HYPERTENSION


See also  and Hypertensive Disorders in Pregnancy and Cardiovascular Drugs

Diagnosis and Classification of Hypertension
Complications of Hypertension
Secondary Causes of Hypertension
Diagnostic Evaluation of Patients with Hypertension

Treatment of Hypertension

Choice of Target BP
Treatment of Prehypertension

Studies on Benefit of Treatment

Treatment with Lifestyle Modification

Treatment with Medication-JNC VII recommended approach

Consideration of cooexisting conditions in treatment of HTN

Studies Comparing Different Antihypertensives

Treatment of "Resistant" Hypertension

Renal Nerve Ablation for Hypertension

"Hypertensive emergencies"

Note: "JNC VII" = The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JAMA 289:2560, 2003)

I. Diagnosis and classification of Hypertension

  1. Per JNC VII
    1. Note that these measurements apply to average of 2 or more office BP measurements in seated adults
    2. These categories have been validated in studies where long-term (e.g. 10y) risk of cardiovascular events were found to be significantly increased from Optimal to Normal to High-normal BP's in both men & women (NEJM 345:1291, 2001--JW)
Category Systolic BP Diastolic BP
Normal < 120 < 80
Prehypertension 120-139 80-89
Stage 1 HTN 140-159 90-99
Stage 2 HTN 160- 100-
  1. Home BP monitoring
    1. Criteria for normal should be < 135/85 (ibid.)
    2. May correlate better with cardiovascular risk c/w in-office measurements (Am. J. Prev. Med. 25:159, 2003)
  2. Ambulatory BP monitoring (usually done for 24h)
    1. Average SBP and DBP from ABP monitoring both independently ass'd with risk for cardiovascular (CV) events, after adjustment for multiple CV risk factors including in-office BP measurement in a 5y prospective trial of 1963 pts w/HTN on meds (“OvA Study”--NEJM 348:2407, 2003)
    2. With elevated office-measured BP’s but mean 24h ambulatory BP’s < 130/80 (“white coat” hypertension) are no more likely than normotensives to have a CV event (Am. J. Prev. Med. 25:159, 2003)
    3. Per US Preventive Services Task Force, ambulatory BP measurement over 24h may be a better predictor of adverse clinical cardiovascular outcomes than in-office BP measurement per "multiple fair quality prospective cohort studies" (6 refs).  Included in these are studies that have shown that pts with elevated office-measured BP’s but mean 24h ambulatory BP’s < 130/80 (“white coat” hypertension) are no more likely than normotensives to have a CV event.  Ambulatory BP measurement may be especially useful in "stratifying" individuals who had normal BP's at home but elevated BP's in office.(Am. J. Prev. Med. 2003;25:159-164; Am. J. Prev. Med. 2003;25:151-158)

II. Complications of Hypertension

  1. Hypertensive nephropathy
  2. Coronary artery disease
  3. Congestive Heart Failure
  4. Cerebrovascular disease
  5. Peripheral Arterial Disease
  6. Abdominal Aortic Aneurysm
  7. Hypertensive Retinopathy
    1. More arteriolar attenuation than in DR
    2. Also get cotton-wool spots & flame-shaped hemorrhages (nonspecific findings); go away with treatment
    3. "KWB" classification--4 stages, each indicating longer period of ongoing HTN
    • 1--arteriolar narrowing
    • 2--AV nicking
    • 3--exudates/hemorrhages
    • 4--papilledema (indicates rapid rate of rise)

III. Secondary causes of Hypertension (most cases are of unidentifiable cause and designated "Essential Hypertension")

  1. Chronic renal failure from any cause
    1. Most common cause of HTN in <10yo
    2. Check U/A, BUN, Cr
  2. Renovascular (RA stenosis)
    1. Due to fibromuscular dysplasia (15-30yo, us. women)--Can be tx'd with percutaneous transluminal renal angioplasty (sometimes w/stent)
    2. Atherosclerotic stenosis--May be amenable to surgical revascularization
    3. Suspect if:
      1. Onset < 30yo or > 55yo, esp. w/o family hx
      2. Abdominal bruit, esp. if continues into diastole and is lateralized
      3. Resistant to tx
      4. Idiopathic renal failure
      5. Coexisting atherosclerotic disease
      6. Acute renal failure precipitated by antihypertensive Rx
  1. Coarctation of the aorta--check femoral pulses
  2. Hyperaldosteronism
    1. Often accompanied by hypokalemia and high-normal serum sodium concentration
    2. Diagnosis
      1. Traditional approaches are quite complex
      2. Plasma aldosterone-renin ratio
        1. Need to take the pt of anti-aldosterone meds e.g. spironolactone
        2. A:R > 100 (measured in ng/dL and ng/mL/h, respectively) had a positive predictive value of 100% in identifying hyperaldosteronemic pts in one series of 90 pts (Am. J. Kid. Dis. 37:699, 2001--JW)
        3. A:R > 23.6 ng/dL per ng/mL had sensitivity of 97% and specificity of 94% for eventual diagnosis of primary hyperaldosteronism in a retrospective study of 62 pts with suspected primary hyperaldosteronism (Clin. Endocr. Metab. 90:72, 2005--JW) 
    3. Causes include Cushing's disease (ACTH-secreting pit. tumor), Conn's disease (adrenal aldo-secreting adenoma), and adrenal hyperplasia (the most common cause).
    4. Tx includes surgery (if caused by tumor) or Spironolactone (if caused by hyperplasia)
  3. Drugs
    1. Steroids
    2. Sympathomimetics, inc. OTC's
    3. NSAIDS and COX-2 Inhibitors (may contribute to resistance to antihypertensives)
    4. Immunosuppressants, e.g. cyclosporine, tacrolimus
    5. Bromocriptine
    6. MAOIs
    7. Erythrypoietin
    8. Combined Hormonal Contraceptives (very rare)
    9. EtOH
    10. Tobacco
    11. Cocaine, amphetamines
    12. Caffeine (raises BP acutely but tolerance develops rapidly and there is no proven correlation between overall caffeine intake and BP as of 1997)
    13. Certain herbal remedies
    14. Licorice (looks like hyperaldo with low K)
  4. Pregnancy-toxemia
  5. Other tumors
    1. Wilms' (in kids with HTN)
    2. Hemangiopericytoma (a reninoma, mostly in adol.)
    3. Pheochromocytoma (Suggested by paroxysms of HTN accompanied by HA, palpitations, pallor, and perspiration; check postural BPs--often have orthostatic hypotn)
  6. Drug withdrawal, e.g. clonidine, EtOH
  7. Hypothyroidism
  8. Sleep apnea
  9. Vitamin D deficiency (associated in prospective studies with higher incidence of HTN (Health Professionals Follow-Up Study, reported at Am. Soc. HTN meeting 2006 by John Forman; FP News 7/1/06 p. 14)

IV. Diagnostic evaluation of patients with hypertension

  1. Initial workup--consider the following
    1. Physical exam including fundoscopy and listening for abdominal bruits
    2. Lytes to look for electrolyte abnormality
    3. BUN/Cr & urine dipstick for protein to screen for nephropathy
    4. Hematocrit (recc'd by JNC; I don't know why)
    5. Glucose to screen for DM
    6. Cholesterol/HDL
    7. EKG to look for prior MI or LVH
    8. TSH if clinically indicated
    9. Consider limited echo to r/o LVH
  2. Routine surveillance in a pt with HTN
    1. Annual u/a for protein and RBC's; if positive, do 24h urine protein and if > 1g/24h, adjust target BP to < 130/85

V. Treatment of HTN

  1. Choice of target BP
    1. Per JNC (see table below), target is < 140/90 unless DM or chronic renal disease are present in which case it's < 130/80
    2. Note-see section on Diabetes Management for data regarding target BP in diabetics with HTN
    3. Studies comparing different BP targets in nondiabetics
      1. In a study of 18,790 pts from 26 countries, 50-80yo, with baseline DBP 100-115mm Hg, were randomized to pharmacologic tx for HTN (starting with felodipine 5mg/d and adding other agents as needed) with target DBP of 90, 85, or 80mm Hg ("Hypertension Optimal Treatment" (HOT) trial, Lancet 351:1755, 1998)
        1. In the overall analysis, there were no sig. differences in any endpoints, including MI, CVA, major CV events, CV mortality, or total mortality.
        2. Among the subgroup of diabetics, however, there were significant reductions in CV mortality and major CV events, and a nonsignificant decrease in total mortality, with 80mm Hg goal vs. 90mm Hg goal
      2. In a study in 1,111 nondiabetic pts > 55yo with HTN and at least one other cardiovascular risk factor randomized to target SBP of < 140 or < 130mm Hg (with various combinations of furosemide, HTCZ, ramipril, telmisartan, amlodipine, bisoprolol, and clonidine), the prevalence of left ventricular hypertrophy at 2y was sig. lower in the tight-control group (11.4% vs. 17.0%) as was 2y incidence of a secondary endpoint of any of nine adverse cardiovascular events (4.8% vs. 9.4%) (Lancet 374:525, 2009-JW)
    4. Treatment of Prehypertension
      1. 772 pts with prehypertension at baseline (SBP 130-139 mm Hg and diastolic < 90mm Hg or systolic < 140mm Hg and diastolic 85-89mm Hg) randomized to with candesartan 16mg QD vs. placebo x 2y followed by 2y of placebo for both groups. At 4y, prevalence of stage 1 HTN was sig. lower in candesartan group (53% vs. 63%) (Trial of Preventing Hypertension ("TROPHY") study; presented at Am. Coll. cardiol; reported in FP News 4/1/06)
  1. Studies on benefit of treatment
    1. Reduces risk of death, CVA, MI, CHF, and end-stage renal disease
    2. Benefits of treatment of hypertension in the elderly
      1.  In a study in 3,845 generally healthy pts > 80yo with systolic BP > 159mm Hg and diastolic BP < 110mm Hg randomized to antihypertensive treatment (indapamide sustained-release 1.5m QD + perindopril titrated from 2-4mg/d to goal of BP < 150/80) vs. placebo, over mean 2.1y f/u, the incidence of overall mortality was sig. lower (10% vs. 12%) ("Hypertension in the Very Elderly Trial" ("HYVET"), NEJM 358:1887, 2008)
      1. Pharmacologic tx of HTN in pts > 80yo was associated with reductions in risk of CVA, coronary events, and CHF, butwith a slight increase in all-cause mortality in a meta-analysis of 1,670 pts in 7 randomized trials with avg. 3.5y f/u (Lancet 353:793, 1999--JW)
    3. Isolated systolic HTN (50% of hypertensives; more common in elderly): DBP <90 & SBP >160 (if <65yo) or SBP > 140 (if >65yo)
  1. Associated with similar risks as other forms of HTN ("SHEP [Systolic Hypertension in the Elderly Project]-JAMA June '91)
  2. 4,700 pts > 60yo w/SBP 160-219 and DBP < 95 randomized to placebo vs. nitrendipine and, if nec., HCTZ and/or enalapril; median f/u 2y; RR for CVA 0.6 for those on active tx; 0.7 for fatal or nonfatal CV events (both sig.); overall and CV mortality was not sig. diff. in both groups
  3. Swedish study looked at a randomly selected cohort of 484 men age 70y; followed for with 3 visits over 20 years. At each visit, checked who was on antihypertensives. Most on antihypertensives were on beta-blockers or diuretics. Those on antihypertensives had greater incidence of ischemic cardiac events. For those with DBP > 90, this increased risk was abolished when adjusting for diffeences in smoking, BP, cardiovascular disease, hyperlipidemia, diabetes, obesity, and creatinine leve. For those with DBP < 90, had RR 3.9 even after adjustment for these confounders. So, increased risk of cardiac ischemic events in men on antihypertensives whose DBP < 90 compared with men not on antihypertensives. (BMJ 313:457, 1996-JW)
  4. Treatment of isolated systolic HTN  (with Ca-blocker alone or with ACEI and/or diuretic) was ass'd with sig. decrease in cardiovascular events vs. placebo in pts with "moderate sustained" HTN (avg. SBP > 159 on 24h ambulatory BP monitoring) but not in those with "mild sustained" HTN (avg. SBP 140-159) or "nonsustained" HTN (avg. SBP < 140) in a randomized study of 695 pts followed x 4y (Circ. 102:1139, 2000--JW)
  5. Tx for isolated systolic HTN (SBP > 160mm Hg but DBP < 95mm Hg) in pts > 60yo was ass'd with sig. reduced incidence of CVA, CAD events, CV mortality, and total mortality in a meta-analysis of 8 RCT's (Lancet 2000;355:865-872)
  1. A meta-analysis of 5 RCT's showed that persons with DBPs 90-109mm Hg have lower incidence of CVA but not MI or total mortality, except in pts > 60yo who did have reduced total mortality (J. Hum. Hypertens. 1996;10:1-8)

  1. Treatment with lifestyle modification (sources include Arch.. Int. Med. 153:159, 1993):
  1. Weight loss if overweight
  2. Aerobic exercise
  3. Moderation in EtOH intake (mo more than 2 drinks/day for men, 1 drink/day for women or light weight men)
  4. Smoking cessation
  5. Reduce dietary Na to 2g/d
    1. Won't reduce BP in all pts--more likely to be Na-sensitive if African-American or elderly
    2. In two meta-analyses, dietary Na restriction as above resulted in average decreases in SBP of 3.7-4.8 mm Hg and in DBP of 0.9-2.5mm Hg (JAMA 275:1590, 1996 and Am. J. Clin. Nutr. 65:Suppl:643S-651S, 1997)
  1. Maintain adequate K intake (90mmol/d)
  2. Diet rich in fruits, veggies, and low-fat dairy with reduced sat. fat and total fat (the Dietary Approaches to Stop Hypertension ("DASH") diet)
    1. 459 adults with SBP < 160 and DBP 80-95 randomized to typical American diet vs. the DASH diet x 8wks.  No change in body weight, but sig. greater reduction in SBP and DBP with DASH diet than w/control diet in pts overall and in subgroup w/baseline BP > 140/90 (133 pts; mean decrease w/DASH diet in those pts was 11.4/5.5 mm Hg) (NEJM 336:1117, 1997)
    2. In a 3mo study using the same diet in 412 adults with BP 120-160/80-95, randomized to DASH vs. a "typical U.S." diet and sub-randomized to 50, 100, or 150mmol/d dietary Na, both DASH and reduced Na were ass'd with sig. decrease in BP, with an additive effect.  Reductions in BP with both Na reduction and DASH were seen in all subgroups studied, including those with and without HTN at baseline, African-American vs. non-African-American ethnicity, male vs. female, obese vs. non-obese, etc. (Ann. Int. Med. 135:1019, 2001)
  3. NO evidence as of 1997 that Ca or Mg supplementation lower BP in pts w/HTN
  4. Stress reduction
  5. Soy supplements
    1. In a study in 302 pts 35-65yo with prehypertension or stage 1 hypertension (BP 120-159/80-99) randomized to soybean protein supplements 40g/d vs. a carbohydrate supplement x 12wks, the soy protein supplement group had sig. greater reductions in systolic and diastolic BP (4.31 and 2.76,respectively) (Ann. Int. Med. 143:1, 2005--AFP)
  1. Treatment with Medication
  1. General recc'd approach per JNC VII--See also Consideration of Coexisting Conditions in Treatment of HTN for info on how other health issues affect choice of antihypertensive, e.g. DM, CAD, etc.
Stage of HTN Recc'd treatment approach
Prehypertension Meds if chronic renal disease or
DM and BP < 130/80
Stage 1 HTN Meds for "compelling indications" if they exist*
Otherwise Thiazides first-choice &
ACEI, ARB, beta-blocker, CCB 2nd-choice
Stage 2 HTN Meds for "compelling indications" if they exist*
Otherwise 2-drug combination first choice
(Thiazides and either ACEI, ARB, beta-blocker,
or CCB)

*--"Compelling indications" = 

  1. Studies comparing clinical outcomes with different antihypertensives in undifferentiated populations:
Note--Two important sources of data for such comparisons are:
  • The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack ("ALLHAT") study (JAMA 288:2981, 2002).  The following is a description of the study; data from relevant secondary analyses is incorporated in the sections below: 33,357 pts > 55yo with HTN and at least 1 other CAD risk factor (prior MI or CVA, other atherosclerotic disease, LVH on ECG or echo, type 2 DM, cigarette use, or HDL < 35) randomized to the following with tx to target BP < 140/90 (additional drugs could be added if neeed, including atenolol, clonidine, and reserpine): chlorthalidone 12.5-25mg/d, amlodipine 2.5-10mg/d, or lisinopril 10-40mg/d (a doxazosin arm was dropped early b/c of sig. higher incidence of main endpoint c/w chlorthalidone).  Over mean 4.9y f/u, incidence of (nonfatal MI or coronary death) and all-cause mortality were not sig. diff. between any of the treatments.  However, analysis of secondary endpoints did show some differences (see below).
  • A “network” meta-analysis of 42 long-term (at least 1y) RCT’s that assessed major CV disease endpoints and/or all-cause mortality comparing various antihypertensive meds as first-line therapies vs. other meds, placebo, or no tx.  There were six different first-line active-treatment interventions in the various trials: low-dose diuretics (12.5-25mg/d chlorthalidone or equivalent), beta-blockers, ACEIs, Ca-blockers, alpha-blockers, and ARB’s.  All tx’s were ass’d with similar BP changes.  Low-dose diuretics were at least as good as all the others at every outcome evaluated (CHD events, CHF incidence, CVA, CVD events, CVD mortality, and total mortality).  Treatments that fared worse than low-dose diuretics, and the corresponding outcomes and RR for those outcomes with low-dose diuretics as compared with those treatments, are given below: (JAMA 289:2534, 2003)
  1. Beta-Blockers vs. Placebo--No difference?
    1. In a meta-analysis of 4 randomized trials of atenolol vs. placebo in pts with primary hypertension, involving 6,825 pts over mean 4.6y f/u, atenolol was ass'd with sig. greater BP lowering than placebo but no sig. diff. in overall mortality, cardiovascular mortality, of MI.  CVA incidence was nonsig. lower with atenolol (RR 0.85) (Lancet 364:1684, 2004)
    2. In a meta-analysis of 7 randomized trials involving 27,400 pts comparing beta-blockers to other antihypertensives, placebo or no-treatment as first-line therapy for primary hypertension:
      1. Beta-blockers vs. other antiypertensives were associated with sig. higher incidence of CVA (RR 1.16) but no sig. diff. in all-cause mortality or MI
      2. Beta-blockers vs. placebo or no tx were associated with sig. reduction in incidence of CVA (RR 0.81) but no sig. diff. in all-cause mortality or MI (Lancet 366:1545, 2005--AFP)
  1. Beta-Blockers vs. other antihypertensives--Beta-blockers worse in pts < 60yo
    1. In a meta-analysis of 21 studies of beta-blockers vs. other drugs for treatment of hypertension, in the subgroup of pts < 60yo, there were no sig. diffs. in outcomes but for pts > 60yo, the incidence of major cardiovascular events was sig. (but slightly) higher with beta-blockers (RR 1.06) (CMAJ 174:1737, 2006--JW)
  1. ARB's vs. non-ARBs/non-ACE in pts with uncontrolled HTN-ARBs may be better
    1. In a study in 3,042 pts with uncontrolled HTN and high cardiovascular risk (DM, LVH on ECG, obesity, smoking, or h/o CAD), adding valsartan vs. adding a non-ARB/non-ACE therapy (the paper didn't specify what!), over mean 3.27y f/u, was associated with sig. lower (RR 0.55%) incidence of (CVA, MI, angina, hospitalization for heart failure, coronary revascularization, renal failure, or new-onset peripheral artery disease) (NNT = 21), primarily due to a reduction in incidence of CVA and new-onset angina; there was no sig. diff. in incidence of MI or all-cause mortality.  ("Kyoto Heart Study", Eur. Heart J. 30:2461, 2009-abst)
  2. ARB's vs. Beta-Blockers in pts with LVH-ARBs better
    1. 9193 pts 55-80yo with HTN (BP 160-200/95-115) and LVH on ECG randomized to losartan 50mg/d vs. atenolol 50mg/d titrated to BP < 140/90; hydrochlorothiazide 12.5mg/d added if needed.  None were on ACEI's, ARB's, or other beta-blockers.  BP reduction was similar in both groups.  Over avg. 4.8y f/u, incidence of primary endpoint (CV death, MI, or CVA) was sig. lower with Losartan (11% vs. 13%), mostly from reduced CVA incidence.  All-cause mortality was nonsig. lower with Losartan.  Overall BP control similar in the two groups.  New-onset DM sig. less common with Losartan.  All-cause mortality WAS significantly lower in the subgroup of pts with DM (RR 0.61) ("LIFE" study, Lancet 359:995, 2002; Lancet 359:1004, 2002)
    2. In a separately reported subgroup analysis of the 6886 pts with no clinically evident vascular disease (CAD, cerebrovascular disease, or PVD) at randomization, incidence of the same primary endpoint was sig. lower in Losartan pts (17.5 vs. 21.8 per 1000 pt-years, RR = 0.81), including after adjustment for BP reduction.  Losartan was ass’d with nonsig. greater SBP and nonsig. lesser DBP reductions than atenolol.  In analysis of specific outcomes, CVA but not MI was sig. less frequent in Losartan recipients.  Also, incidence of DM was sig. lower in losartan recipients (RR 0.69). (Ann. Int. Med. 139:169, 2003)
    3. In a separately reported study of a separate cohort in the same study with isolated systolic HTN at baseline (BP 160-200/<90),  who also had LVH, in the same age range, randomized to the same treatments: BP reduction was similar in both groups.  Over avg. 4.7y f/u, RR of the main outcome was 0.75 in the Losartan group (nonsig. after adjustment for risk and degree of LVH); total mortality, was less in Losartan group and barely achieved clinical significance (10% vs. 14%; RR 0.72) (JAMA 288:1491, 2002--abst)
  1. ARB's vs. Calcium channel blockers--No difference
    1. 15,245 pts with HTN and other cardiovascular risk factors randomized to amlodipine vs. valsartan; over mean 4.2y f/u, no sig. diff. in incidence of cardiac events (Valsartan Antihypertensive Long-Term Use Evaluation Trial ("VALUE"); Lancet 363:2022, 2004--Med. Lett., JW)
  1. Calcium channel blockers vs. Diuretics, Beta-blockers, or ACEIs-Ca-blockers worse
    1. In a systematic review of 9 randomized trials involving 27,743 pts comparing Ca-blockers with either diuretics, beta-blockers, ACEIs, or clonidine, there was no sig. diff. in control of BP BUT Ca-blocker recipients had sig. higher risk for MI, CHF, and total cardiovascular adverse events, though no sig. diff. in incidence of CVA or all-cause mortality; sig. or nearly-sig increases in risk of total cardiovascular adverse events seen in all subgroups of trials based on types of Ca-blockers used (dihydropyridine-only, nondihydropyridine-only, long-acting, and short- or intermediate-acting)  (Lancet 356:1949, 2000--JW)
    2. In ALLHAT Study (see above):
      1. Amlodipine group had sig. higher 6y incidence of heart failure than chlorthalidone (10.2% vs. 7.7%; RR 1.38)
      2. Over median 5y f/u, amlodipine group had sig. lower average BPs than lisinopril group (by 1.5/1.1 mm Hg); there were no sig. diffs. in incidences of primary outcome (CAD-related death or nonfatal MI), all-cause mortality, major CAD events, Ca, or end-stage renal disease, but amlodipine had sig. lower incidence of CVA (5.4% vs. 6.3%), cardiovascular events (32.0% vs. 33.3%), or peripheral arterial disease (4.7% vs. 3.7%); lisinopril group had sig. lower incidence of hospitalization for heart failure (6.9% vs. 8.4%) (Hypertension 48:374, 2006--JW)
    3. 6,321 pts 55-80yo with HTN and at least 1 additional CV risk factor randomized to nifedipine XL 30mg/d vs. HCTZ/amiloride 25/2.5 QD. No sig. diff. at 4y f/u in BP reduction, incidence of primary endpoint (CV death, MI, CHF, or CVA) or total mortality (Nifedipine GITS Study: Intervention as a Goal in Hypertension Treatment ("INSIGHT")--Lancet 356:366, 2000--JW)
    4. 16,602 pts with HTN and 1 or more additional risk factors for cardiovascular disease randomized to controlled-release verapamil (Covera-HS) 180mg/d vs. atenolol 50mg/d or hydrochlorothiazide 12.5mg/d (choice between the two at discretion of treating physician.  After mean 3y f/u, incidence of (first CVA, MI, or CV-related death) and all-cause mortality were not sig. diff. between verapamil and atenolol/HCTZ groups ("CONVINCE" trial, JAMA 289:2073, 2003--abst) 
    5. 6614 pts 70-84yo with HTN (BP > 180/105) randomized to "conventional treatment" (diuretics or beta-blockers), Ca-blockers (felodipine or isradipine), or ACEIs (enalapril or lisinopril).  Over 4-6y f/u, no sig. diff. in BP decrease, CV mortality, or (fatal or nonfatal CV events).  However, CHF incidence was lower in ACEI group than Ca-channel blocker group (Swedish Trial in Old Patients with Hypertension-2 ("STOP-2")--Lancet 354:1751, 1999--abst)
    6. In the "network" analysis cited at the start of this section, diuretics were ass'd with sig. lower risk for CV events (RR 0.94) and CHF incidence (RR 0.74)
    7. In an observational study of 15,787 hypertensive postmenopausal women without other cardiovascular disease who were tx'd with diuretics, ACEIs, beta-blockers, and/or Ca-blockers, over mean 6y f/u, incidence of cardiovascular death was sig. greater in Ca-blocker monotherapy recipitents than diuretic monotherapy recipients (HR 1.55); no sig. diff. between beta-blockers or ACEIs and diuretics (JAMA 292:2849, 2004--JW)
  1. Diuretics vs. Alpha-blockers-Diuretics better
    1. 24,335 pts > 55yo with HTN and at least 1 other cardiac risk factor randomized to doxazosin 2-8mg/d vs. chlorthalidone 12.5-25mg/d. At median 3.3y f/u, doxazosin group had RR 1.09 for CHD events, RR 1.19 for CVA, RR 2.04 for CHF, and RR 1.25 for all CV events (all sig.); not limited to any one subgroup of pts; the endpoints of (coronary death or nonfatal MI) and total mortality were not sig. different in the two groups ("ALLHAT" (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack) study; JAMA 283: 1967, 2000--JW)
    2. In the "network" analysis cited at the start of this section, diuretics were ass'd with sig. lower risk for CHF (RR 0.51) and CV events (RR 0.84)
  1. Diuretics vs. Beta-Blockers-Diuretics better
    1. In the "network" analysis cited at the start of this section, diuretics were ass'd with sig. lower risk for CV events (RR 0.89)
    2. Higher rates of BP control on monotherapy and greater reduction of mortality in a meta-analysis of 10 trials in pts > 60yo; JAMA 79:1903, 1998--JW
  1. ACE Inhibitors vs. Diuretics-Mixed data--Diuretics possibly better in African-Americans, ACEIs possibly better in men (advantage may be limited to white men)
    1. In ALLHAT, lisinopril group had sig. higher 6y incidence of combined CV events (33.3% vs. 30.9%, RR 1.10), CVA (6.3% vs. 5.6%, RR 1.15), and heart failure (8.7% vs. 7.7%, RR 1.19) than chlorthalidone.  These differences were maintained in analysis of various subgroups including diabetics, except that the differences between lisinopril and chlorthalidone in incidence of combined CV events and CVA were limited to African-American patients.
    2. In the "network" analysis cited at the start of this section, diuretics were ass'd with sig. lower risk for CHF incidence (RR 0.88), CV events (RR 0.94), and CVA (RR 0.86)
    3. 6083 pts 65-84yo mostly white pts with HTN (SBP > 160mm Hg or (SBP > 140 and DBP > 90) randomized to ACEIs vs. diuretics as first-line therapy.  87% had no prior h/o coronary or cerebrovascular disease; only 7% had DM.  Those on antihypertensive meds at randomization were taken off, and choice of initial med, within the assigned med class, was up to treating physician, though enalapril and hydrochlorothiazide, respectively, were recommended.  Other categories of meds could be added as needed.  At the end of the study roughly 60% of each group were still receiving assigned tx.  Tx was open-label but determination of endpoints was blinded.  Over median 4.1y f/u, incidence of primary endpoint (incidence of cardiovascular events or death) was sig. lower in ACEI group (HR 0.89); this effect was limited to male patients (HR 0.83 for males; 1.00 for females).  HR for all-cause mortality was 0.90 (nonsig.) in ACEI group.  BP reduction was not sig. diff. between the two groups at any time point. ("Second Australian National Blood Pressure Study Group"--NEJM 348:583, 2003--JW)
    4. 10,985 pts w/HTN (11% had DM) randomized to captopril or "conventional tx" (diuretics and/or beta-blockers); Over 6y f/u, no sig. diff. in BP reduction but captopril group had sig. lower all-cause mortality (RR 0.54), incidence of (combined MI, CVA, or cardiovascular death) (RR 0.59), and MI (RR 0.34). Has been criticized b/c of unbalanced randomization and post-hoc subgroup analyses (Captopril Prevention Project ("CAPPP")--Lancet 353:611, 1999)
  1. ACE Inhibitor + Calcium channel blocker vs. Diuretic + Beta-Blocker-ACEI/Ca-blocker better
    1. In a study in 19,257 pts with HTN (baseline BP > 160/100 if untreated or > 140/90 if treated) and no CAD but at least 3 other CAD risk factors (mean age 63yo, 77% male) randomized to (amlodipine 5-10mg/d + perindopril 4-8mg/d) vs. (atenolol 50-100mg/d + bendroflumethiazide 1.25-2.5mg/d), after mean 5.5y the study was halted because of a sig. lower incidence (7.8% vs. 8.9%) of all-cause mortality in the amlodipine-perindopril group, which also had sig. lower incidence of new-onset DM (RR 0.68) and cardiovascular mortality (RR 0.76) (Anglo-Scandinavian Cardiac Outcomes Trial Blood Pressure-Lowering Arm; "ASCOT-BLPA," Lancet 366:895, 2005--JW).
  1. Studies showing little or no difference among agents
    1. 10,881 pts 50-74yo w/HTN randomized to diltiazem, diuretics, beta-blockers, or diuretics + beta-blockers; no sig. diff. in BP reduction, CV events, or all-cause mortality; sig. less CVA in diltiazem group, but many comparisons were made (Nordic Diltiazem ("NORDIL") study--Lancet 356:359, 2000--JW)
    2. In a meta-analysis of 147 randomized studies involving over 464,000 pts (not all of whom had HTN), there was no sig. diff. in coronary events among (thiazides, beta-blockers, ACE inhibnitors, ARBs, and Ca-blockers) (BMJ 338:b1665, 2009-JW)
  1. Studies comparing efficacy at reaching target BP with different antihypertensives:
    1. In a systematic review of 9 randomized trials involving 27,743 pts comparing Ca-blockers with either diuretics, beta-blockers, ACEIs, or clonidine, there was no sig. diff. in control of BP (Lancet 356:1949, 2000--JW; see also above re: different data from same study)
  1. Renal Nerve Ablation for hypertension
    1. Hypertension is often associated with increased renal sympathetic activity
    2. Procedure involves catheter-delivered radiofrequency energy applied to sympathetic nerves in adventitia of the renal arteries to achieve bilateral sympathetic denervation 
    3. Associated with significant reductions in blood pressure in one uncontrolled trial in pts with persistent hypertension despite use of multiple antihypertensive medications (Lancet 373:1275, 2009-JW)
    4. In a study in 64 pts with primary hypertension in-office SBP > 159mm Hg (or > 149mm Hg if diabetic) on three antihypertensive drugs assigned to RSD procedure vs. control group.  The RSD recipients had sig. reduced SBP and DBP at 1mo and 6mos (mean reduction 28mm Hg and 9 mm Hg, respectively, at 6mos). and also had sig. reductions in mean interventricular septal thickness. mean ejection fraction, and diastolic function at 6 months. (J Am Coll Cardiol 9:901, 2012-JW)
  2. Treatment of "Resistant" Hypertension
    1. Definition: BP above target in a pt on 3 drugs at maximal or near-maximal doses, with at least 1 diuretic
    2. Common causes:
      1. "Pseudoresistance"--white coat HTN, wrong size cuff, pseudohypertension due to stiff arteries
      2. Noncompliance
      3. Volume overload (high Na consumption, chronic renal failure, inadequate diuresis)
      4. Drugs which increase BP (see above)
      5. Obesity
      6. Sleep apnea
      7. Chronic pain
      8. Arteritis
  1. "Hypertensive emergencies"
    1. "Elevated BP alone, in the absence of symptoms or new or progressive target organ damage, rarely requires emergency therapy" (JNV VI)
    2. Treatment:
      1. IV meds: nitroprusside, NTG, enalaprilat, hydralazine, esmolol, labetolol, nicardipine)
      2. Oral/SL meds not recc'd for tx of hypertensive emergencies
      3. Try to lower by no more than 25% over the first couple of hours
      4. Then shoot for 160/100 within 2-6h of tx
      5. Precipitous falls may be harmful, e.g. trigger ischemic CVA
    3. Examples of true hypertensive emergencies:
      1. Hypertensive encephalopathy
      2. Intracranial hemorrhage
      3. Unstable angina or acute MI
      4. Acute LV failure with pulmonary edema
      5. Dissecting aortic aneurysm
      6. Eclampsia
    4. Less urgent situations, in which PO meds can be used:
      1. Upper levels of stage 3 HTN
      2. HTN with papilledema but not frank encephalopathy
      3. Severe perioperative HTN