Effective control of hypertension is perhaps the most important role for physicians in stroke prevention. Smoking cessation and a Mediterranean diet may rank equally or higher in importance on a population basis,[1] but they are interventions that are carried out mostly by the people themselves. The physician is more involved in control of hypertension, and in patients with resistant hypertension, control of blood pressure is paramount. A population-based study in Sweden[2] found that 90% of strokes occurred in patients with uncontrolled hypertension. Unfortunately, blood pressure control is poor in most countries. In the United States, blood pressures of less than half of hypertensives are adequately controlled[3] despite recent improvements in many aspects of hypertension care, and control rates are closer to 30% in much of the world. In the Middle East and North Africa, approximately 60% of stroke is attributable to hypertension.[4] The proportion is probably higher in sub-Saharan Africa. Recently,[5] hypertension has been found to be the most important contributor to the worldwide burden of disease.

Although some studies show benefits of angiotensin receptor antagonists[6] or angiotensin converting enzyme inhibitors[7] compared with diuretic and β-blocker-based therapies for prevention of stroke, either of which might be preferred in patients with easily controlled hypertension, it is more important to achieve blood pressure control than to be overly concerned with the class of antihypertensive agent used.

Conversely, comorbidities in hypertensive patients such as diabetes and kidney disease need to be taken into account when choosing drugs for antihypertensive therapy.

Special considerations

  1. Top of page
  2. Abstract
  3. Special considerations
  4. Management of resistant hypertension
  5. Summary and conclusions
  6. References

It is safe to lower blood pressure in the elderly and in patients with carotid stenosis,[8] and until randomized trials show that it is safe to withhold treatment in patients with white coat hypertension, it is also probably prudent to treat patients with elevated office pressures.[9]

Management of resistant hypertension

  1. Top of page
  2. Abstract
  3. Special considerations
  4. Management of resistant hypertension
  5. Summary and conclusions
  6. References

There are three main reasons for resistant hypertension: noncompliance, consumption of substances that aggravate hypertension, and secondary hypertension.


Noncompliance (the term preferred by experts in the field to the politically correct adherence) may not be such a problem with antihypertensive drugs as with lipid-lowering drugs. Compliance rates appear to be around 70–80%,[10] at least in Canada, where most patients have their drug costs covered. In low- and middle-income countries the problem may be much worse. Approximately half of patients will admit to not taking their medication. One study reported that 74% of patients will miss medication on up to 3 days, and 28% take “drug holidays” of 4 days or more.[11] Maneuvers to improve compliance and blood pressure control include using single daily doses of longer-acting drugs,[12] fixed combination drugs,[13] and pharmacy programs.[14] Unfortunately, most interventions to improve compliance are of limited effectiveness in the long term.[15]

There is evidence that drugs with fewer adverse effects are associated with better persistence.[16, 17] An important issue is that the long lists of drug “side effects” often provided to patients with their medication may be an impediment to compliance, if they are simply a list of every symptom reported by persons taking that medication without regard to causality. Such lists are usually all the same, reporting such common symptoms that are equally as frequent on placebo as on active therapy: fatigue, headache, dizziness, nausea, vomiting, diarrhea, and constipation. It would be much more useful to provide information about causally related adverse effects and advise the patient that such common symptoms are likely to be due to causes other than the medication, and instead of stopping the medication, they should work with their physician to determine the cause and solve it.[18] An issue seldom given sufficient consideration is that if a patient with severe resistant hypertension is noncompliant, which may be a reason to pursue surgical or other interventional options, discussed below under secondary hypertension.

Consumption of substances that aggravate hypertension

Blood pressure control may be impaired by excess consumption of sodium, licorice, ethanol, nonsteroidal anti-inflammatory drugs (NSAIDs), decongestants, and oral contraceptives. The recommended daily intake of ethanol is around nine standard drinks per week for women or 14 for men. Licorice should be limited or avoided, because of its minerallocorticoid effect. Special considerations are required for sodium restriction and NSAIDs.

Sodium restriction

Sodium restriction improves blood pressure control[19]; despite efforts of the salt industry to confuse the issues,[20] it is clear that sodium restriction is an important part of blood pressure control to reduce stroke.[21] Nevertheless, for instance in Finland drug-treated hypertensive patients have a higher salt intake than others, even though patients with hypertension should limit their intake of salt (sodium chloride) to 2–3 grams daily. This would mean not using added salt and also avoiding salty foods: one dill pickle contains a whole days' worth of salt, and there is a surprising amount of added salt in many foods such as commercial soups, tomato juice, bread, cured meats, and many prepared meals. Salt restriction can be easier than many people think, if the following is explained to them: the use of salt is a vicious circle: added salt causes downregulation of salt taste buds on the tongue, so added salt is needed to restore the customary taste. Removing salt results in upregulation of salt receptors, so that food again tastes salty without adding salt. People can learn to use pepper, spices, herbs, ginger, garlic, green peppers, curry powder, paprika, balsamic vinegar, etc; mustard powder can be added to soups, sauces, and marinades to improve their flavor.[18]

Nonsteroidal anti-inflammatory drugs

NSAIDs increase blood pressure by causing salt and water retention. This effect is probably due to inhibition of renomedullary prostaglandins.[22] The only NSAID that does not raise blood pressure is sulindac (47), which reduces systemic vasoconstrictor prostaglandins such as thromboxane, but does not reduce levels of renally produced prostacycline. That finding, reported in 1986, has been ignored or forgotten by much of the world, and should be heeded. For patients with renal impairment and gout for whom NSAIDs are contraindicated, another old remedy that is often forgotten is colchicine.

Secondary hypertension

This is a rare situation but clinically important. If noncompliance or consumption of substances that aggravate hypertension do not seem to be the problem, then patients who are resistant to usual therapy (for example, blood pressures not reaching target levels despite three antihypertensive medications or patients having adverse effects that limit their ability to take some medications such as diuretics) should be investigated for the underlying cause. Figure 1 shows the central role of the renin/angiotensin/aldosterone axis in hypertension.


Figure 1. The physiology of therapy for resistant hypertension. When the kidney senses low blood pressure, renin is released, leading to production of angiotensin II. In turn, angiotensin II activates production of aldosterone by the adrenal cortex, which leads to salt and water retention. Under healthy conditions, this system is turned off once normal body water levels are restored. Impairment of this system can cause hypertension. To identify the best primary therapy for patients with resistant hypertension, the physiological mechanism underlying the blood pressure elevation must be identified (Table 1). Abbreviation: ACE, angiotensin-converting enzyme. Reproduced by permission of Nature Publishing Group from: Spence JD. Secondary stroke prevention. Nat Rev Neurol 2010;6:477–86.

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Increasingly it is recognized that many cases of primary aldosteronism are due to bilateral hyperplasia rather than to a unilateral adenoma[23, 24]; for that reason most cases should be treated medically and surgery reserved for patients who cannot be controlled (including those who cannot or will not take medication). A randomized trial of plasma renin activity profiling showed that this approach improves blood pressure control with less medication[25]; however, to differentiate primary aldosteronism from Liddle's variants it is important to measure both plasma renin and aldosterone.[26, 27] Table 1 outlines an approach to individualized therapy for resistant hypertension.

Table 1. Physiologically individualized therapya based on renin/aldosterone profile
 Primary hyper-aldosteronismLiddle's syndrome and variants (renal Na+ channel mutations)Renal/renovascular
  1. a

    It should be stressed that this approach is suitable for tailoring medical therapy in resistant hypertensives; further investigation would be required to justify adrenalectomy or renal revascularization.

  2. b

    Levels of plasma renin and aldosterone must be interpreted in the light of the medication the patient is taking at the time of sampling. In a patient taking an angiotensin receptor blocker (which would elevate renin and lower aldosterone), a plasma renin that is in the low normal range for that laboratory, with a plasma aldosterone in the high normal range, probably represents primary hyperaldosteronism, for the purposes of adjusting medical therapy.

  3. c

    Angiotensin receptor antagonists are less effective because of aldosterone escape via non-ACE pathways such as chymase and cathepsin. Reproduced by permission of Elsevier from Ref. [26].

Primary treatmentAldosterone antagonist (spironolactone or eplerenone)AmilorideAngiotensin receptor blocker or renin inhibitorc (rarely revascularization)
Amiloride for men where eplerenone is not available (rarely surgery)

Summary and conclusions

  1. Top of page
  2. Abstract
  3. Special considerations
  4. Management of resistant hypertension
  5. Summary and conclusions
  6. References

Preventing and controlling hypertension is perhaps the most important medical intervention for stroke prevention. Most strokes occur among patients with inadequately controlled hypertension, and a proper control of hypertension has the potential to reduce stroke by half. Resistant hypertension should lead to investigation of the cause so that specific individualized therapy can be identified.


  1. Top of page
  2. Abstract
  3. Special considerations
  4. Management of resistant hypertension
  5. Summary and conclusions
  6. References
  • 1
    Hackam DG, Spence JD. Combining multiple approaches for the secondary prevention of vascular events after stroke: a quantitative modeling study. Stroke 2007;38:18811885.
  • 2
    Li C, Engström G, Hedblad B, Berglund G, Janzon L. Blood pressure control and risk of stroke: a population-based prospective cohort study. Stroke 2005;36:725730.
  • 3
    Gu Q, Burt VL, Dillon CF, Yoon S. Trends in antihypertensive medication use and blood pressure control among United States adults with hypertension: the National Health And Nutrition Examination Survey, 2001 to 2010. Circulation 2012;126:21052114.
  • 4
    Tran J, Mirzaei M. The population attributable fraction of stroke associated with high blood pressure in the Middle East and North Africa. J Neurol Sci 2011;308:135138.
  • 5
    Lim SS, Vos T, Flaxman AD, et al. A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012;380:22242260.
  • 6
    Dahlof B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002;359:9951003.
  • 7
    PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood pressure-lowering regimen among 6105 individuals with previous stroke or transient ischemic attack. Lancet 2001;358:10331041.
  • 8
    Rothwell PM, Howard SC, Spence JD. Relationship between blood pressure and stroke risk in patients with symptomatic carotid occlusive disease. Stroke 2003;34:25832590.
  • 9
    Spence JD. White-coat hypertension is hypertension. Hypertension 2008;51:1272.
  • 10
    Natarajan N, Putnam W, Van Aarsen K, Beverley LK, Burge F. Adherence to antihypertensive medications among family practice patients with diabetes mellitus and hypertension. Can Fam Physician 2013;59:e93e100.
  • 11
    Grigoryan L, Pavlik VN, Hyman DJ. Patterns of nonadherence to antihypertensive therapy in primary care. J Clin Hypertens (Greenwich) 2013;15:107111.
  • 12
    Leenen FH, Wilson TW, Bolli P, et al. Patterns of compliance with once versus twice daily antihypertensive drug therapy in primary care: a randomized clinical trial using electronic monitoring. Can J Cardiol 1997;13:914920.
  • 13
    Feldman RD, Zou GY, Vandervoort MK, Wong CJ, Nelson SA, Feagan BG. A simplified approach to the treatment of uncomplicated hypertension. A cluster randomized, controlled trial. Hypertension 2009;53:646653.
  • 14
    Lee JK, Grace KA, Taylor AJ. Effect of a pharmacy care program on medication adherence and persistence, blood pressure, and low-density lipoprotein cholesterol: a randomized controlled trial. JAMA 2006;296:25632571.
  • 15
    Haynes RB, Ackloo E, Sahota N, McDonald HP, Yao X. Interventions for enhancing medication adherence. Cochrane Database Syst Rev 2008;(2):CD000011.
  • 16
    Bloom BS. Continuation of initial antihypertensive medication after 1 year of therapy. Clin Ther 1998;20:111.
  • 17
    Marentette MA, Gerth WC, Billings DK, Zarnke KB. Antihypertensive persistence and drug class. Can J Cardiol 2002;18:649656.
  • 18
    Spence JD. How to prevent your stroke. Nashville: Vanderbilt University Press, 2006.
  • 19
    Sacks FM, Svetkey LP, Vollmer WM, et al. Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet. DASH-Sodium Collaborative Research Group. N Engl J Med 2001;344:310.
  • 20
    Whelton PK, Appel LJ, Sacco RL, et al. Sodium, blood pressure, and cardiovascular disease: further evidence supporting the American Heart Association sodium reduction recommendations. Circulation 2012;126:28802889.
  • 21
    Campbell NR, Spence JD. Stroke prevention and sodium restriction. Can J Neurol Sci 2008;35:278279.
  • 22
    Cibattoni G, Boss AH, Patrignani P, et al. Effects of sulindac on renal and extrarenal eicosanoid synthesis. Clin Pharmacol Ther 1987;41:380383.
  • 23
    Spence JD. The current epidemic of primary aldosteronism: causes and consequences. J Hypertens 2004;22:20382039.
  • 24
    Stowasser M. Update in primary aldosteronism. J Clin Endocrinol Metab 2009;94:36233630.
  • 25
    Egan BM, Basile JN, Rehman SU, et al. Plasma renin test-guided drug treatment algorithm for correcting patients with treated but uncontrolled hypertension: a randomized controlled trial. Am J Hypertens 2009;22:792801.
  • 26
    Spence JD. Lessons from Africa: the importance of measuring plasma renin and aldosterone in resistant hypertension. Can J Cardiol 2012;28:254257.
  • 27
    Spence JD. Physiologic tailoring of treatment in resistant hypertension. Curr Cardiol Rev 2010;6:119123.