Controversy on optimal blood pressure on haemodialysis: lower is not always better

Gérard M. London

Manhes Hospital, Fleury-Mérogis, France

Blood pressure as a risk factor in the general population

In Western population the relationship between blood pressure (BP) levels and cardiovascular disease (CVD) is a continuous function. The evidence for this ‘linear’ relationship derives from prospective observational studies of the incidence of stroke and coronary heart disease and from the results of randomized trials on the effect of antihypertensive therapy [14]. Systolic (SBP) and diastolic BP (DBP) have been shown to be positively and continuously related to the risk of stroke across a wide range of BP values. No lower threshold of BP could be identified below which the risk of stroke did not continue to decline [5,6]. A meta-analysis of placebo-controlled, randomized trials of hypertensive subjects showed a 43% reduction in the incidence of stroke with pharmacological treatment [4]. Most studies found that the lowest treated DBPs, ranging from below 80 to below 85 mmHg, were associated with the lowest mortality from stroke [7]. While the benefit on coronary heart disease (CHD) was smaller than that on stroke, BP levels have also been shown to be positively and continuously related to the risk of major CHD [5]. The strength of the association is less pronounced than for stroke, but is similar across a large range of BP values, including the range of normotension. Again no lower level could be identified below which the risk did not continue to decline.

A relationship between BP and renal failure has also been observed, but there is little qualitative information from prospective studies on how tight the relationship is [8]. Nevertheless, there is evidence that: (i) in each stratus with 5 mmHg lower DBP the risk of end-stage renal disease (ESRD) is lowered by 25% [8]; (ii) hypertension is an independent risk factor for ESRD in African–Americans [9]; (iii) high BP values, whether the cause or the consequence of renal disease, are a determinant of the risk of ESRD [10]; and (iv) treatment of BP will slow the progression of renal failure [11].

All these above-mentioned facts and considerations led the Joint National Committee in the United States [12] and the WHO-ISH Guidelines Committee [13] to adopt new definitions and a new classification of hypertension. This new classification defines optimal BP as <120/80 mmHg and hypertension as SBP of 140 mmHg or greater and DBP of 90 mmHg or greater. Considering these definitions, the goals of antihypertensive treatment would be to reduce BP at lease below 140/90 mmHg or even lower in patients with diabetes or renal disease (<130/85 mmHg). Still lower values (125/75 mmHg) have been proposed for patients with proteinuria. Most of the studies assessing BP as risk factor for CVD were based on cohorts of young and middle-aged individuals in whom the SBP and DBP rose in parallel and in whom the principal haemodynamic alteration is increased vascular resistance. While there is no doubt that the new definitions and treatment recommendations apply to young and middle-aged subjects with essential or secondary hypertension, the question is whether the same criteria and recommendations apply to patients on haemodialysis (HD) as well.

Blood pressure as a risk factor in HD patients

Prospective studies regarding the relationship between BP and mortality in HD populations have been inconsistent and controversial. Some studies suggested poorer outcome in patients with uncontrolled hypertension, while others showed that lower BP was associated with excess mortality. Observational studies supporting the beneficial role of lower BP values have been anything but consistent. Charra et al. [14] found better survival in patients with predialysis mean BP mean BP lower than 99 mmHg, but these data were not adjusted for confounders such as age, gender, and previous history of cardiovascular diseases. Moreover, taking mean BP as a discriminant is not justified in patients with predominant isolated systolic hypertension. Mean BP or 99 mmHg does not discriminate between BP of 140/90 or 180/70, and epidemiological studies showed that high sytolic BP and increased pulse pressure are stronger cardiovascular risk factors.

Others found no direct relationship between BP and mortality in adequately haemodialysed patients [15], and several observational studies showed that low BP was independently associated with mortality in ESRD patients on HD [1619]. In the study by Zager et al. [16] in 5433 HD subjects the overall impact of BP on cardiovascular mortality was modest and increased pre-dialysis BP values, either SBP or DBP, were not associated with higher mortality. A U-shaped association between post-dialysis BP and mortality was seen for SBP>180 mmHg and<110 mmHg. Moreover, low SBP was associated with increased mortality pre- and post-dialysis. Another study by Port et al. [17] in a large sample of 4499 US HD patients confirmed the association of low pre-dialysis SBP with increased adjusted mortality risk. In a study of 1243 patients in Okinawa, Iseki et al. [18] showed that low DBP was associated with a higher death rate. The adjusted odds ratio of death was 0.84 (0.71–0.99) for each 10 mmHg increase in diastolic BP when taking DBP of 69 mmHg as the reference value. A similarly poor prognosis in HD patients with low DBP value and with high overall and cardiovascular mortality was observed by Blacher et al. [19]. To explain the discrepancies between the results observed in HD patients and in the general population, it is necessary to analyse the mechanisms which are responsible for changes in SBP and DBP. The expression of a pressure load in terms of SBP or DBP is an oversimplification, these pressures being non-specific surrogate markers of pressure load. The classical approach tends to overemphasize the importance of these two pressure values, but does not provide an analysis of the pathophysiological mechanisms underlying the modifications of these pressures [20].

Mechanisms responsible for BP characteristics in the general population

Patients with essential and/or secondary hypertension (including patients with parenchymal renal diseases and non-dialysed patients with chronic renal insufficiency) have most frequently a parallel increase in SBP and DBP. From the haemodynamic point of view this type of hypertension is characterized principally by increased vascular resistances with variable alterations of cardiac output. The latter is usually within the normal range in essential hypertension and is increased in renal patients [21]. The increase in vascular resistances is multifactorial and is due to vasoconstriction or rarefaction of resistance vessels.

Independently of the intrinsic and specific mechanisms responsible for hypertension, the BP and its haemodynamic characteristics are profoundly influenced by the ageing process [22]. In industrialized countries the BP increases with age. This process starts in childhood and continues into adulthood with a different pattern for SBP and DBP. Whereas SBP continues to rise until the eighth and ninth decade, DBP tends to remain constant or decline after the fifth or sixth decade. As a consequence the pulse pressure increases progressively with age [22]. The haemodynamic characteristics are also modified during ageing. Ageing is principally characterized by a progressive increase in arterial stiffness which becomes the dominant haemodynamic alteration in both normotensive and hypertensive subjects. This explains why systolic–diastolic hypertension is prevalent in the middle-age group, while with ageing the systolic BP rises and systolic or isolated systolic hypertension (SBP>140–DBP<90 mmHg) prevails in the elderly [22].

Under these conditions increasing SBP and pulse pressure, together with decreasing DBP are surrogate markers of arterial stiffening and progression of large artery damage, whether due to arteriosclerosis or atherosclerosis [23,24]. In middle-aged and elderly individuals the increased pulse pressure was associated with an increased risk of CVD, especially of CHD [25,26]. The risk of CHD rose when pulse pressure increased even when there was no change in SBP. This increase in pulse pressure was related to a decrease of diastolic BP. These BP changes are the consequence of progressive alterations of the large arteries. Such alterations are the culprits directly responsible for the negative association between DBP and CHD which was observed in several recent studies [24,27]. The J-shaped relationship between DBP and CHD is a source of continuing debate, and controversy surrounds the notion that lowering DBP may even increase the risk of CHD.

Blood pressure characteristics in patients in haemodialysis

Using the JNC and WHO definitions of hypertension as readings over 140/90 mmHg the majority of HD patients exhibit predominant or isolated systolic hypertension, the proportion of patients characterized by predialysis systolic–diastolic hypertension being lower than 20% [20,28]. The mortality associated with low SBP [16] reflects more probably the presence of cardiac disease and left ventricular dysfunction than an effect of BP per se. In ESRD the principal mechanism responsible for higher SBP, but also for normal or decreased DBP, is increased arterial stiffness. In HD patients stiffness of the arterial system is associated with dilatation–hypertrophy of the large central elastic arteries [29]. These changes are those typically observed in the general population during ageing [30]. The difference is that in HD patients these changes occur 15–20 years earlier. In addition to the accelerated ageing or arteries in HD patients (arteriosclerosis), a second type of pathology of arteries is seen, causing occlusive lesions (atherosclerosis). The association of mortality with lower DBP reflects therefore more the presence of advanced arterial dysfunction than an effect of low DBP per se [19]. The BP profile in HD patients is very similar to that observed in elderly patients and patients with co-morbid vascular lesions in the general population.

Which therapeutic approach?

The question is, what is the optimal BP and how far should BP be lowered in these patients, since lowering BP may be potentially hazardous, especially for those with cerebrovascular disease and those with arterial occlusive disease. The results of randomized trials provided evidence of the benefit of antihypertensive treatment in the general population across all age groups, up to an age of about 80 years. The benefit of treatment has been demonstrated among elderly subjects with classical systolic–diastolic as well as isolated systolic hypertension [31,32]. Above the age of 80 years too few patients were included and no reliable evidence of benefit could be provided.

The question is, however, what is the optimal BP one should aim for? In an attempt to answer this question the authors of EWPHE study retrospectively analysed the relationship between mortality and SBP. The data showed a U-shaped curve with the lowest mortality around SBP of 150 mmHg which seemed optimal [33]. The results of a meta-analysis of these trials showed that in older patients and patients with systolic hypertension the target BP to be reached should be based on SBP pressure rather than DBP. In therapeutic trials aimed at the treatment of systolic hypertension in the general population, the target was a SBP below 160 mmHg. The question remains open whether there is a potential risk of lowering DBP as well, even if it was low or normal at baseline. Several studies have reported a J-shaped curve relating DBP lowering to fatal and non-fatal myocardial infarctions. The authors advocated a DBP around 85 mmHg as optimal [34, 35]. These studies were usually open and retrospective and for these reasons they were criticized. A number of prospective randomized studies documented a benefit from lowering DBP with beta blockers in patients who suffered from CHD [36]. Nevertheless, one could argue against these studies that coronary perfusion is critically dependent on diastolic–tension–time index (integral of diastolic pressure over the diastolic time) [37]. With beta blockers the decrease in DBP is largely compensated by increased diastolic time so that we do not know whether one can extrapolate from beta blockers to the effect of other antihypertensive agents.

In HD patients, large scale, prospective, placebo-randomized trials looking at the effect of antihypertensive treatment on long-term patient outcome are not available. Can we extrapolate the results of intervention trials in the general population to dialysis patients? From a theoretical point of view the results can be extrapolated only to a given, defined population. This cannot be really done in the case of HD patients for at least one reason, i.e. that these patients are never in a steady state condition. They are submitted to intermittent changes in extracellular fluid volume and a hemodynamic instability on dialysis, and post-dialysis hypotension is known to be associated with poor outcome.

BP is the easiest measurable index of the load applied on the cardiovascular system but is only a surrogate marker of pathophysiological mechanisms. Therapeutic approach and optimization of treatment should depend on the real causes behind the BP profile. Considering the different mechanisms and resulting clinical profiles of hypertension, my personal opinion concerning the target BP in renal patients and HD patients could be summarized by the following few statements:

(i) in patients with renal disease and chronic renal insufficiency who are not yet on dialysis and present systolic–diastolic hypertension, follow the JNC and WHO-ISH guidelines (i.e. lower is better).
(ii) in HD patients with classical systolic–diastolic hypertension, set the predialysis BP optimum at <140/90 mmHg.
(iii) in the majority of HD patients in whom essentially only the systolic BP is increased the JNC and WHO-ISH guidelines are not applicable and no data are presently available as to how low BP should be. Lowering pre-dialysis BP too much could be hazardous in elderly patients or patients who frequently suffer from various forms of atherosclerotic arterial disease. This is especially true for patients with systolic hypertension and low diastolic BP values. In these subjects the mean BP is not the appropriate frame of reference [38]. One should take into consideration systolic BP as well as pulse pressures. In the absence of prospective controlled studies the goal of pre-dialysis BP should be at present between 160 and 150 mmHg for systolic BP and 85–90 mmHg for diastolic BP.

Notes

Correspondence and offprint requests to: G. M. London, Centre Hospitalier Manhes, 8 Grande Rue, F-917100 Fleury-Mérogis, France. Back

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