Dept. of Internal Medicine, Wayne State University School of Medicine, Detroit MI 48201 USA
"To what level should blood pressure be lowered while optimizing antihypertensive therapy?" is a question that does not have a good answer. The traditional view has been "the lower the blood pressure the better it is".
In various trials of antihypertensive treatment significant benefits in terms of stroke reduction have been shown but the decrease in coronary heart disease (CHD) events has not been that impressive. Recently there have been suggestions that lowering diastolic blood pressure (DBP) below certain levels could be dangerous. Excessive reductions in blood pressure may be the reason why major clinical trials did not show an adequate reduction in coronary artery disease events1,2. These authors proposed the existence of J- curve relationship between blood pressure and cardiovascular morbidity and mortality.
'J' curve hypothesis was first proposed by Stewart3 who showed 5 times increased relative risk of myocardial infarction in those with treated diastolic blood pressure of <90mm Hg compared to those with 100-109 mm Hg. This view was endorsed by Anderson4 upon re-analysis of unsmoothed Framingham data. Subsequently, similar results came from a number of studies5-15 showing that lowering DBP below a particular limit was of no benefit or could be deleterious. Lowest point of 'J' varies between different studies and ranged from 80-109 mm Hg (Table 1).
The Heart Attack Primary Prevention in Hypertension (HAPPHY) trial demonstrated a 'dog leg' or J- relation between treated DBP and CHD deaths with a threshold at 85mm Hg5. In an uncontrolled observation, Cruickshank et al6 studied 939 patients of moderate to severe hypertension treated with atenolol for 10 years. They found that lowering of DBP <85 mm Hg in both young and old subjects with prior coronary artery disease led to increased incidence of death from myocardial infarction. A similar 'J' relation was found between treated systolic blood pressure (SBP) and stroke with a nadir at around 144 mm Hg but there was no 'J' relation between SBP and CHD mortality.
In DHSS Hypertension care computing project7 a similar 'J' relation for DBP was found both for patients with and without pre- existing CHD. The Goteberg Primary Prevention trial found a 'J' relation for treated DBP as well SBP8. The New York Employees Cohort (NYEC) Study9 reported 'J' relationship between magnitude of fall of DBP and cardiovascular events. Highest incidence of myocardial infarction was found in those with reduction of DBP > 17mm Hg. Cooper et al found a similar relation with magnitude of blood pressure reduction in their analysis of Hypertension Detection and Follow-up Program (HDFP) data10. McClosky et al16 demonstrated a 'J' curve both for the absolute level of treated DBP and the magnitude of DBP fall. In a randomized study of elderly hypertensives12, death rate from CHD tended to be greater in those patients of isolated systolic hypertension whose DBP was <90 mm Hg. This 'J' relation was found both in the treated and the control group and therefore found to be independent of treatment.
Farnett and co-workers17 published a meta-analysis of 13 studies involving 48,000 individuals and concluded that there is a consistent 'J' shaped relationship between cardiac event rate and DBP level, most marked in those with existing cardiac disease. Since 'J' relation was also found in the control subjects, it was probably independent of treatment. In both Multiple Risk Factor Intervention Trial (MRFIT)18 and Hypertension Detection and Follow-up Program (HDFP)19 studies, individuals with baseline ECG changes were found to have higher mortality in special care group having DBP 5-6 mm Hg lower than usual care/referred care group.
On the other hand the traditional goal "the lower the better" is supported by the results of large observational studies and actuarial data20-24. Although most of these studies often included normotensive subjects as well and used baseline levels of blood pressure rather than treated blood pressure, they are cited as major support for this view. Based on the data from these studies a positive linear relationship between baseline diastolic blood pressure (DBP) and cardiovascular events has been shown without any threshold points in between. MacMohan et al25 in a recent meta-analysis of nine large, population based prospective studies concluded that there is a continuous and positive correlation between DBP and cardiovascular events and there is no threshold DBP level below which incidence of cardiovascular events tends to increase. They rejected the very idea of J curve and attributed it to certain irregularities in the supporting studies.
The debate regarding the existence of 'J' curve became further confused by questions about cause and effect relationship between low DBP and increased cardiac mortality. A large Finnish study involving >50,000 subjects apparently supported the existence of 'J' curve26. Further analysis of the causes of death revealed that the increased mortality at low blood pressure levels was due to existing cardiac and other diseases that had lowered the blood pressure. Another study from Sweden that had initially shown the existence of 'U' curve found that it existed only during the first half of the study27. Incidence of chronic disease was significantly higher in those who died in the low BP group. In the second half of the study, when most of those with chronic diseases had already died, this 'U' curve disappeared. In a community survey of >10,000 subjects 60-79 years old, death from CHD and SBP levels showed a 'J' curve relation corresponding to lowest SBP of 160-179 mm Hg28.
When subjects with existing cardiac disease, diabetes and bronchial asthma were excluded, the increase in mortality at lower pressures disappeared. Hence a new question has arisen: Whether low blood pressure is a cause of increased mortality or it is the effect of existing chronic ailments responsible for mortality? Further studies on the subject are needed to answer this question. Floras et al29,30 demonstrated that patients getting ß-blockers have substantially low BP during sleep but they are not associated with increased risk of CHD events during sleep probably because of simultaneous decrease in cardiac work and myocardial oxygen consumption.
Collins et al31 pointed out that significant reduction in mortality occurred in post myocardial infarction patients with DBP <70mm Hg when given ß-blockers, a strong evidence against 'J' curve hypothesis. A similar argument can be made from the results of the Survival and Ventricular Enlargement (SAVE) study32 that showed an improvement in cardiovascular mortality in patients with postinfarction left ventricular dysfunction after captopril treatment although a very low DBP was induced.
Results of a Medical Research Council Trial33 and a Systolic Hypertension in Elderly Patients (SHEP) Trial34, posed additional questionmarks on the 'J' curve hypothesis. The SHEP trial demonstrated 27% reduction in the incidence of myocardial infarction in those whose SBP was reduced from 171 mm Hg to 142 mm Hg accompanied by reduction in DBP from >77 to 68 mm Hg. The BBB study35 looked at the effect of intensified antihypertensive treatment (DBP <80 mm Hg) in comparison to unchanged therapy (DBP >90-100 mm Hg). Although a difference of 7.0-7.5 mm Hg in DBP was achieved between the two groups over >4 years yet there was no difference in mortality and morbidity from stroke and cardiovascular disease. The continuing Hypertension Optimal Treatment (HOT) study36, a randomized trial involving 19196 hypertensive patients is looking at the relationship between three different levels of target DBP and cardiovascular morbidity and mortality. Results of this study may provide a valuable insight into this intriguing question.
Whether 'J' curve exists or not and what is the cause and effect relation between
cardiovascular events and low DBP are still not clear.
As the existing data do not suggest a consistent 'J' relation between stroke and DBP, it
is reasonable to consider reducing BP to conventional levels (70-90 mm Hg) to prevent
stroke mortality.
Unfortunately such reductions may be deleterious in precipitating cardiac events
particularly in the patients with known cardiac disease.
Therefore a reasonable compromise at current stage is to be cautious in lowering diastolic
blood pressure below 85 mm Hg in the patients with known coronary artery disease.
Table 1
THE TRIALS FOR (+) AND AGAINST (-) J-CURVE
| STUDY | "A" M.I. Incidence |
"B" M.I. Mortality |
"C" J Curve threshold D.B.P |
Cruickshank et al6 |
(-) |
(+) |
85-90 |
| DHCP7 | (-) | (+) | 86-91 |
| HDFP10 | (+) | (+) | * 26 |
| Waller et al14 | (-) | (+) | 91-98 |
| HEP12 | (+) | (+) | 80-89 |
| Stewart3 | (+) | (+) | 100-109 |
| NYEC9 | (+) | (+) | >17* |
| EWPHE11 | (-) | (+) | ** |
| PPT8 | (+) | (+) | 86-89 |
| IPPPSH15 | (+) | (+) | 92 |
| ANBP13 | (+) | (+) | 85-89 |
| MRC33 | (-) | (-) | *** |
| HAPPHY5 | (+) | (+) | 85 |
| SHEP34 | (-) | (-) | *** |
| BBB35 | (-) | (-) | *** |
* Magnitude of change in D.B.P.
** Increase relation, no threshold
*** Not J relation.
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Address For Correspondence and corresponding author:
Dr. Anil Kumar Goel, MD DM
3737 Beaubien Blvd. #908
Detroit MI 48201 USA
Ph: & fax: (USA) 313 832 4172
Email: anil_goel@hotmail.com
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