Hypertension

Introduction

Ambulatory blood pressure monitoring

Thresholds for pharmacological treatment of blood pressure (BP)

Targets for pharmacological treatment

Compelling indication for the use of specific antihypertensives

(See Strength of Recommendations Taxonomy (SORT) for explanation of Grade A-C)

INTRODUCTION 

Systemic hypertension is common in type 2 diabetes mellitus and will affect the majority of patients at some point in the course of their disease. People with type 2 diabetes mellitus are at a greater risk than non-diabetics for developing hypertension¹ and are more likely to develop target organ damage.² The development and progression of organ damage due to hypertension in diabetes appears to differ from that for the nondiabetic population.

Hypertension is an important modifiable risk factor for micro and macrovascular disease. Blood pressure (BP) must be measured at every clinic visit, after the patient has been seated and has rested for at least five minutes. It is essential to use an appropriately sized cuff, as small cuffs will yield falsely elevated pressure readings. Measure the BP in both arms at the initial consultation, and thereafter in the arm with the higher BP. The systolic BP should first be estimated by palpation and then by auscultation, to avoid missing the auscultatory gap. The diagnosis of hypertension is confirmed if the BP remains > 140/90 mmHg on two separate days.

AMBULATORY BLOOD PRESSURE MONITORING 

Ambulatory blood pressure monitoring (ABPM) is determined using a device worn by the patient over a period of 24 to 48 hours and measures blood pressure at regular intervals, usually every 15 to 20 minutes.³ The device records all the blood pressure readings taken during this time period. If full 24 hour readings cannot be obtained, then six to eight hours of ABPM may be adequate.⁴ 

From this, the average day and night blood pressures can be determined. When using ABPM, hypertension is defined as a 24-hour average blood pressure greater than or equal to 130/80 mmHg.⁵

While ABPM is not available in most clinicians’ offices, it is considered to be the gold standard for the diagnosis of hypertension. When compared with ABPM, the sensitivity and specificity of office-based BP measurements are poor (75% for both).⁶

Indications for measuring ABPM:^7,8,9

• Suspected white coat hypertension
• Hypertension resistant to increasing medications
• Hypotensive symptoms while taking antihypertensive medications
• Autonomic dysfunction
• Suspected episodic hypertension (e.g. phaeochromocytoma)

THRESHOLDS FOR PHARMACOLOGICAL TREATMENT OF BLOOD PRESSURE (BP)

The benefit of lowering blood pressure was initially shown by the Blood Pressure Lowering Treatment Trialists Collaboration.This analysis showed that a modest drop of 6.4 mmHg of systolic blood pressure was associated with a decrease in stroke, cardiovascular disease and total mortality.¹⁰

Two large meta-analyses have shown that treatment of a systolic blood pressure of greater than or equal to 140 mmHg, results in more benefit than harm.^11,12 In the Brunström meta-analysis,¹¹ 49 trials (73 738 participants) were included, while in the Emdin meta-analysis, 40 trials judged to be of low risk of bias (100 354 participants) were included.¹² 

Given the slightly different weighting of trials in the two meta-analyses, the findings of benefit and harm of various organ systems differ slightly, but the threshold for initiating treatment remains constant.

In the Brunström meta-analysis, if the baseline BP was greater than 150 mmHg, antihypertensive treatment reduced the risk of all cause mortality, cardiovascular mortality, myocardial infarction, stroke and end stage renal disease. If baseline systolic blood pressure was between 140 and 150 mm Hg, additional treatment reduced the risk of all-cause mortality, myocardial infarction and heart failure. If baseline systolic blood pressure was less than 140 mm Hg, further treatment increased the risk of cardiovascular mortality with a tendency towards an increased risk of all cause mortality.¹¹ 

The Emdin meta-analysis showed that each 10 mmHg reduction of systolic blood pressure was associated with significantly lower risk of mortality, cardiovascular events, coronary heart disease, stroke, albuminuria, and retinopathy. However, when trials were stratified by mean baseline SBP greater than or equal to 140 mmHg or less than 140 mmHg, blood pressure–lowering treatment was associated with lower risks of stroke and albuminuria, regardless of initial systolic blood pressure.¹²

TARGETS FOR PHARMACOLOGICAL TREATMENT

The Brunström meta–analysis specifically focused on the evidence for positive or negative outcomes for attained systolic BP’s in clinical trials.¹¹ The following outcomes were observed:

• The all-cause mortality reduction observed with treatment at a threshold of 140 mmHg was lost when the BP was lowered below 130 mmHg
• Trend towards harm for CV mortality was observed when the BP was lowered to below 130 mmHg
• The myocardial infarction threshold for harm was at 132 mmHg
• Stroke benefit was achieved only with a BP below 130 mmHg
• Heart failure was reduced for an achieved BP between 130-140 mm Hg, but this benefit was lost if the BP dipped below 130 mmHg
• End-stage renal disease appeared to only be reduced if the pretreatment BP was >150 mmHg and was treated to between 140 and 150 mmHg
• Albuminuria was reduced by 29% if the BP was reduced to <140 but >130 mmHg and by 14% if the BP was dropped below 130 mmHg. The risk for retinopathy did not appear to be reduced significantly with BP lowering

Diastolic BP targets for benefit and risk for harm were assessed by the Brunström analysis. Threshold for treatment appeared to be 90 mmHg and a 28% increase in CV mortality was noted for each 10 mmHg drop in BP below a threshold of 78 mmHg.

COMPELLING INDICATION FOR THE USE OF SPECIFIC ANTIHYPERTENSIVES 

In the Emdin review, all classes of anti-hypertensive drugs appeared to be efficient in reducing all cause and cardiovascular mortality, a finding supported by other researchers.^12,13 Heart failure was significantly reduced by angiotensin receptor blockers and diuretics (17% reduction), but increased by calcium channel blockers (CCB). CCBs were however associated with a lower risk of stroke, and beta-blockers with a higher risk of stroke.

A recent review of angiotensin system blockers compared to active comparators showed no extra benefit other than a reduction of heart failure when compared to CCBs.¹⁴

Within the class of diuretics, thiazide–type (TT) and thiazidelike (TL) drugs must be specified. A meta-analysis of these drugs looking at outcomes of CV events and mortality as well as BP control, clearly showed a difference with a 12% reduction of CV events and 21% less heart failure with TL compared with TT drugs.¹⁵ A further meta-analysis of head to head comparisons of hydrochlorothiazide (HCTZ) with indapamide (INDAP) and chlorthalidone, confirmed that INDAP was more potent than HCTZ with a 54% greater BP reduction at comparable doses, without greater metabolic side effects.¹⁶ 

The duration of action of INDAP was found to be >24-36 hours depending on the formulation, compared to the ^{12,13,14,15,16} hour effect of HCTZ.

INDAP was also noted to reduce the left ventricular mass by 17%, more than that of enalapril, and was comparable to captopril and enalapril in reducing albuminuria in diabetic subjects. HCTZ has neither of these effects. Not specific to diabetes, indapamide has been shown to not have an adverse effect on serum lipids. Due to its widespread availability, and low cost, indapamide is considered to be the diuretic of choice in the management diabetic patients with hypertension.

The non-dihydropyridine CCBs, (verapamil and diltiazem) have been shown to have significant antiproteinuric effects in diabetic kidney disease.¹⁷ The dihydropyridine CCBs (amlodipine and nifedipine) have been shown to have no consistent effect on protein excretion.

There is currently limited data regarding the potential benefits of combining therapy with ACE inhibitors and ARBs. While several small studies have shown an additive antiproteinuric effect when these drugs were used in combination, these finding were not reproducible in all studies. In the COOPERATE study (randomised controlled trial in non-diabetic renal disease), combination therapy with ACE inhibitors and ARBs was shown to be more effective that either drug alone in slowing the decline of GFR.¹⁸ Until additional information and data for combination use in diabetes is made available, the use of either an ACE inhibitor or an ARB is recommended, rather than the combination of both classes.

Most patients with diabetes and hypertension require multiple drug therapies to reach target blood pressure treatment goals. If the blood pressure remains uncontrolled, despite confirmed adherence of at least three antihypertensive agents of different classes (at optimal doses), the clinician should consider evaluation for secondary causes of hypertension.

Authors: Susan L. Brown and Zaheer Bayat
Editor: Aslam Amod

References

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