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Heart rate reduction as a goal in hypertension

Heart rate reduction as a goal in hypertension

What is the target for blood pressure reduction? How low should we go?

Epidemiological studies show a continuous relationship between blood pressures above 115/70 mmHg and the risk of coronary and cerebrovascular events, which doubles for every 20/10 mmHg rise in blood pressure. Data from intervention studies support current guidelines that clinic blood pressure should be reduced to 140/90 mmHg in all hypertensives and to lower levels of 130/80 mmHg in those with higher cardiovascular risk1.  Reducing blood pressure to lower levels than these may actually increase the risk of cardiac ischaemic events, particularly in those patients with underlying coronary artery disease (CAD).  This was shown in a post hoc analysis of the International Verapamil-Trandolapril Study (INVEST) in patients with hypertension and CAD, where the relationship between blood pressure and the primary outcome, all-cause death, and total MI was J-shaped, particularly for diastolic pressure, with a nadir at 119/84 mmHg and the J-shaped relationship between diastolic pressure and the primary outcome persisted after adjustments2. Patients who had undergone revascularization procedures were able to tolerate a lower diastolic blood pressure than those who had not.

Likewise, in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial in high risk patients with hypertension and type 2 diabetes, there was no advantage in the primary composite outcome with more aggressive systolic blood pressure reductions to less than 120 mmHg, as compared with less than 140 mmHg, but there was a reduction in stroke3. Also, in the Randomised Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) study, olmesartan treatment reduced blood pressure to low levels and delayed the onset of microalbuminuria in patients with type 2 diabetes, but was associated with a greater incidence of all cardiovascular deaths, probably related to the low blood pressures achieved in patients with established CAD4.  As the coronary circulation receives its perfusion mostly during diastole, excessive reduction in diastolic pressure should be avoided in patients with CAD who are being treated for hypertension, although further reductions may be beneficial in preventing stroke or renal disease.

1. Mancia G, Laurent S, Agabiti-Rosei E, et al. Reappraisal of European guidelines on hypertension management: a European Society of Hypertension Task Force document. J Hypertens 2009;27:2121-58.
2. Messerli FH, Mancia G, Conti CR, et al. Dogma disputed: can aggressively lowering blood pressure in hypertensive patients with coronary artery disease be dangerous? Ann Intern Med 2006;144:884-93.
3. Cushman WC, Evans GW, Byington RP, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med 2010;362:1575-85.
4. Haller H, Ito S, Izzo JL, Jr., et al. Olmesartan for the delay or prevention of microalbuminuria in type 2 diabetes. N Engl J Med 2011;364:907-17.

Does blood pressure variability influence the prognosis?

It is known that excessive variation of blood pressure over 24 hours and longer periods increases the risk of cardiovascular events. This was shown by Franz Halberg many years ago and he coined the term circadian hyper-amplitude tension (CHAT) to describe this phenomenon which was associated with increased cardiovascular risk. This excessive diurnal variation differs from the normal reduction of blood pressure during sleep called dipping which is considered desirable and subjects who are non-dippers appear to be at increased risk of hypertension-related organ damage and cardiovascular events.

More recently it has been shown that increased visit-to-visit variability of systolic blood pressure in treated hypertensives is a strong predictor of stroke, independent of mean systolic blood pressure1. In an analysis from the Anglo-Scandinavian Cardiac Outcomes Trial Blood Pressure Lowering Arm (ASCOT-BPLA), blood pressure variability for visit-to-visit, within-visit and on 24 hour ambulatory blood-pressure monitoring (ABPM) was lower in the amlodipine-based compared with the atenolol-based treatment group2. Another analysis showed that variability in systolic blood pressure was increased more by nonselective beta-blockers than by beta1 -selective agents and that the increase in stroke risk in comparisons with other antihypertensives was more marked with nonselective beta-blockers than with beta1-selective drugs3. It is not certain whether a short duration of action of the drugs involved might also contribute to increased blood pressure variability, but it seems appropriate that to prevent stroke most effectively, blood-pressure-lowering regimens should reduce mean blood pressure throughout the 24 hours without increasing blood pressure variability.

1. Rothwell PM, Howard SC, Dolan E, et al. Prognostic significance of visit-to-visit variability, maximum systolic blood pressure, and episodic hypertension. Lancet 2010;375:895-905.
2. Rothwell PM, Howard SC, Dolan E, et al. Effects of beta blockers and calcium-channel blockers on within-individual variability in blood pressure and risk of stroke. Lancet Neurol 2010;9:469-80.
3. Webb AJ, Fischer U, Rothwell PM. Effects of beta-blocker selectivity on blood pressure variability and stroke: a systematic review. Neurology 2011;77:731-7.

Can the response to different classes of antihypertensive drug be predicted?

Some guidelines recommend that first- line antihypertensive therapy should be chosen depending on the age or ethnicity of the patient1,2. This is largely based on findings that older patients and those of African origin have less activation of the renin-angiotensin-aldosterone system (RAAS) and lower levels of plasma renin activity and will respond better to thiazide diuretics or calcium channel blockers3. Younger and non-black patients should respond better to drugs which inhibit the RAAS such as angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, and beta-blockers. However, age and ethnicity may not predict the levels of plasma renin activity accurately or the response to different antihypertensive drugs in all cases.  In a meta-analysis from the Blood Pressure Lowering Treatment Trialists’ Collaboration, there was no difference between the effects of the different drug classes on major cardiovascular events between younger and older patients (<65 vs. ≥65 years) or when age was fitted as a continuous variable4.

There is considerable interest in the possibility of predicting the response to antihypertensive drugs from genetic factors and extensive research is being conducted in this field5. However, currently there are no genetic factors which that can accurately predict the blood pressure response or cardiovascular outcomes with different classes of antihypertensive drug. The choice of drug is often influenced by indications or contraindications of different classes of drug within an individual patient rather than the predicted blood pressure reduction6.

1. Williams B, Poulter NR, Brown MJ, et al. Guidelines for management of hypertension: report of the fourth working party of the British Hypertension Society, 2004-BHS IV. J Hum Hypertens 2004;18:139-85.
2. National Institute for Health and Clinical Excellence (NICE). Hypertension (update): full guideline. Available from: 2011.
3. Brown MJ. Personalised medicine for hypertension. BMJ 2011;343:d4697.
4. Turnbull F, Neal B, Ninomiya T, et al. Effects of different regimens to lower blood pressure on major cardiovascular events in older and younger adults: meta-analysis of randomised trials. BMJ 2008;336:1121-3.
5. Johnson JA. Pharmacogenomics of antihypertensive drugs: past, present and future. Pharmacogenomics 2010;11:487-91.
6. Mancia G, Laurent S, Agabiti-Rosei E, et al. Reappraisal of European guidelines on hypertension management: a European Society of Hypertension Task Force document. J Hypertens 2009;27:2121-58.

When is it appropriate to start antihypertensive treatment with combination therapy?

It is well established that antihypertensive monotherapy will only be effective in achieving blood pressure targets in the minority of hypertensive patients. A meta-analysis showed that combining standard doses of two drugs from different classes was more effective in reducing blood pressure than doubling the dose of a single agent1. Appropriate combinations of drugs from different classes are not only more effective in reducing blood pressure and thereby increase the likelihood of achieving the blood pressure goal in a timely manner, but they may also result in fewer side effects by the balancing out of some adverse effects. For instance, combining an angiotensin converting enzyme (ACE) inhibitor or angiotensin II receptor antagonist with a calcium channel blocker can reduce the side effect of peripheral oedema and combining a beta-blocker with a calcium channel blocker can reduce tachycardia and palpitations. Current guidelines from the United States, Europe and Japan all recommend combination therapy as the first step in patients with moderate to severe hypertension (>20/10 mmHg above the target) or those at high cardiovascular risk2-4.  Combination therapies in low doses are usually well tolerated but it is advisable to be cautious in some elderly patients and those at risk for orthostatic hypotension, such as some patients with diabetes or autonomic dysfunction. Combination therapy in single tablet form can also improve medication compliance.

1. Law MR, Wald NJ, Morris JK, Jordan RE. Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials. BMJ 2003;326:1427.
2. Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. J Am Med Assoc 2003;289:2560-72.
3. Mancia G, De Backer G, Dominiczak A, et al. 2007 ESH-ESC Practice Guidelines for the Management of Arterial Hypertension: ESH-ESC Task Force on the Management of Arterial Hypertension. J Hypertens 2007;25:1751-62.
4. Ogihara T, Kikuchi K, Matsuoka H, et al. The Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2009). Hypertens Res 2009;32:3-107.

When is the best time of day to take antihypertensive medication?

It is common practice for patients to take their antihypertensive therapy first thing in the morning and this is usually appropriate if the drug regimen provides effective 24 hour blood pressure reduction.  There have been several studies of chronotherapy with medications given at different times in the day and many have found that taking the antihypertensive medication in the evening or before bed has an advantage in reducing cardiovascular risk1,2. The renin-angiotensin-aldosterone system is activated during nighttime sleep so that taking angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) at nighttime is likely to have a greater therapeutic effect on the sleeping blood pressure and help to restore the normal circadian blood pressure profile3.

If the patient is found to be a non-dipper on 24 hour ambulatory blood pressure monitoring, it may be an advantage to take one or more antihypertensive medications in the evening to restore the nocturnal blood pressure dipping pattern. It is also important that the antihypertensive medication should be effective around the time of waking in the morning when there is an early morning blood pressure surge and peak incidence of myocardial infarction and cerebrovascular events.  Some antihypertensive drugs given once daily in the morning, such as atenolol, may not provide adequate antihypertensive effect at the vulnerable time of morning waking and may be better given twice daily, although more frequent dosing may reduce medication compliance.

1. Hermida RC, Ayala DE, Mojon A, Fernandez JR. Sleep-time blood pressure as a therapeutic target for cardiovascular risk reduction in type 2 diabetes. Am J Hypertens 2012;25:325-34.
2. Hermida RC, Ayala DE, Mojon A, Fernandez JR. Decreasing sleep-time blood pressure determined by ambulatory monitoring reduces cardiovascular risk. J Am Coll Cardiol 2011;58:1165-73.
3. Hermida RC, Ayala DE, Fernandez JR, Portaluppi F, Fabbian F, Smolensky MH. Circadian rhythms in blood pressure regulation and optimization of hypertension treatment with ACE inhibitor and ARB medications. Am J Hypertens 2011;24:383-91.

Brian Tomlinson

Specialist in Internal Medicine & Clinical Pharmacology
Department of Medicine and Therapeutics
Adjunct Professor
The Chinese University of Hong Kong
Hong Kong, China
heart rate reduction
heart failure
Heart rate and cardiovascular outcomes
Cardiovascular outcomes of heart rate reduction
Vascular benefit of heart rate reduction