Hypertension 1996 : One Medicine, Two Cultures

Arterial hypertension, not valvular atrial fibrillation and stroke

Sergio Matteoli, Massimo Trappolini, Fabio Massimo Chillotti
II Clinica Medica, Unità Coronarica, Università degli studi di Roma “La Sapienza”

The acute cerebrovascular event prevention represents one of the most important challenges of modern medicine, intended to contrast the social high costs, in terms of mortality and morbidity caused by those events.
In the western world cerebrovascular diseases, represent the third mortality cause, after the coronaric disease and cancer. It is the most frequent motive of acquired disability in the adult age (1), in spite of the preventive action and the therapeutic progresses during the years have leaded to a gradual reduction of mortality for cerebrovascular events, without determining a parallel incidence's decrease (1,2).
For a best comprehension of the problem, we have to remember that in USA, every year occur about 500,000 cases of stroke, whose, something less than 1/3, is fatal (1,2) cerebrovascular disease represents an important pathology, also under the economic profile: the expenses sustained, every year, for the disease, are estimated around sixty thousand millions of dollars, a part for the direct costs (hospitalisation, rehabilitation, medical cures), and an other part, for the indirect costs (loss of productivity), without considering the relative's economic and the human price (3).
Also in Italy with an incidence of more than 200 new cases for 100,000 inhabitants/year, ictus represents a particular human and social involvement's field (4).
From those considerations, to reduce the incidence of stroke and its social and economic weight the preventive measures have the main role identifying and correcting the original risk factors.
Among the “unchangeable” risk factors as: the age, the sex the race, the inheritance, the age has a particular importance, mostly considering, the population's gradual ageing (5). In females, the risk is minor, and it decreases in the older ages.
Among “changeable” risk factors are: arterial hypertension, cardiopathy, atrial fibrillation, Diabetes Mellitus, hypercholesterolemia, smoke, alcohol. Arterial hypertension has the main role, principally for the high prevalence (25-40%) of this disease, in general population (6).
The stroke risk, associated to the hypertension, decreases with the age, but it still remains significant (7) in the population of Framingham, the 56% of the strokes, in males, and the 66% in females, has been directly attributed to the hypertension (6); the 80.3% had hypertension, the 7% had ischaemic cardiopathy, the 14.5 had cardiac insufficiency and the 14.5% had atrial fibrillation.
The percentage of strokes associated to the atrial fibrillation, is particularly relevant in the old age, reaching the 36% of cases, in patients with the age included between 80 and 89 years.
The increase of the average and of the number of subjects with atrial fibrillation, a larger knowledge of the thromboembolic risk, justifies the renewed interest of such arrhythmia. Concerning the recidivation of stroke only the arterial hypertension atrial fibrillation results significantly associated to an increase of the risk (9). Furthermore, a vast experience has been acquired, and it has been desumed from many trials of primary and secondary prevention, to demonstrate the efficiency of a proper treatment, in reducing the incidence of cerebrovascular disease (2).
Our intervention will be dedicated to those two affections.

Arterial hypertension

Arterial hypertension represents a risk factor for all the main kinds of stroke: major for the ischaemic tied with the cerebral small vases, or secondary to a cerebral haemorrhage, smaller for the ischaemic events, successive to the atherosclerotic disease of the aorta and of the epiaortics vases, minor for the subaracnoidh haemorrhage cases (10). Hypertension favours and accelerates atherogenesis processes at the aortic arch, carotid and vertebral vases level that can promote ischaemia, by haemodynamic and thromboembolic mechanisms (10 11, 12). Epidemiological and clinical evidences, on the contrary, enhance the low-pressure values protective role in atherogenesis. Hypertension co-operates with the cariopathies development, which also are stroke’s risk factors, specially cardioembolic and it determines a constant involvement of the brain’s small penetrating arteries that go towards hyaline degeneration and aneurysmatic dilatation. The micro-atheromas and micro-aneurysm formation, which comes from, induces the perforating arteries to the occlusion and/or to the brake, therefore to lacunar infarct, and/or to intracranical haemorrhage (10, 12). Though lacunar forms are more directly connected with the negative effects of The high tensive values, recent clinical observations suggest that hypertension is an important cortical infarct inducing factor (12).
Doubts, still present few years ago, about the light and mild hypertension treatment have been erased by the epidemiological evidences, and by the results of the checked clinical trials.
Epidemiological studies, as evidenced in a recent metanalysis (13), demonstrate that hypertension is an important cardiovascular risk factor, and that there is a linear relation between systolic and diastolic pressures and the risk of cerebrovascular events. The arterial pressure levels still constitute an important stroke risk factor, not only in hypertensive, but also in normotensives, among which, there are more than the 50% of stroke (13).
O n the base of the data, deduced from the observations, it has been possible to estimate, for an average reduction of 5 mmHg for the diastolic pressure and of 9 mmHg for the systolic pressure, a decrease of the stroke’s incidence of about one third, that can be halved for average reductions of 7.5 mmHg for the diastolic pressure. From those observations, they have been done checked clinical studies, to demonstrate the efficiency of an antihypertensive treatment, to prevent cardio and cerebrovascular complications. As a recent metanalysis, conducted on 14 studies, and involving 37,000 patients, has demonstrated, the pharmacological therapy benefit, has resulted, for the cerebrovascular morbidity and mortality, overlapping to those expected from the epidemiological studies (14). Successive, have confirmed that a reduction of 5-6 mg for the diastolic pressure determines an incidence decrease of stroke of 38% and coronary events of 16% (15).
Nevertheless the risk reduction entity does not seem conditioned by diastolic pressure values taken during the entrance into the studio; and it is similar for both the fatal cerebrovascular events, and for the non-fatal ones (5).
Also in the old, many trials have demonstrated the benefit of the pharmacological therapy in reducing the cerebrovascular morbidity and mortality in patients with systo-diastolic hypertension, and the systolic isolated (l6).
Although “relative benefit” comma from the therapy, meant as the prevented events percentage is almost uniform and independent from the seriousness of the hypertension from the age and from the cerebrovascular precedents; the “absolute benefit” i.e. the number of prevented events for the number of treated patients, is greater in patients, whose risk is bigger, as the old (16, 17, 18).
The prevalence of the isolated systolic hypertension in senility, present in 10-20% of the subjects in an age included between 70 and 80 years, has to be underlined (19). Nonetheless the epidemiological evidences of an increased cardiovascular risk (20), the treatment of this affection has been neglected for a long time until the spreading of the SHEP studio's results (21), that has been the first to show the efficiency of the pharmacological treatment, in subjects older than 60 years with isolated systolic hypertension, to reduce the fatal and non-fatal stroke risk, also among the over-eighties (22).
Considering the high prevalence of systo-diastolic hypertension, and the high risk of stroke in the old patient, and applying the SHEP's results to the population of USA, to more than 4 million of over-sixty with isolated systolic hypertension, it has been estimated that, every year, more than 24,000 strokes and 44,000 more serious vascular events (22), could be prevented.
Although the data of this studio don’t support a possible increase of the cerebrovascular risk, for the reduction of the arterial diastolic pressure under 80 mmHg, in any case, in the old people, the treatment of both the isolated systolic and the systo-diastolic hypertension should be carefully started. In fact, the autoregulation troubles of the cerebral flow are more evident in the old subjects, in whom, even normally, spontaneous reductions of the cerebral flow can occur, as a consequence of simple postural variation (23).
In the therapeutic approach, all the possible alterations of the cerebral flow’s autoregulation mechanisms, of the baroceptors reflexes and the reduction of vascular compliance, mainly of the big vases, as the possible ischaemic consequences, caused by an excessive pressure drop, mainly in presence of haemodynamically significant lesions at the coronaric carotic and/or vertebral level, have to be considered.
The anti-hypertensive treatment doesn't seem to influence negatively the quality of life, that is a critic aspect mainly, in old patients, who are more inclined to concomitant pathologies. Contrarily to the expectations, the different trials have shown that the percentage difference of subjects, who suspend the active treatment for adverse reactions, is similar between middle-aged and old subjects’ (18).
At last.' we have to consider that also the border line systolic hypertension, defined for the following values: 140 mmHg<PAS< 160 mmHg; PAD <90 mmHg; the most common form of the old subject's hypertension (24), leads to a sensible increase of the cerebrovascular events' risk and of the tendency to a defined hypertension status (24), and a therapeutic intervention is justified, also with non-pharmacological nature measures.

Atrial fibrillation

AF is a frequent arrhythmia, whose prevalence, same of 0.4% in the adult population (25), dramatically increases with the age up to values over 10% beyond the 75 years (26). With the progressive decline of the rheumatic cardiopathy, the most common pathologies associated to AF are: arterial hypertension, cardiac decompensation, ischaemic cardiopathy, cardiomyopathy; in a variable percentage from 3% to 20%, singes or symptoms of an organic cardiopathy aren't detectable, therefore it is called “idiopathic” atrial fibrillation or “isolated” (27, 28, 29, 30).
AF also constitutes an independent risk factor of stroke, together with arterial hypertension, ischaemic cardiopathy, and cardiac decompensation. Differently from these, where the relative risk tends to decrease with the years, the one connected to AF is mainly determinant in the older ages (8); in fact, in patients hit by ictus the prevalence of AF increase with the age, changing from 6.7% in the age between 50 and 59 years, to 36.2% between 80 and 89 years (8).
A high thromboembolitic risk has been known for a long time in patients with AF and rheumatic valvulopathy, but just now, we know that an evident risk exists also in patients with Non Valvular Atrial Fibrillation (NVAF), or associated to other clinical conditions, different from the rheumatic valvulopathy. The epidemiological studies (31, 30, 32, 33) have shown, in patients with (NVAF), a stroke risk 5 times superior than the checked one in sinusal rhythm, with an annual events incidence variable from 1.4% to 5%, in base of the checked population's characteristic. Such incidence is not very different from the one, recently learnt in checked patients subjected to placebo in clinical trial randomised of anti-thrombotic therapy (34, 35, 36, 37, and 38).
In cerebral ischaemic events genesis, though the cardioembolic phenomenon is the most realizable and more frequently involved, aortic and carotic arteriosclerotic lesions can occur, mainly in older subjects observed in 30% of patients with NVAF (39). The frequent association between NVAF and arteriosclerotic disease, makes difficult the exact valuation of the cardioembolic mechanism prevalence (40) estimable, reported to the clinical, arteriographyc, ultrasonographyc carotic and autopsic data, around 50-70% (41). Among patients with NVAF, subgroups with a different risk profile of thromboembolic events can be identified. The risk can be major and minor, reported to clinical, instrumental, and of laboratory, predictive variables as: age, sex, aetiology, arterial hypertension, cardiac decompensation, embolic precedent, arrhythmia’s characteristics, echocardiographic reports, associated aortic and carotic lesions, TC relief of a silent ischaemic insult and haemo-coagulative factors (42).
A recent collaborating analysis on the data's pool deduced from 1236 patients, randomised at placebo in the five clinical trials of primary prevention (43), has identified the successive predictive clinical variables of embolic risk: arterial hypertension history, previous stroke or TIA, diabetes mellitus, recent cardiac decompensation and old age. The echocardiogram's evidence of global left ventricle dysfunction and of left atrial dilatation, have resulted, to a (multivariate) analysis conducted in the SPAF study, predictive factors of an additional risk to the clinical variables (44).
In this context, it has to be underlined, the un-renounceable contribution of the trans-oesophageal echocardiography, that gives an easy identification of the auricular thrombosis and it allows to observe the low speeds of the flow in the left auricle, and the spontaneous echo-contrast, that are factors representing something more than simple precursors of the thrombus formation (45). The predictive value of these markers has been estimating in SPAF III and in other prospective studies.
A correct layering of the embolic risk represents a crucial moment; it is critic to program a right preventative intervention, respecting a positive balance risk-benefit.
The primary prevention studies (34, 35, 36, 37, 38) demonstrated the efficiency of the anti -coagulant therapy, also in case of a modest (scoagulation), to reduce the embolic risk of more than 2/3, but the increment of serious haemorrhages' risk, included between 0.8 and 2% a year, discourages the extension of such treatment to the low-risk subjects; not considering the treatment's social costs, and the necessity of verifying in the clinical practice the haemorrhage risk observed in the therapeutic trials.
The aspirin's therapeutic action is debated. It is without any statistically remarkable effects in The AFASAK study (36) and able to significantly reduce, of 46%, the risk of stroke in the SPAF study (38); the protective action of the aspirin seems limited to subjects under 75 years, and to the prevention of stroke of intended non cardioembolic nature (46). The minor efficiency of the therapy with aspirin, in the Danish Study has been explained with the characteristic of the population, engaged in age terms, (average 74.2 vs. 66.6), of cardiac deconpensation’s prevalence and of ischaemic cardiopathy, and with a lower dosage of aspirin (75 mg/die vs. 325 mg/die).
SPAF II has given an important contribution on the efficiency and the security of The anti-coagulant therapy and aspirin, reported to the age (75 aa or >75 aa) (47). Warfarin resulted more efficient than aspirin in both groups of patients, with a yearly incidence reduction of ischaemic events equal to 0.8%, but this benefit is mostly lost in subjects over 75 years when intracranic haemorrhages also are considered in the analysis. In patients younger than 75 years, without any risk factors (previous embolic event, decompensation, hypertension), treated with aspirin, it has been observed a really low incidence of primary events equal to 0.5 % a year.
The message given by these trials, is that an anti-coagulant therapy in the old patient, must be applied very carefully, paying attention to the (scoagulation) degree and to the predictive clinical elements of haemorragic risk, among whom, a proper control of the arterial pressure values, doesn't have to neglected.
There are still doubts on the anti-coagulant therapy's modalities (times and doses), after a primitive cardioembolic stroke; the fearful complication of the ischaemic lesion's haemorragic transformation opposes itself to the potential benefits coming from the reduction of the praecox recidivation's risk. The extended infarcts, with hypo density at a praecox TAC, occurring in patients over 70 years and with a continuous high arterial pressure values (49), have a higher risk of haemorragic transformation.
An important contribution to our knowledge is given by the result of the European results of the European Atrial Fibrillation Trial (EAFT), a secondary prevention study, (50), and by the first data of the Studio Italiano Fibrillazione Atriale (SIFA) (51, 52).
The EAFT study, confirmed the high risk of stroke recidivations, equal to 12% a year, in checked patients with placebo; almost triplicate, reported to that observed in primary prevention trials, stated the anti-coagulant therapy efficiency, in reducing such risk by more than 2/3 (67%).
The aspirin action is minor, with a benefit similar to the one observed in other anti-thrombotic therapy studies, in patients with TIA or minor stroke.
The Studio Italiano Fibrillazione Atriale (SIFA), multicentric, randomized, checked, not blind, that has involved more than eighty neurologic centres, collaborating with other cardiologic centres, has estimated, in patients with chronic or paroxysmal FANV, the efficiency and the tolerability of the oral anti-coagulant treatment with Warfarin (INR 2.0-3.5) vs. a thrombocytic antiaggregant, indobufene, in the cerebral ischaemic events prevention and other probable cardioembolic events, successive to a first recent cerebral ischaemic event, in two weeks.
It has been observed an incidence of major events, around the 10%, without a statistically significant difference between the two groups of treatment in the studies SIFA and EAFT, excepted for the treatment's duration and for the time passed between the qualifying event and the engaging, they are similar for the inclusion criteria, for the end-points definitions for the engaged patients' characteristics, and then it is possible to make a comparison between the two trials.
In subjects with anti-coagulant therapy, there is an incidence of major events and of stroke similar in both the trials; in the patients assigned to the indobufene, in the SIFA study, it has been observed an incidence of events slightly superior than in patients treated with warfarin, but a less inferior than the one told, in the EAFT study, in patients treated with aspirin and/or placebo.

Conclusions

Though we augur that the progress of the therapeutic strategies, leads to a rapid improvement of the ictus' prognosis, both in terms of mortality and of disability, major benefits are, still now, expected from the preventative measures.
It has to be emphasised the necessity of an intervention in subjects with major risk, as those with arterial hypertension, atrial fibrillation and/or with more coexisting risk factors.
The hypertension therapy is the base of the primary prevention of cerebrovascular diseases. Similarly the unsatisfactory hypertension check in the population is the cause of the partial failures obtained in this sector.
Atrial fibrillation is a common arrhythmia, mainly in the old patient, and the stroke, certainly represents its most serious complication. It is possible in patients with FANV, a therapeutic preventive strategy for the cerebral ischaemic events, maybe more efficient than the one realizable in other conditions.
The choice of the treatment, anticoagulant and antiaggregant, has to consider of the patient's profile, with regard to the conditions of thromboembolic risk and to the susceptibility to haemorragic events.
It has been estimated that more than the 50% of the strokes, could be prevented by proper interventions in patients with atrial fibrillation and with arterial hypertension.
There are studies that will allow, in the near future, to:

  • Have a greater knowledge of the various subtypes of stroke, which can give a different answer to the preventive measures.
  • Value the effect of the intervention (antihypertensive therapy) on more variables, for the frequent concomitance of more risk factors.
  •  Verity the efficiency of multifactorial interventions, with studies aimed both to the prevention of the events than to the regression of the organ's damage.

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