaluation of 41 consecutive
patients with treatment-resistant hypertension, 83% were diagnosed
with unsuspected sleep apnea based on an apnea hypopnea index 10
events/h.
• Obstructive sleep apnea is observed in 30% to 40% of patients with
hypertension and in 60% to 70% of patients with resistant
hypertension
Circulation June 24, 2008

19. PRIMARY ALDOSTERONISM
• Recent studies indicate that primary aldosteronism is a much more
common cause of hypertension than had been demonstrated
historically
• In patients referred to hypertension specialty clinics, as many as 20%
demonstrate PA
• The diagnosis may have been overlooked during the initial evaluation
when the patient was first diagnosed with hypertension because
many of these patients actually have normal potassium levels.

20. RENAL ARTERY STENOSIS
• The prevalence of Reno vascular hypertension in overall hypertensive
population is unknown
• Renovascular disease is a common finding in hypertensive patients
undergoing cardiac catheterization, with more than 20% of patients
having unilateral or bilateral stenoses (with a degree of obstruction
70%).
• however, the role of such lesions in causing hypertension unknown.

23. RENAL PARENCHYMAL DISEASE
• CKD is both a common cause and complication of poorly controlled
hypertension.
• In ALLHAT, CKD as indicated by a serum creatinine of 1.5 mg/dL was a
strong predictor of failure to achieve goal blood pressure.
• Treatment resistance in patients with CKD is undoubtedly related in
large part to increased sodium and fluid retention and consequential
intravascular volume expansion

24. PHEOCHROMOCYTOMA
• Pheochromocytoma represents a small but important fraction of
secondary causes of resistant hypertension.
• The prevalence of pheochromocytoma is 0.1% to 0.6% of
hypertensives in a general ambulatory population
• Hypertension occurs in about 80-90% of patients with
pheochromocytoma
• About - 50% sustained hypertension,
- another 45% present with paroxysmal hypertension,
- while 5-15% are normotensive.

25. CUSHING’S SYNDROME
Hypertension is present in 70% to 90% of patients with Cushing’s
syndrome
• main mechanism of hypertension in Cushing’s syndrome is
overstimulation of then nonselective mineralocorticoid receptor by
cortisol.
• activation of the renin angiotensin system (RAS)
• other factors such as sleep apnea and the insulin resistance syndrome
are major contributors to hypertension in this disease

26. GENETICS
ENaC β,γ
Liddle’s
CYP3A5
ACE Gene

27. EVALUATION AND MANAGEMENT

28. • The evaluation of patients with resistant hypertension should be
directed toward confirming true treatment resistance.
• identification of causes contributing to treatment resistance,
including secondary causes of hypertension and documentation of
target-organ damage

30. STEP 1

31. STEP 2

32. • Adherence can be monitored with patient self-report, pill counts, or
prescription refill rates. Self report tends to overestimate adherence
to antihypertensive medications by as much as 80% compared with
electronic monitoring of pillboxes.
• Similarly, pill counts are accurate in determining adherence in only
50% to 70% of patients compared with electronic pillboxes.
• more sensitive technique for nonadherence is - therapeutic drug
monitoring in the serum samples.

33. • Once medication nonadherence is established, every effort should be
made to identify barriers to medication adherence.
• These barriers may include
- adverse effects to antihypertensivedrugs,
- excessively complex drug regimens,
- financial limitations, or
- Patient cognitive dysfunction.
• A plan for improved adherence should be developed in partnership
with each patient according to his/her specific situation

34. WHITE COAT EFFECT

35. JAMA June 4, 2014 Volume 311, Number 21

36. STEP 3

37. • Weight loss, although not specifically evaluated in patients with
resistant hypertension, has a clear benefit in terms of reducing blood
pressure and often allows for reduction in the number of prescribed
medications.

38. SALT RESTRICTION
• The benefit of dietary salt reduction is well documented in systolic
and diastolic blood pressure of 5 to 10 and 2 to 6 mm Hg,
respectively.
• African-American and elderly patients tend to show larger benefit
• dietary salt restriction, ideally to less than 100 mEq of sodium/24-
hour should be recommended for all patients with resistant
hypertension

40. STEP 4

41. STEP 5

42. Treatment of Obstructive Sleep Apnea
• Treatment of sleep apnea with continuous positive airway pressure (CPAP)
likely improves blood pressure control, although the benefit in CPAP
intervention trials has been variable.
• CPAP resulted in modest blood pressure reductions in patients with
resistant hypertension approximating 3 to 5 mmHg. However, greater
blood pressure reductions of 7 to 10 mmHg were reported in patients with
resistant hypertension who regularly adhered to the CPAP treatment
• Review of randomized CPAP intervention trials suggests that CPAP use can
be expected to lower blood pressure in hypertensive patients, with the
largest benefit being seen in patients with severe sleep apnea and in
patients already receiving antihypertensive treatment.

43. Treatment of Renal Artery Stenosis
Fibromuscular dysplasia
• Angioplasty of fibromuscular lesions almost always benefits, and is
often curative, of the associated hypertension and therefore is the
recommended treatment of choice.
• Restenosis,however, may occur in excess of 20% of patients after 1
year

46. CONCLUSION
• renal-artery stenting did not confer a significant benefit with respect
to the prevention of clinical events when added to comprehensive,
multifactorial medical therapy in people with atherosclerotic renal-
artery stenosis and hypertension or chronic kidney disease.

47. STEP 6

48. Initial Therapy for Resistant Hypertension
• Pharmacological treatment for patients with uncontrolled blood
pressure despite a triple-drug regimen should begin with optimization
of diuretic use
• Chlorthalidone, is at least twice as potent as hydrochlorothiazide, a
thiazide-type diuretic, in lowering blood pressure.
• Chlorthalidone was more effective than lisinopril in reducing the risk
of heart failure and stroke in black patients and, therefore, should be
considered as an initial therapy for patients with resistant
hypertension

49. • In the British 2011 National Institute for Health and Clinical Excellence
(NICE) consensus statement, indapamide, another thiazidelike
diuretic, is recommended over hydrochlorothiazide due to greater
antihypertensive efficacy based on a meta-analysis.
• chlorthalidone is the only diuretic recommended by the 2008 AHA
position statement, whereas the 2014 report from the JNC did not
specify that thiazide diuretic was preferred for lowering blood
pressure

50. COMBINATION THERAPY
• After optimizing diuretic therapy, the combination of both
angiotensin- converting enzyme inhibitors and calcium channel
blockers should be prescribed for resistant hypertension.
• This combination regimen is superior to the combination of both
angiotensin converting enzyme inhibitors and thiazide diuretics in
reducing cardiovascular events in hypertensive patients with high
cardiovascular risk

55. FOURTH DRUG

56. Hypertension. 2011;57:1069-1075

58. • The APBM night time systolic, 24-hour ABPM systolic, and office systolic BP
values were significantly decreased by spironolactone whereas the fall of
the respective diastolic BP values was not significant
• In conclusion, spironolactone is an effective drug for lowering systolic BP
in patients with resistant arterial hypertension.
Hypertension. 2011;57:1069-1075

61. • The antihypertensive associations of both spironolactone and
eplerenone were observed even in the presence of normal serum
aldosterone levels

62. This is an observational analysis from a clinical trial involving 10 069 patient
treated with amlodipine plus perindopril vs atenolol plus bendroflumethiazide
showed that adding doxazosin to either treatment combination was associated
with a lower blood pressure by 12/7 mm Hg without an increase in heart failure.

63. INTERVENTIONS

64. RENAL DENERVATION
• Efferent sympathetic outflow to the kidney stimulates
- renin release,
- increases tubular sodium reabsorption, and
- reduces renal blood flow.
• afferent signals from the kidney modulate central sympathetic
outflow and contribute to neurogenic hypertension

66. • The Symplicity renal denervation system was proven to be superior to
medical management in the Symplicity HTN-2 clinical trial.
• Symplicity HTN-2 was a randomised, controlled clinical trial of 106
patients. Patients randomised to RDN therapy plus antihypertensive
medications achieved a significant reduction in mean blood pressure
(-32/-12 mmHg) at 6 months.
• whereas patients in the control group randomised to receive
antihypertensive medications alone had blood pressures that did not
vary from baseline (+1/0 mmHg).

70. CONCLUSION
• This blinded trial did not show a significant reduction of systolic blood
pressure in patients with resistant hypertension 6 months after renal-
artery denervation as compared with control.

71. CAROTID BAROREFLEX ACTIVATION
• Another device based therapy of resistant hypertension is carotid
baroreflex activation, in which stimulating electrodes are implanted in
the perivascular space around the carotid sinuses

74. FUTURE
• creation of a venous-arterial fistula
• neurovascular decompression by surgical interventions, which has
been found to lower BP in a few cases of severe resistant
hypertension
• Ultrasonic renal denervation

78. TAKE HOME MESSAGE
• Diagnosis of true resistant hypertension important by excluding
pseudo resistant hypertension.
• Initial drug should be diuretics followed by ACEI/ARBs and CCBs
• There is convincing evidence that spironolactone should be a fourth
drug. Other drugs are alfa blocker, b blocker, vasodilators, centrally
acting sympatholytic etc can be used.