© Springer International Publishing AG 2016
Md. Shahidul Islam (ed.)Hypertension: from basic research to clinical practiceAdvances in Experimental Medicine and Biology95610.1007/5584_2016_97Treatment of Hypertension: Which Goal for Which Patient?
(1)
Research Unit 12ES14, Faculty of Medicine, Sfax University, Sfax, Tunisia
(2)
Nephrology Department, H. Chaker University Hospital, Sfax, 3029, Tunisia
Abstract
Hypertension remains the most important risk factor for cardiovascular disease. If antihypertensive drugs choice is well guided today, blood pressure (BP) target still a subject of controversies. Residual risk is matter of debate and the lower- the better dogma is come back again regarding to data reported from recent trials. The J curve, reason for European Society of Hypertension Guidelines reappraisal in 2009, is criticized by recent data. The one goal (<140/90 mmHg) fit 90 mmg 90 mmHg) fit all should be adapted as a personalized goal guided by evidence generated by randomized controlled trials. Target controversy is back because of the results of ACCORD and SPRINT trials challenging the common systolic BP target less 140 mmHg to less than 120 mmHg. The first was performed in diabetic patients and the second in patients at high cardiovascular risk; elderly aged of 75 years and above, or patients with chronic kidney disease, or with pre-existing subclinical or clinical cardiovascular disease or a Framingham 10-year cardiovascular disease risk score of 15 % or above, however non diabetic. If the first trial was negative, SPRINT reports a huge reduction of the composite primary outcome, which included myocardial infarction, other acute coronary syndromes, stroke, heart failure or death from cardiovascular causes by 25 %, and the risk of death from all causes by 27 %, when target systolic BP is lower than 120 mmHg compared to lower than 140 mmHg. However, BP was measured by automated office BP technique which correlates more with home BP measurement than auscultatory office BP measurement. Also, only significant less heart failure in the intensive arm was driving the difference in mortality favoring the intensive arm in SPRINT. The greater use of diuretics may have demasked latent heart failure in hypertensive patients with rather high cardiovascular risk.
More convincing data suggest that BP should be diagnosed early and treatment should be started at BP level of 140 mmHg and above, based on an office BP measurement, confirmed by an out-of-office BP measurement. Target systolic BP should be less than 140 mmHg if BP is measured by classic auscultatory method, less than 120 mmHg in high risk patients if BP is measured by automated office BP measurement. These targets are relevant in elderly patients if no orthostatic hypotension occurred, patients with non proteinuric chronic kidney disease (eGFR < 60 ml/mn/1.73 m2) and patients with cardiovascular disease or a Framingham score more than 15 %. However attention should be taken on diastolic BP if lower than 70 mmHg because of an increasing risk of ischemic heart event and on renal function since acute renal failure is more frequently reported at these low targets.
In diabetic patients, SBP target should be less than 140 mmHg according to ACCORD trial. However, for patients with protein-creatinine ratio >500 mg/g (albumin-creatinine ratio > 300 mg/g), with or without diabetes, lower SBP target should be proposed for renal protection aiming SBP < 130 mmHg as recommended by KDIGO guidelines.
In patients at low or intermediate risk, without cardiovascular disease, SBP should start to be treated when SBP is above 140 mmHg, and when treated, target BP should be less than 140 mmHg as reported by HOPE-3 trial.
Keywords
Hypertension in the diabeticsHypertension in the elderlyBlood pressure goalsHypertension and cardiovascular preventionHypertension and microvascular complicationsSPRINT trialACCORD trialAmbulatory blood pressure measurement1 Introduction
Cardiovascular diseases are a worldwide leading cause of mortality and morbidity, even in most developing countries, as Tunisia, where cardiovascular mortality is the leader, accounting for about 29 % causes of deaths (Hajem and Hsairi 2013). Hypertension remains the most important risk factor. According to the recently published global, regional and national comparative risk assessment of 79 behavioral, environmental and occupational, and metabolic risks or clusters of risks in 188 countries, (GBD 2013 Risk Factors Collaborators 2015), high systolic blood pressure (BP) accounted for 6.9 million deaths in 1990 and 10.4 million deaths in 2013 with a 49.1 % progression and 208.1 million DALYs (disability-adjusted life-years) in 2013. This data contrast with the emergence of many treatment choices for hypertension in the last three decades, reflecting the magnitude of this clinical problem and highlighting that the treatment of hypertension remains difficult.
If BP was measured since eighteenth century by Stephen Hales (Lewis 1994), we have to wait for the contribution of the Framingham Heart Study to recognize that high BP is an eminent cardiovascular risk factor (Kannel et al. 1961). The Veterans Administration Cooperative Study on Antihypertensive Agents was the first study demonstrating in 1967 the benefit of BP reduction ([no authors listed] 1967). It included men with diastolic BP (DBP) of 115–129 mmHg. The treatment, including hydrochlorothiazide, reserpine and hydralazine hydrochloride, caused a remarkable average BP reduction of systolic/diastolic (SBP/DBP) by 43/30 mmHg in the active treatment arm. This reduction resulted in a reduction of cardiovascular events after only 11 months follow-up, with 21 fatal or morbid events in placebo arm as opposed to one event in the active treatment arm. The study was therefore stopped prematurely. The second larger Veterans Administration Cooperative Study conducted in patients with milder hypertension (HTN) confirmed the effect of BP control on stroke and congestive heart failure occurrence ([no authors listed] 1970). From then on, several questions were raised: what is the definition of HTN? at which level of BP should one start to treat? and down to which level should BP be reduced to obtain the highest protective effect?
2 Definition of Hypertension
The best definition of HTN at a personnel point of view was given by G. Rose (1980); indeed, hypertension is the level of arterial BP at which the benefits of intervention exceed those of inaction. However, it is difficult to translate this definition to the daily practice, there is a need for a numerical definition. Earlier in 1980s and early 1990s the definition of HTN was BP > 160/95 mmHg, up to 1993 where the definition of HTN was reduced to a level equal or above 140/90 mmHg. This definition still adopted nowadays by all guidelines.
The definition of HTN relates an attributable risk to a BP level. In most populations and age groups, there is a linearly relationship between systolic blood pressure (SBP) and risk of cardiovascular mortality, cardiovascular events and strokes. Among patients younger than 65 years, there is a progressive increase in the risk of stroke and coronary artery disease with a parallel increase in SBP. Increasing risk is, however, not equivalent for DBP. For the population of 65 years old and above, the risk continues to increase with the increase of SBP, however, a reversal occurs with the DBP where the risk of cardiovascular events increases with the rise of DBP but also with the fall of it, showing a J curve (Neaton and Wentworth 1992).
The Multiple Risk Factor Intervention Trial (MRFIT) assessed the combined influence of BP, serum cholesterol level, and cigarette smoking on death from coronary heart disease (CHD) for 316,099 men screened in whom 6327 deaths from CHD have been identified after an average follow-up of 12 years. Strong graded relationships between SBP above 110 mmHg, and DBP above 70 mmHg and mortality due to CHD were evident. SBP was a stronger predictor than DBP; however, the greater risk was attributed to the highest SBP (≥160 mmHg) and the lowest DBP (<70 mmHg) highlighting the pulse pressure as a powerful actor in this coronary artery disease related death risk (Neaton and Wentworth 1992). The definition of HTN based on DBP in the 1960s was therefore not justified. However all current guidelines define HTN without focusing on the non linearity of the risk attributed to DBP with a fixed SBP level.
In Joint National Committee 7 guidelines (Chobanian et al. 2003) and ESH 2007 guidelines (ESH-ESC Task Force on the Management of Arterial Hypertension 2007) was introduced the terms of Pre-Hypertension (BP 120–139/80–89 mmHg) and High-normal BP (BP 130–139/85–90 mmHg) respectively. In fact, a stepwise increase in cardiovascular event rates was noted in persons with higher baseline blood-pressure categories.
The Framingham Heart Study investigated 6859 subjects, 35–64 years of age, free from cardiovascular disease and HTN (Vasan et al. 2001). As compared with optimal BP (<120/80 mmHg), high-normal BP (130–139/85–89 mmHg) was associated with a risk-factor–adjusted hazard ratio for cardiovascular disease of 2.5 (95 % CI, 1.6–4.1) in women and 1.6 (95 % CI, 1.1–2.2) in men. However, the 10-year cumulative incidence of cardiovascular disease was lower in younger individuals; 4 % for women and 8 % for men; than in older subjects (those from 65 to 90 years old), the incidence was 18 % for women and 25 % for men.
These data should make HTN definition change to 130/85 mmHg or even lower, however; there is a need for data showing that reduction of BP from 130 to less than 120 mmHg for SBP will induce a reduction of cardiovascular events. Also, the definition of HTN takes in account the economic challenge of BP reduction from 140/90 to 130/85 mmHg; even if controlling BP with medication is unquestionably one of the most cost-effective methods of reducing premature cardiovascular morbidity and mortality (Elliott 2003). This evidence has many limits since BP reduction by treatment should reduce the risk of development of renal, cerebral and cardiovascular diseases to validate starting treatment at the level of which risk is increased.
3 Impact of Blood Pressure Control
An increasing number of trials have provided evidence that antihypertensive therapy to attain BP control provides a relative cardiovascular protection. The best evidence was shown by trials reporting BP reduction with antihypertensive treatment compared to placebo or no antihypertensive treatment. The last on date was HYVET trial including 3845 patients aged 80 or older who were randomized to active treatments or placebo without antihypertensive medications (Beckett et al. 2008).
According to the intention-to-treat analysis and as compared to the baseline value 173.0/90.8 mmHg, SBP/DBP values obtained while the patient was seated had fallen by a mean of 14.5 ± 18.5/6.8 ± 10.5 mmHg in the placebo group and by 29.5 ± 15.4/12.9 ± 9.5 mmHg in the active-treatment group at 2 years. This reduction of SBP/DBP by active treatment was associated with a 30 % reduction in the rate of fatal or nonfatal stroke (p: 0.06), a 39 % reduction in the rate of death from stroke (p: 0.05), a 21 % reduction in the rate of death from any cause (p: 0.02), a 23 % reduction in the rate of death from cardiovascular causes (p: 0.06), and a 64 % reduction in the rate of heart failure (p < 0.001).
A meta-analysis including 11 randomized controlled trials and 67,475 individuals compared antihypertensive therapy with placebo and aimed to investigate whether the benefits of BP-lowering drugs are proportional to baseline cardiovascular risk. Patients were risk stratified according to their estimated 5-year risk of having a major cardiovascular event. Lowering BP provides similar relative protection at all levels of baseline cardiovascular risk, but progressively greater absolute risk reductions were obtained when baseline risk increases, yielding to a possible benefit for more intense BP reduction in high risk patients (Blood Pressure Lowering Treatment Trialists’ Collaboration 2014).
More recently, Thomopoulos et al. (2014) reported a meta-analysis on the effects at different baseline and achieved blood pressure levels on cardiovascular disease. Results of this meta-analysis favor BP-lowering treatment even in grade 1 hypertension at low-to-moderate risk, and lowering SBP/DBP to less than 140/90 mmHg. Achieving less than 130/80 mmHg appears safe, but only adds further significant reduction in stroke and all-cause death. Is it important to achieve earlier BP target on the occurrence of cardiovascular outcomes?. A response strand was generated by the VALUE Trial. This study (Julius et al. 2004) compared the effect on cardiovascular morbidity and mortality of a calcium channel blocker based strategy versus an angiotensin II receptor blocker based strategy in a high cardiovascular risk population. An unexpected equivalence between the two strategies was reported. The result was explained, in part, by a significantly better earlier BP control achieved in the amlodipine group. In fact, after the first month of treatment, SBP is on average 4 mmHg lower, DBP by 2.1 mmHg lower (p <0.0001). A respective difference of 2 and 1.6 mmHg persists after the sixth month until the end of the study (p <0.001).
It is so clearly proved that control of BP results in saving lives and reducing cardiovascular death and events. The debate becomes down to which level BP should be dropped?
4 Is the Lower the Better? – The Dogma of J Curve
Observational studies show a direct linear relationship between SBP/DBP values as low as 115–110 and 75–70 mmH respectively, and cardiovascular events, without evidence within this range of a J curve phenomenon. The Prospective Studies Collaboration (Lewington et al. 2002) performed a meta-analysis including one million adults from 61 prospective trials. Authors reported that within each decade of age at death, the proportional difference in the risk of vascular death associated with a given absolute difference in usual BP is about the same down to at least 115 mmHg usual SBP and 75 mmHg usual DBP, below which there is little evidence.
At ages 40–69 years, each difference of 20 mm Hg usual SBP is associated with more than a twofold difference in the stroke death rate, and with twofold differences in the death rates from ischemic heart disease and from other vascular causes.
So, evidence that achieving lower BP targets by treatment may enhance protection in hypertensive patients at higher risk, yielded ESH/ESC task force (for the management of arterial hypertension- 2007guidelines) to suggest that target BP should be at least <130/80 mmHg in diabetics and in high or very high risk patients, such as those with associated clinical conditions (stroke, myocardial infarction, renal dysfunction, proteinuria) (ESH-ESC Task Force on the Management of Arterial Hypertension 2007).
The evidence available on the BP targets of antihypertensive treatment has been reviewed by Zanchetti et al. (2009). In uncomplicated hypertensive patients, SBP reduced to less than 140 mmHg with active treatment was associated with a difference in outcome. This evidence supports the recommendation of guidelines to reduce SBP to less than 140 mmHg in the general population of patients with grade 1 or 2 hypertension and low or moderate total cardiovascular risk. However, for the elderly hypertensive patients, these authors reported no trial evidence in support of the guidelines recommendation to adopt the less than 140 mmHg SBP target in this population suggesting a target SBP of less than 150 mmHg.
When considering diabetic patients, lower BP goal less than 130/80 mmHg is also not supported by incontrovertible trial evidence. Even if HOT (Hansson et al. 1998) and Syst-Eur (Tuomilehto et al. 1999) trials, reported a greater absolute reduction of cardiovascular outcomes for a small BP difference in diabetic but not in nondiabetic hypertensive patients, these data were not confirmed by ACCORD trial (ACCORD Study Group 2010). This landmark trial in diabetic population tested a strict BP control (SBP less than 120 mmHg) compared to a standard target (SBP less than 140 mmHg) on the primary composite outcome (nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes). The only benefit reported was significant fewer strokes, but counterbalanced by a significant high level of serious adverse events as hypotension and fall of eGFR to less than 30 ml/mn/1.73 m2.
STENO-2 trial showed a significant reduction of microvascular complications 8 years and all cardiovascular events 13 years after study start with an intense treatment strategy including a BP < 130/80 mmHg versus less strict strategy with a standard BP goal of 130–139 mmHg in type 2 diabetic patients with microalbuminuria (Gaede et al. 2003, 2008). However, the positive results attributed to the intense strategy cannot be directly attributed to a strict BP target, since the two groups were not comparable elsewhere. This study however, highlights the importance of a combined optimal strategy to reduce cardiovascular and microvascular events in type 2 diabetes.
Out of cardiovascular prevention, there are solid data regarding the benefits of a SBP target less than 130 mmHg when considering diabetic patients with proteinuria aiming to reduce renal events (end stage renal disease). The meta analysis of Bakris et al. (2000) considering type 2 diabetic patients with proteinuria reported less estimated glomerular filtration rate loss (eGFR) when BP is under 130/85 than at 140/90 mmHg. In type 2 diabetic patients without proteinuria, however, no evidence was reported by ACCORD trial (ACCORD study Group 2010).
The Kidney Disease Improving Global Outcome KDIGO clinical practice guideline for the management of BP in chronic kidney disease outlined the strict target of BP < 130/80 mmHg only in patients with abnormal albumin excretion rate, meaning those with microalbuminuria or A2 category as defined by urine albumin-creatinine ratio more than 30 mg/g or A3 category (severely increased) as defined by urine albumin-creatinine ratio above 300 mg/g or Protein-creatinine ratio above 500 mg/g, with or without diabetes (Kidney Disease: Improving GlobalOutcomes (KDIGO) Blood Pressure Work Group 2012). However, since microalbuminuria is also a marker of vascular damage, defining target BP based on the presence of microalbuminuria should consider the presence of subclinical coronary heart disease (Jarraya et al. 2013).
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