Hypertension

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Hypertension is a multisystem disease whose hallmark is the elevation of blood pressure. Primary hypertension has no apparent cause, constitutes the majority of cases, and is treated with measures to reduce blood pressure. Secondary hypertension does have an abnormality that is causing the elevation in blood pressure, such as a tumor that secretes hormones that raise blood pressure; removing the cause may be curative. Primary hypertension is generally not curable and needs to be managed as a chronic disease.

Classification

Classification of blood pressure for adults[1]
Blood pressure classification Initial blood pressure mm Hg Followup recommended
SBP DBP
Normal <120 and <80 Recheck in 2 years
Prehypertension 120-139 or 80-99 Recheck in 1 year
Stage 1 Hypertension 140-159 or 90-99 Confirm within 2 months
Stage 2 Hypertension ≥ 160 or ≥100 "Evaluate or refer to source of care within 1 month. For those with higher pressures (e.g., >180/110 mmHg), evaluate and treat immediately or within 1 week depending on clinical situation and complications... 2 drug combination for most."
Hypertensive urgency ≥ ~ 180 or ≥ ~ 120
("without acute target-organ damage"[1])		 "usually do not require hospitalization, but they should receive immediate combination oral antihypertensive therapy"[1]
Hypertensive emergency ≥ ~ 180 or ≥ ~ 120
(with "acute target-organ damage"[1])		 "require hospitalization and parenteral drug therapy"[1]

Diagnosis

A systematic review by the Rational Clinical Examination has reviewed the research on blood pressure determination.[2]

Ambulatory blood pressure monitoring

Clinical practice guidelines by National Institute for Health and Care Excellence (NICE) recommend routine use of ambulatory monitoring for patients newly found to have high blood pressure readings in clinic.[3][4] This approach may reduce the cost of care.[5]

Ambulatory may better predict future complications than monitoring the office blood pressure.[6]

Regarding whether the ambulatory pressure should guide treatment, the office pressure may be better.[7]

A randomized controlled trial of comparing ambulatory versus office monitoring was announced but never completed.[8]

Confirmation

If the diastolic pressure is below 110 mm Hg, it should be confirmed on two addition visits as some patients will have a lower blood pressure on repeat measurements.[9] A larger cuff should be used for obese patients.[10]

White coat hypertension

For more information, see: White coat hypertension.

White coat hypertension is a temporary increase in the blood pressure caused by being examined by a medical professional in a clinical environment. If the only measurements being taken are in medical offices, white coat hypertension may cause the appearance of sustained hypertension.[11]

White coast hypertension may not be as important to treat.[12]

Pseudohypertension

Elderly patients may have pseudohypertension due to inability of the blood pressure cuff to compress stiff arteries.[13] Pseudohypertension may be detected by Osler's maneuver.[13]

Excluding secondary hypertension

Causes of secondary hypertension[14]
Cause Prevalence or effect
Oral contraceptives 1%
Alcohol 6-7 drinks/day may increase BP by 5 mm Hg[15]
Renal artery stenosis < 1%
Hyperaldosteronism ?
Pheochromocytoma ?
Coarctation of the aorta ?

Since secondary hypertension may be curable, ruling it out is essential. A starting point is listening for an abdominal bruit, especially if it is both systolic and diastolic, may help detect underlying renal artery stenosis.[16]

Among patients with resistant hypertension (blood pressure >140/90 mm Hg despite a three drug regimen, 20% of patients had serum aldosterone and plasma renin activity ratio of more than 65:16 with a aldosterone concentration above 416 pmol/L. However, only 10% of all patients had primary aldosteronism. Half of these patients have a normal serum potassium.[17]

Treatment

Current clinical practice guidelines are:

  • 2001 guidelines by National Institute for Health and Clinical Excellence[3]
  • 2003 guidelines by the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7)[1]
  • 2007 guidelines by the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC).[18]

In addition, drugs for hypertension (antihypertensives) have been reviewed by the Medical Letter.[19]

A systematic review by the Cochrane Collaboration has summarized the benefits of treatment.[20]

Several randomized controlled trials have shown that treating hypertension can reduce morbidity or mortality. These trials include:

  • MRC trial[21]
  • Hypertension Detection and Follow-up Program[22]
  • Treatment of Mild Hypertension Study (TOMHS) [23]
  • Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).[24]
  • Veterans Affairs Cooperative trial[25][26]
  • Losartan Intervention For Endpoint reduction in hypertension study (LIFE)[27]

Treatment goals

Per the JNC7 Guidelines:[1]

  • "Treating "most patients" SBP and DBP to targets that are <140/90 mmHg is associated with a decrease in cardiovascular complications.
  • In patients with hypertension and diabetes or chronic kidney disease, the BP goal is <130/80 mmHg.

The European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC) 2007 guidelines add to diabetes and chronic kidney disease that tight control (<130/80 mmHg) is needed for patients with:[18]

Mild hypertension may not warrant treatment. "Antihypertensive drugs used in the treatment of adults (primary prevention) with mild hypertension (systolic BP 140-159 mmHg and/or diastolic BP 90-99 mmHg) have not been shown to reduce mortality or morbidity in RCTs" according to a meta-analysis by the Cochrane Collaboration. [28] In a meta-analysis of randomized controlled trials of patients with mild hypertension, the relative risk ratio of pharmacotherapy, as compared to placebo, for mortality was 0.85 and the relative risk reduction was 15.0%. This finding did not reach statistical significance[28] Similarly, intensive blood-pressure control ("a mean arterial pressure of 92 is lower than the traditional blood-pressure target of 130/80 mm Hg") had no effect on progression of chronic kidney disease according to a randomized controlled trial. [29]

Recent trials present alternative evidence:

  • An industry-sponsored, unblinded randomized controlled trial suggests benefit from treating any patient with a cardiac risk to a goal systolic pressure of 130 mm Hg.[30] The HOPE trial reported similar results.[31] Although 39% of HOPE patients had diabetes, the benefit occurred in patients with and without diabetes.

J-curve

Overly aggressive treatment of hypertension may be harmful due to the "j-curve" effect.[32][33] It is not clear if this is due to excessive reduction in systolic pressure[34] or low diastolic pressure after treatment[33] or due to general bad health rather than treatment[35].

According to the HOT randomized controlled trial, the nadir of the j-curve must be below 80 mm Hg.[36]

Non-drug treatment

Initial medication

Clinical practice guidelines have tried to make blanket recommendations for all patients:

  • "Thiazide-type diuretics for most" patients are recommended by the JNC7 clinical practice guidelines.[1] Chlorthalidone may be the best choice based on the Multiple Risk Factor Intervention Trial[37] and other studies.[38][39][40] In the MRFIT trial, the clinics that predominantly used chlorthalidone reported lower mortality than the clinics using hydrochlorothiazide (5% versus 7%).
  • "First-line low-dose thiazides reduce all morbidity and mortality outcomes. First-line ACE inhibitors and calcium channel blockers may be similarly effective but the evidence is less robust. First-line high-dose thiazides and first-line beta-blockers are inferior to first-line low-dose thiazides" according to the Cochrane Collaboration.[41]
  • ß-blockers
    • ß-blockers are the preferred initial medication for patients with coronary heart disease according to a systematic review.[42]
    • "ß-blockers, especially in combination with a thiazide diuretic, should not be used in patients with the metabolic syndrome or at high risk of incident diabetes" is noted by the European ESH/ESC clinical practice guidelines.[18] The ESH/ESC guidelines cite the LIFE[27] and ASCOT[43] trials. Unlike the ALLHAT study[44], both of these trials were in largely anglo populations, supported by industry, and at the same institution. All patients in the LIFE trial had left ventricular hypertrophy (LVH). Based on these two trials, a meta-analysis has concluded that beta blockers should not be the first choice treatment.[45]
  • For Stage 2 Hypertension (SBP ≥ 160 or DBP≥100) consider starting two medications for more effect.[46][1]

Refinements in selection

Selected trials comparing initial medications
Trial Patients Intervention Result
Race BMI Age
(mean)
ALLHAT[24]
2002		 47% anglo 30 70 Chlorthalidone Diuretics (chlorthalidone) better than calcium channel blockers and angiotensin-converting enzyme inhibitors
ANBP2[47]
2003		 95% anglo 27 72 Hydrochlorothiazide Diuretics (hydrochlorothiazide) not as good angiotensin-converting enzyme inhibitors
ACCOMPLISH[48]
2008		 84% anglo 31 68 Hydrochlorothiazide Diuretics (hydrochlorothiazide) not as good as calcium channel blockers

Several randomized controlled trials have compared initial medications for hypertension. As summarized in the table, the disparate results may be due to racial and gender differences in responses to medications.[24][47][49][25][48]

Should renin levels guide decisions?
Predicting response to anti-hypertensives based on demographics
Category name demographics Comments Best anti-hypertensive categories
High renin demographic less than 50 years old, anglo salt-sensitive; diuretic responsive diuretics, calcium channel blockers
Low renin demographic more than 50 years old, non-anglo* ace-inhibitors, ß-blockers
* Obesity and female[50] are also associated with low renin.

Some authors have proposed that either the renin level or the renin level indexed to urinary sodium excretion in 24 hours.[51][52]

Efficacy of different drugs. From Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents.[25]

However, the Veterans Affairs Cooperative trial suggests the initial drug may be better selected based on the patient's age, race, and gender.[25][26] The patient's demographic roughly corresponds with their renin profile, but is more predictive than the renin profile.[26] The molecular basis is being determined.[53] In the Veterans Affairs Cooperative, among the high renin demographic (young whites), diuretics had similar efficacy to placebo; whereas in the low renin demographic (older blacks), the ace-inhibitors had similar efficacy to placebo in the Veterans Affairs Cooperative Study Group on Antihypertensive Agents (see figure).[25] Similarly, a meta-analysis has concluded that beta-blockers are a good first choice for younger patients, but not for older patients.[54]

More recently, plasma renin activity was found to predict response to adrenergic beta-antagonists versus diuretics better than using demographic predictors.[55]

Race, gender, and age demographic may partly predict frequency of drug toxicity to different anti-hypertensive medications.[56]

Contraindications

There are contraindications to each of the four major classes, even when other indicators suggest a particular class might be best for the hypertensive patients:

Comorbidities

Given that the antihypertensive is likely to be a lifelong treatment, selection also may be guided by other chronic diseases of the patient.

Labile hypertension

While labile hypertension may be due to a pheochromocytoma, it may be due to baroreflex failure. This can be treated with clonidine 0.3 to 2.4 mg orally total per day.[57]

Resistant hypertension

Blood pressure may be difficult to treat, especially in older patients.[58][59] A third of cases may be due to white coat hypertension.[60] Clinical practice guidelines from the American Heart Association (AHA) address the management of resistant hypertension.[61]

Physiology

Resistant hypertension is characterized by volume expansion and abnormalities of the renin-angiotensin system with high aldosterone and cortisol with low renin levels in the plasma[62][63] in spite of many patients taking thiazide diuretics.[63]{ This suggests that high corticotropin may contribute[63], in some cases due to an abnormal cytochrome P-450 3A5 allele that may reduce metabolism of cortisol and corticosterone (a precursor of aldosterone).[64] Resistant hypertension is also associated with insulin resistance.[65]

Evaluation

The AHA defines resistant hypertension as "blood pressure that remains above goal in spite of the concurrent use of 3 antihypertensive agents of different classes."

First, 'pseudoresistance' should be considered:[61]

  • Medication noncompliance
  • Inadequate prescribing by the health care provider[66] may be the most common cause of persistent hypertension.[67][68]
  • White coat hypertension, pseudohypertension and other problems of measurement.[69]

Next, secondary hypertension should be considered:[61]

Treatment

A low sodium (50 mmol or 1150 mg of sodium) diet may help.[71]

The AHA recommends that one of the three medicines use for hypertension should be a diuretic.[61]

"Three drugs at half standard dose in combination" may be better than one drug at standard dose according to a systematic review.[42]

In an unblinded, uncontrolled extension of the ASCOT randomized controlled trial, spironolactone 25-50 mg per day as a fourth medication reduced the blood pressure by 21.9/9.5. This result was not affected by whether one of the first three medications included a diuretic.[72] A second study study, also uncontrolled, corroborated the role of spironolactone.[73] In this study, 54% of patients were African-American, 45% had primary hyperaldosteronism.

Catheter-based renal sympathetic denervation has been studied for resistant hypertension.[74]

Hypertensive emergency

Treatment must be from a critical care perspective. While the blood pressure must be lowered quickly to avoid end-stage organ failure or crises such as cerebral hemorrhage, lowering it too quickly may create a different end-stage organ failure through decreased perfusion. "Treat the patient, not the number".

Systolic hypertension

For more information, see: Systolic hypertension.


Diabetes

Randomized controlled trials of treating hypertension in patients with diabetes mellitus type 2[75][76]
Trial Population Intervention Comparison Outcome Comments
ACCORD[75]
2010		 4,733 patients Systolic pressure goal of less than 120 mm Hg for 4.7 years Systolic pressure goal of less than 140 mm Hg Mortality Insignificantly increased
ADVANCE[76]
2007		 11,140 patients Fixed combination of perindopril and indapamide that achieved blood pressure of 136/73 for 4.3 years Achieved blood pressure of 130/73 Mortality Significantly reduced

Geriatrics

Treatment of hypertension in the geriatrics is effective.[20]

However, treatment of patients over age 80 is not clear.[20][34] A randomized controlled trial included in this meta-analysis found that treating patients aged 80 years or older for two years who have a systolic pressure over 160 mm hg (the average entry pressure was 173/91 mm Hg) and treating to 150/80 mm Hg reduced morbidity.[77] In this trial, the average seated blood pressure at the end of the study in the treatment group was 143/78.

The Cochrane Collaboration has also performed a meta-analysis of this topic and concluded "treating healthy persons (60 years or older) with moderate to severe systolic and/or diastolic hypertension reduces all cause mortality and cardiovascular morbidity and mortality. The decrease in all cause mortality was limited to persons 60 to 80 years of age."[20]

Prognosis

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 Chobanian AV, Bakris GL, Black HR, et al (2003). "The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report". JAMA 289 (19): 2560-72. DOI:10.1001/jama.289.19.2560. PMID 12748199. Research Blogging. http://www.nhlbi.nih.gov/guidelines/hypertension/jnc7full.pdf
  2. ↑ Reeves RA (1995). "The rational clinical examination. Does this patient have hypertension? How to measure blood pressure". JAMA 273 (15): 1211–8. PMID 7707630. [e]
  3. ↑ 3.0 3.1 Krause T, Lovibond K, Caulfield M, McCormack T, Williams B, Guideline Development Group (2011). "Management of hypertension: summary of NICE guidance.". BMJ 343: d4891. DOI:10.1136/bmj.d4891. PMID 21868454. Research Blogging.
  4. ↑ National Institute for Health and Care Excellence CG127 Hypertension. 2011
  5. ↑ Lovibond K, Jowett S, Barton P, Caulfield M, Heneghan C, Hobbs FD et al. (2011). "Cost-effectiveness of options for the diagnosis of high blood pressure in primary care: a modelling study.". Lancet 378 (9798): 1219-30. DOI:10.1016/S0140-6736(11)61184-7. PMID 21868086. Research Blogging.
  6. ↑ Staessen JA, Thijs L, Fagard R, O'Brien ET, Clement D, de Leeuw PW et al. (1999). "Predicting cardiovascular risk using conventional vs ambulatory blood pressure in older patients with systolic hypertension. Systolic Hypertension in Europe Trial Investigators.". JAMA 282 (6): 539-46. PMID 10450715. [e]
  7. ↑ Staessen JA, Den Hond E, Celis H, Fagard R, Keary L, Vandenhoven G et al. (2004). "Antihypertensive treatment based on blood pressure measurement at home or in the physician's office: a randomized controlled trial.". JAMA 291 (8): 955-64. DOI:10.1001/jama.291.8.955. PMID 14982911. Research Blogging. Review in: Evid Based Nurs. 2004 Jul;7(3):80
  8. ↑ Clement DL (1990). "Office versus ambulatory recordings of blood pressure (OvA): a European multicenter study. The Steering Committee.". J Hypertens Suppl 8 (6): S39-41. PMID 2150533. [e]
  9. ↑ Hartley RM, Velez R, Morris RW, D'Souza MF, Heller RF (1983). "Confirming the diagnosis of mild hypertension". Br Med J (Clin Res Ed) 286 (6361): 287–9. PMID 6402075. [e] PubMed Central
  10. ↑ Nielsen PE, Larsen B, Holstein P, Poulsen HL (1983). "Accuracy of auscultatory blood pressure measurements in hypertensive and obese subjects". Hypertension 5 (1): 122–7. PMID 6848459. [e]
  11. ↑ Mancia G, Bombelli M, Facchetti R, Madotto F, Quarti-Trevano F, Polo Friz H et al. (2009). "Long-term risk of sustained hypertension in white-coat or masked hypertension.". Hypertension 54 (2): 226-32. DOI:10.1161/HYPERTENSIONAHA.109.129882. PMID 19564548. Research Blogging.
  12. ↑ Fagard RH, Staessen JA, Thijs L, Gasowski J, Bulpitt CJ, Clement D et al. (2000). "Response to antihypertensive therapy in older patients with sustained and nonsustained systolic hypertension. Systolic Hypertension in Europe (Syst-Eur) Trial Investigators.". Circulation 102 (10): 1139-44. PMID 10973843. [e]
  13. ↑ 13.0 13.1 Messerli FH, Ventura HO, Amodeo C (1985). "Osler's maneuver and pseudohypertension". N. Engl. J. Med. 312 (24): 1548–51. PMID 4000185. [e]
  14. ↑ Lewin A, Blaufox MD, Castle H, Entwisle G, Langford H (1985). "Apparent prevalence of curable hypertension in the Hypertension Detection and Follow-up Program.". Arch Intern Med 145 (3): 424-7. PMID 3872106. [e]
  15. ↑ Parker M, Puddey IB, Beilin LJ, Vandongen R (1990). "Two-way factorial study of alcohol and salt restriction in treated hypertensive men.". Hypertension 16 (4): 398-406. PMID 2210807. [e]
  16. ↑ Turnbull JM (1995). "The rational clinical examination. Is listening for abdominal bruits useful in the evaluation of hypertension?". JAMA 274 (16): 1299–301. PMID 7563536. [e]
  17. ↑ 17.0 17.1 Douma S, Petidis K, Doumas M, et al (June 2008). "Prevalence of primary hyperaldosteronism in resistant hypertension: a retrospective observational study". Lancet 371 (9628): 1921–6. DOI:10.1016/S0140-6736(08)60834-X. PMID 18539224. Research Blogging.
  18. ↑ 18.0 18.1 18.2 Mancia G, De Backer G, Dominiczak A, et al (June 2007). "2007 Guidelines for the management of arterial hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC)". Eur. Heart J. 28 (12): 1462–536. DOI:10.1093/eurheartj/ehm236. PMID 17562668. Research Blogging.
  19. ↑ (June 2005) "Drugs for hypertension". Treat Guidel Med Lett 3 (34): 39–48. PMID 15912125. [e]
  20. ↑ 20.0 20.1 20.2 20.3 Musini VM, Tejani AM, Bassett K, Wright JM (2009). "Pharmacotherapy for hypertension in the elderly.". Cochrane Database Syst Rev (4): CD000028. DOI:10.1002/14651858.CD000028.pub2. PMID 19821263. Research Blogging.
  21. ↑ (July 1985) "MRC trial of treatment of mild hypertension: principal results. Medical Research Council Working Party". British medical journal (Clinical research ed.) 291 (6488): 97–104. PMID 2861880. PMC 1416260. [e]
  22. ↑ (January 1997) "Five-year findings of the hypertension detection and follow-up program. I. Reduction in mortality of persons with high blood pressure, including mild hypertension. Hypertension Detection and Follow-up Program Cooperative Group. 1979". JAMA : the journal of the American Medical Association 277 (2): 157–66. PMID 8990344. [e]
  23. ↑ Neaton JD, Grimm RH, Prineas RJ, et al (August 1993). "Treatment of Mild Hypertension Study. Final results. Treatment of Mild Hypertension Study Research Group". JAMA : the journal of the American Medical Association 270 (6): 713–24. PMID 8336373. [e]
  24. ↑ 24.0 24.1 24.2 The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group (December 2002). "Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)". JAMA : the journal of the American Medical Association 288 (23): 2981–97. PMID 12479763. [e]
  25. ↑ 25.0 25.1 25.2 25.3 25.4 Materson BJ, Reda DJ (1994). "Correction: single-drug therapy for hypertension in men". N. Engl. J. Med. 330 (23): 1689. PMID 8177286. [e]
  26. ↑ 26.0 26.1 26.2 Preston RA, Materson BJ, Reda DJ, et al (1998). "Age-race subgroup compared with renin profile as predictors of blood pressure response to antihypertensive therapy. Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents". JAMA 280 (13): 1168–72. PMID 9777817. [e]
  27. ↑ 27.0 27.1 Dahlöf B, Devereux RB, Kjeldsen SE, et al (March 2002). "Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol". Lancet 359 (9311): 995–1003. DOI:10.1016/S0140-6736(02)08089-3. PMID 11937178. Research Blogging.
  28. ↑ 28.0 28.1 Diao D, Wright JM, Cundiff DK, Gueyffier F (2012). "Pharmacotherapy for mild hypertension.". Cochrane Database Syst Rev 8: CD006742. DOI:10.1002/14651858.CD006742.pub2. PMID 22895954. Research Blogging. Review in: Ann Intern Med. 2012 Dec 18;157(12):JC6-6
  29. ↑ Appel LJ, Wright JT, Greene T, Agodoa LY, Astor BC, Bakris GL et al. (2010). "Intensive blood-pressure control in hypertensive chronic kidney disease.". N Engl J Med 363 (10): 918-29. DOI:10.1056/NEJMoa0910975. PMID 20818902. Research Blogging.
  30. ↑ Verdecchia, Paolo; Jan A Staessen, Fabio Angeli, Giovanni de Simone, Augusto Achilli, Antonello Ganau, Gianfrancesco Mureddu, Sergio Pede, Aldo P Maggioni, Donata Lucci, Gianpaolo Reboldi (2009-08-15). "Usual versus tight control of systolic blood pressure in non-diabetic patients with hypertension (Cardio-Sis): an open-label randomised trial". The Lancet 374 (9689): 525-533. DOI:10.1016/S0140-6736(09)61340-4. ISSN 0140-6736. Retrieved on 2009-08-14. Research Blogging.
  31. ↑ Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G (January 2000). "Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators". N. Engl. J. Med. 342 (3): 145–53. PMID 10639539. [e]
  32. ↑ Messerli FH, Panjrath GS (2009). "The J-curve between blood pressure and coronary artery disease or essential hypertension: exactly how essential?". J Am Coll Cardiol 54 (20): 1827-34. DOI:10.1016/j.jacc.2009.05.073. PMID 19892233. Research Blogging.
  33. ↑ 33.0 33.1 Farnett L, Mulrow CD, Linn WD, Lucey CR, Tuley MR (1991). "The J-curve phenomenon and the treatment of hypertension. Is there a point beyond which pressure reduction is dangerous?". JAMA 265 (4): 489-95. DOI:10.1001/jama.1991.03460040065031. PMID 1824642. Research Blogging.
  34. ↑ 34.0 34.1 Bejan-Angoulvant T, Saadatian-Elahi M, Wright JM, Schron EB, Lindholm LH, Fagard R et al. (2010). "Treatment of hypertension in patients 80 years and older: the lower the better? A meta-analysis of randomized controlled trials.". J Hypertens 28 (7): 1366-72. DOI:10.1097/HJH.0b013e328339f9c5. PMID 20574244. Research Blogging.
  35. ↑ Boutitie F, Gueyffier F, Pocock S, Fagard R, Boissel JP, INDANA Project Steering Committee. INdividual Data ANalysis of Antihypertensive intervention (2002). "J-shaped relationship between blood pressure and mortality in hypertensive patients: new insights from a meta-analysis of individual-patient data.". Ann Intern Med 136 (6): 438-48. PMID 11900496. [e]
  36. ↑ Hansson L, Zanchetti A, Carruthers SG, Dahlöf B, Elmfeldt D, Julius S et al. (1998). "Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group.". Lancet 351 (9118): 1755-62. PMID 9635947. [e]
  37. ↑ (November 1990) "Mortality after 10 1/2 years for hypertensive participants in the Multiple Risk Factor Intervention Trial". Circulation 82 (5): 1616–28. PMID 2225366. [e]
  38. ↑ Ernst ME, Carter BL, Goerdt CJ, et al (March 2006). "Comparative antihypertensive effects of hydrochlorothiazide and chlorthalidone on ambulatory and office blood pressure". Hypertension 47 (3): 352–8. DOI:10.1161/01.HYP.0000203309.07140.d3. PMID 16432050. Research Blogging.
  39. ↑ Carter BL, Ernst ME, Cohen JD (January 2004). "Hydrochlorothiazide versus chlorthalidone: evidence supporting their interchangeability". Hypertension 43 (1): 4–9. DOI:10.1161/01.HYP.0000103632.19915.0E. PMID 14638621. Research Blogging.
  40. ↑ (January 2009) "Drugs for hypertension". Treat Guidel Med Lett 7 (77): 1–10. PMID 19107095. [e]
  41. ↑ Wright JM, Musini VM. (2009) First-line drugs for hypertension. Cochrane Database Syst Rev. 2009 Jul 8;(3):CD001841. PMID 19588327
  42. ↑ 42.0 42.1 Law MR, Morris JK, Wald NJ (2009). "Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies". BMJ 338: b1665. PMID 19454737. PMC 2684577. [e]
  43. ↑ Dahlöf B, Sever PS, Poulter NR, et al (2005). "Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial". Lancet 366 (9489): 895–906. DOI:10.1016/S0140-6736(05)67185-1. PMID 16154016. Research Blogging.
  44. ↑ Appel LJ (December 2002). "The verdict from ALLHAT--thiazide diuretics are the preferred initial therapy for hypertension". JAMA 288 (23): 3039–42. PMID 12479770. [e]
  45. ↑ Lindholm LH, Carlberg B, Samuelsson O (2005). "Should beta blockers remain first choice in the treatment of primary hypertension? A meta-analysis". Lancet 366 (9496): 1545–53. DOI:10.1016/S0140-6736(05)67573-3. PMID 16257341. Research Blogging. ACP Journal Club review
  46. ↑ Wald DS, Law M, Morris JK, Bestwick JP, Wald NJ (March 2009). "Combination therapy versus monotherapy in reducing blood pressure: meta-analysis on 11,000 participants from 42 trials". Am. J. Med. 122 (3): 290–300. DOI:10.1016/j.amjmed.2008.09.038. PMID 19272490. Research Blogging.
  47. ↑ 47.0 47.1 Wing LM, Reid CM, Ryan P, et al (2003). "A comparison of outcomes with angiotensin-converting--enzyme inhibitors and diuretics for hypertension in the elderly". N. Engl. J. Med. 348 (7): 583-92. DOI:10.1056/NEJMoa021716. PMID 12584366. Research Blogging.
  48. ↑ 48.0 48.1 Jamerson K, Weber MA, Bakris GL, et al (December 2008). "Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients". N. Engl. J. Med. 359 (23): 2417–28. DOI:10.1056/NEJMoa0806182. PMID 19052124. Research Blogging.
  49. ↑ Materson BJ, Reda DJ, Cushman WC, et al (1993). "Single-drug therapy for hypertension in men. A comparison of six antihypertensive agents with placebo. The Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents". N. Engl. J. Med. 328 (13): 914-21. PMID 8446138. [e]
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  77. ↑ Beckett, N. S., Peters, R., Fletcher, A. E., Staessen, J. A., Liu, L., Dumitrascu, D., et al. (2008). Treatment of Hypertension in Patients 80 Years of Age or Older. N Engl J Med, NEJMoa0801369. DOI:10.1056/NEJMoa0801369

See also

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