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Frontiers of Hypertension Treatment

A More Rigorous Approach to Blood Pressure
Graham MacGregor
St. George's Hospital Medical School, London, UK

Antihypresentive Therapy and Cardiovascular Prognosis: Recent Evidence from Clinical Outcome Trials
Jan A. Staessen
University of Leuven, Leuven, Belgium

Advances in the Treatment of Hypertensive Patients with Diabetes
Toshiro Fujita
University of Tokyo, Tokyo, Japan




A More Rigorous Approach to Blood Pressure

Graham MacGregor
St. George's Hospital Medical School, London, UK



In Japan, the most common cause of death is stroke, cerebral hemorrhage, cerebral thrombosis, which are directly related to the level of blood pressure, and heart failure. As the population increasingly ages, hypertensive heart failure is the most common cause of heart failure. Coronary heart disease is becoming more common in Japan, associated with the increasing consumption of a Western diet.

Blood pressure is the major risk for cardiovascular disease. Recently published data show that the risks of blood pressure have been underestimated by about 50%. Importantly, it is not just elevated blood pressure, but blood pressure throughout the entire range that is associated with increased risk. A person with a systolic blood pressure (SBP) of 145 mm Hg is at much greater risk for stroke than a person with a SBP of 120 mm Hg.

More people have blood pressure levels in the upper range of normal than have very severe hypertension. More strokes occur in persons with blood pressure in the upper range of normal than in persons with severe hypertension, at least in Western countries.  Population measures must be adopted to lower blood pressure in the entire population, and in particular to stop the increase in blood pressure with age. In Japan, 80% of the population over 60 years of age has blood pressure above the upper range of normal. 

Cardiovascular (CV) disease (stroke, heart failure, MI) is totally preventable if diet and lifestyle are changed. Population strategies must be adopted to have a true effect on reducing CV disease, rather than the current high-risk strategy that identifies and treats persons with elevated blood pressure and other risk factors. Population strategies include addressing smoking, fat intake, salt intake (the single biggest risk factor for death in Japan), and consuming more fruits, vegetables and potassium, as well as decreased weight decrease and increased exercise. 

 

Salt intake and blood pressure

The relation between salt intake and stroke is well-documented, including data from Japan in the 1950s. Some 50 studies show the role of controlling salt intake to control blood pressure in the population, particularly because of the rise of blood pressure with age. Migration studies from Kenya and Ethiopia clearly show that moving from a low to a high salt intake environment results in increased blood pressure, partly due to increased salt intake. A 50% reduction in salt intake resulted in marked differences in blood pressure compared to no reduction in an important intervention study in Portugal.

Interestingly, chimpanzees have dramatic increases in blood pressure when fed the same amount of salt as in a typical Japanese diet, which reduces in about 3 months after stopping the increased salt intake. It would seem the diet would have the same effect in humans. Kidney function, either diminished ability to excrete sodium or to hold sodium, is involved with the genetic causes of hypertension or hypotension. In total, the evidence for salt is stronger than for any other dietary constituent for cardiovascular disease.

A reduced salt intake resulted in a decrease in stroke in Japan. A public health campaign in Japan to reduce salt intake in the 1960s, at the same time that there was an increase in weight, fat consumption, and cigarette smoking and a decrease in exercise, resulted in a reduction in stroke. The DASH Sodium study in the US showed that a diet high in fruit and vegetables reduced blood pressure, and that salt restriction further reduced blood pressure.

A greater reduction in salt intake results in a greater reduction in blood pressure. A dose-response reduction in blood pressure in relation to salt restriction was shown in a meta-analysis by MacGregor and colleagues. 

The WHO has set a target of 5 grams of sodium per day. The Japanese Ministry of Health has set a target of 10 grams of sodium per day. A reduction in the daily sodium intake from the usual 12-14 grams per day to 8 grams per day would result in a reduction in SBP of 7 mm Hg in hypertensives and 4 mm Hg in normotensives in  Japan. A 6 gram reduction in daily salt intake would result in a 24% reduction in stroke.

Other harmful effects of salt include sodium and water retention, left ventricular hypertrophy, aggravating effect on asthma, direct cause of stomach cancer, and aggravating bone demineralization by leaching out calcium out of the bones into the urine.

Processed foods are responsible for most of the salt consumed, making reduction in the salt content of processed foods over time a key population strategy. In the UK, the salt content of all processed foods is being slowly reduced, with no noticeable change in taste. A similar approach is needed in Japan, to reduce over time the salt content of soy sauce, pickles, and other high-salt foods.

 

Benefits of treatment

The benefit of treatment is clear. Treatment should include lifestyle changes including reduction of salt intake to a maximum of 5 grams daily, reduction of fat and alcohol, increased intake of fruits and vegetables, and increased exercise. All risk factors, such as elevated blood sugar and lipids, are treated. The need for 2 or more drugs to control blood pressure renders irrelevant the question of which of the five classes of drugs to use to initiate treatment.

The ALLHAT study compared 3 major classes of antihypertensive agents, diuretics (chlorthalidone), ACE inhibitors (lisinopril), and calcium channel blockers (amlodipine). Amlodipine was slightly more effective than chlorthalidone in reducing stroke, but not statistically significant, while lisinopril was slightly less effective in stroke. Each drug had the same effect on CHD. The study design, which did not allow adding these drugs together as would be done in real clinical practice, makes analysis problematic. The lisinopril group, as would be expected, had higher blood pressure, perhaps explaining the difference in stroke. Very small differences in blood pressure can make quite big differences in outcome.

The conclusion that diuretics should be first-line treatment is not supported by the study data. Hypokalemia is one danger of diuretic-based treatment. The SHEP study, in isolated systolic hypertension in the elderly, showed that chlorthalidone-based treatment reduced cardiovascular events by about 50%, provided that potassium was not lowered. In a subgroup in which potassium was lowered to less than 3.5 by chlorthalidone, treatment was not beneficial. Thus, caution must be used with diuretics to prevent a fall in plasma potassium.

The ANBP2 study, a well-controlled comparison between diuretics and ACE inhibitors, showed that the blood pressure and outcome were identical between the two groups. MacGregor states the finding of the ALLHAT study is questionable, and all drugs are equivalent provided the same blood pressure target is achieved. The more important issues are how to combine the drugs to reach target levels and controlling blood pressure—7 of 10 people have uncontrolled blood pressure.

The benefit of reducing blood pressures in the normal range is shown by the HOPE and PROGRESS studies.  In HOPE, patients with CV risk and normal blood pressure had fewer CV events on ramipril versus placebo. In PROGRESS, in post-stroke patients, stroke and CHD were reduced with the combination of a diuretic and ACE inhibitor versus placebo—independent of the initial blood pressure. The benefit was greatest in persons with normal versus elevated blood pressure.


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Antihypresentive Therapy and Cardiovascular Prognosis: Recent Evidence from Clinical Outcome Trials

Jan A. Staessen
University of Leuven, Leuven, Belgium



Reducing blood pressure improves prognosis based on evidence from clinical intervention studies. Systolic hypertension is a major but reversible risk factor and is a risk factor particularly for stroke and dementia. Controlling blood pressure is the key to preventing these events and may substantially increase quality of life. Management of blood pressure should be an integrated part of the overall risk management of patients.

Studies in the US, UK, Sweden, and New Zealand show a curvilinear relation between increasing age and the risk of stroke. By 60 years of age, the annual incidence of stroke is about 100/100,000 people. Stroke risk is 2-fold greater for 75-84 years of age and 3-fold greater over 85 years. In Japan, the major complication of hypertension is stroke. 

Ischemic heart disease is the leading cause of death and stroke is becoming the second leading cause of death worldwide. The aging population worldwide likely will result in an increase in stroke. The age-specific incidence of dementia is curvilinear, with about a 10% incidence at 65 years of age and a 40% or higher incidence over 80 years.  The Syst-Eur trial showed a 55% reduction in the incidence of dementia in patients on active treatment; primarily a decrease in neurodegenerative dementia. In contrast, in the SHEP trial, the incidence of dementia was lower and there was no difference between the two treatment groups.

Systolic blood pressure (SBP) is a known indicator of risk, particularly in the elderly. The prevalence of isolated systolic hypertension (ISH), defined as a SBP of at least 160 mm Hg, increases with age; at 60 years it is about 8%, at 70-80 years it is 20-25%.

 

Primary prevention data

A meta-analysis of placebo-controlled, randomized clinical trials, including three trials of ISH, showed a significant 30% decrease in fatal and non-fatal stroke with treatment.

Syst-Eur, a double-blind trial, randomized patients to placebo or active treatment (calcium channel blocker, nitrendipine) with the possible addition of enalapril and hydrochlorothiazide. A 42% reduction in the primary endpoint of combined fatal and nonfatal stroke in the active treatment group caused an early termination of the trial. At the end of the double-blind trial, a difference of about 10 mm Hg between the placebo and active treatment groups was found.

In the extended follow-up of Syst-Eur, in which all the study patients were offered the same active treatment as in the study, a 30% reduction in fatal and non-fatal stroke was found. When comparing the participants in the extended follow-up (n=3,516) and the non-participants (n=397), the fatal and non-fatal stroke incidence was the same in the patients on placebo switched to active treatment.

The initial benefit for the patients on active treatment in the double-blind trial may explain the difference in the stroke reduction in the trial and in the extended follow-up.

The clinical message is to initiate treatment immediately when systolic hypertension is diagnosed and treat to target levels to prevent stroke. A delay in treatment is associated with a 30% higher incidence in stroke.

In the ALLHAT trial, a significantly greater proportion of patients remained on first-line treatment (an indication of being controlled by the first-line drug and lack of side effects) in the chlorthalidone and amlodipine groups, compared to the doxazosin and lisinopril groups. More patients in the lisinopril group required combination therapy to control blood pressure, compared to the chlorthalidone, amlodipine, and doxazosin groups, which were similar in the need for combination therapy. The average follow-up was 5 years. Chlorthalidone was associated with the best control of blood pressure, and with amlodipine blood pressure was 1 mm Hg higher, and with lisinopril and doxazosin it was 2 mm Hg higher.

For the primary endpoint of coronary heart disease (CHD) there was no difference between the three treatment groups in ALLHAT. For combined CHD (coronary revascularization and hospitalized angina), a marginally higher risk was seen with doxazosin compared to chlorthalidone. For stroke, no difference between amlodipine and chlorthalidone, but a significant increased risk for stroke with lisinopril and doxazosin (p=0.02 and p=0.04, respectively) was seen.

In active-control trials, calcium channel blockers were associated with a 10% less risk for fatal and non-fatal stroke compared to beta blockers and diuretics. ACE inhibitors are associated with a 10% increased risk of stroke as first-line treatment compared with diuretics and beta blockers.

 

Secondary prevention data

The PROGRESS trial randomized patients to perindopril only or perindopril plus indapamide. A 28% reduction in stroke incidence was found overall. For the perindopril plus indapamide group, a 43% reduction in stroke recurrence was found, compared to no change in the perindopril only group. The difference in SBP was 12 mm Hg in the perindopril plus indapamide compared to only 5 mm Hg in the perindopril only group.

The PROGRESS investigators concluded that the small difference in blood pressure between the groups was responsible for the difference in stroke recurrence. However, the PATS study, conducted in China, with a design similar to PROGRESS, showed that just a 5 mm Hg difference in blood pressure between the two groups was associated with a 30% lower stroke recurrence rate with the addition of indapamide. In the PATS study, even in the normotensive patients (n=90) there was a 40% reduction in stroke recurrence with indapamide.

 

Benefit of lowering blood pressure

A meta-regression analysis of 30 trials in hypertension by Staessen and colleagues showed a curvilinear relationship between the achieved difference in the SBP and the odds ratio for stroke. Clinically important, just a difference of 1 to 5 mm Hg in SBP was associated with a reduction in stroke incidence. In the HOPE trial, a 3 mm Hg greater reduction in SBP was associated with a 30% reduction in fatal and non-fatal stroke.

The incorporation of the LIFE and ALLHAT data in the meta-regression analysis suggests that much of the outcome in these studies can be explained by the blood pressure reduction. In LIFE, s a significant 1 mm Hg difference in SBP between the losartan and atenolol groups and a 3 mm Hg in SBP in the diabetic subgroup was seen. In the ALLHAT study, a 1 mm Hg difference in SBP with amlodipine and a 2 mm Hg difference with lisinopril and doxazosin, all compared to chlorthalidone, was seen. In the elderly patients in ALLHAT, a 3 mm Hg difference in SBP was seen with lisinopril compared to chlorthalidone.


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Advances in the Treatment of Hypertensive Patients with Diabetes

Toshiro Fujita
University of Tokyo, Tokyo, Japan



Diabetes mellitus (DM) is associated with an increased risk of hypertension and an increase in cardiovascular (CV) mortality. Blood pressure reduction is a prime factor responsible for reducing the incidence of CV events and renal disease progression in patients with DM. However, what is sufficient treatment of hypertension to prevent CV is not conclusive, and dispute remains concerning the target blood pressure and choice of antihypertensive agents in patients with DM.

The association between diabetes and hypertension has been demonstrated by several epidemiological studies. In a Japanese epidemiological study, 8% of the general population had diabetes and 27% had hypertension, while 4% had both diabetes and hypertension. The prevalence of diabetes was 3-fold greater in hypertensive than in non-hypertensive subjects, and the prevalence of hypertension was 2-fold greater in diabetic than non-diabetic subjects. The association of diabetes and hypertension is very common in Japan.

Persons with diabetes are at very high risk. Data suggest that diabetes is one of the greatest risks for cerebral, cardiac, and renal target organ damage. An epidemiologic study from Finland showed that the long-term risk for myocardial infarction (MI) was highest in persons with diabetes whether or not they had a previous MI, compared to persons without diabetes. The incidence of a future MI in diabetic patients without a prior MI was the same as that in non-diabetics with a prior MI. The Hisayama epidemiologic study in Japan revealed that diabetics had a 2.5- to 3-fold greater incidence of cerebral infarction and coronary heart disease.

 

Clinical trials with AHA in diabetic patients with HTN

Aggressive blood pressure control is crucial to reduce CV events in diabetic patients with hypertension. The SHEP randomized, placebo-controlled, double-blind study compared diuretic-based care with placebo in 4,736 elderly patients with isolated systolic hypertension over an average of 4.5 years. Post-hoc examination of the diabetic cohort suggested that the benefit of AHA therapy was at least as great in diabetics as in non-diabetics.

The Syst-Eur study reported key data about the safety and efficacy of treating hypertension in elderly patients with diabetes with calcium antagonists. In the diabetic cohort of 492 patients, treatment of hypertension was associated with cardiovascular risk reduction. All-cause mortality, cardiovascular death and fatal and non-fatal cardiovascular events were all significantly reduced with anti-hypertensive therapy in the diabetic cohort compared to the non-diabetic cohort.

Tight blood pressure control, compared to less tight control, was shown in the UKPDS study to be more effective to inhibit the incidence of cardiovascular events compared with intensive plasma glycemic control, versus conventional control, in persons with type 2 diabetes. Diabetes-related endpoints were reduced 24% with tight blood pressure control, compared to less-tight control, while the reduction was only 12% with intensive glycemic control. Similarly, tight blood pressure control reduced microvascular endpoints by 37% while the reduction was only 25% with intensive glycemic control. Tight blood pressure control in UKPDS was only 144/82 mm Hg, which is higher than the currently recommended target blood pressure in persons with diabetes.

The primary aim of the HOT study was to define the optimal target blood pressure in treated hypertension patients, by evaluating the effect of three different diastolic blood pressure (DBP) target levels on cardiovascular morbidity and mortality. There was a trend towards greater benefit the lower the target diastolic blood pressure. In the diabetic cohort, there was a trend towards greater benefit with lower DBP, and the risk of major cardiovascular events was 50% lower in the group with a DBP less than 80 mm Hg compared to less than 90 mm Hg. Although the difference in blood pressure between the 3 groups was less than anticipated at only 4 mm Hg, the risk of cardiovascular events was markedly decreased. This observation strongly supports the result of the UKPDS that there is a definite benefit in targeting lower treated blood pressure in patients with diabetes and hypertension. Based on the HOT results, the target diastolic blood pressure should be less than 80 mm Hg in patients with diabetes.

The Japanese Society of Hypertension guidelines recommend a target blood pressure of less than 130/80 mm Hg in persons with diabetes. The 2002 recommendation from the American Diabetes Association was also < 130/80 mm Hg.

A steep annual increase in the number of patients on hemodialysis in seen in Japan. The prevention of end-stage renal disease (ESRD) is a major problem in Japan. Diabetic nephropathy is the leading cause of ESRD in Japan, while the incidence of chronic glomerulonephritis has been decreasing.

The benefit of renin-angiotensin blockade in patients with diabetic nephropathy is supported by trial evidence. In 1985, captopril was shown to markedly decrease urinary protein excretion in patients with diabetes. In patients with type 1 diabetic nephropathy, captopril was shown to have a reno-protective effect, with a 2-fold decrease in the number of patients with a doubling of serum creatinine, compared to placebo. This was associated with a significant 48% risk reduction. In the RENAAL study, losartan was shown to inhibit the progression of ESRD in patients with type 2 diabetic nephropathy. The number of patients with a doubling of serum creatinine was less in the losartan group compared to placebo, with a 28% and 25% risk reduction, respectively. Angiotensin receptor blockers (ARBs) are similar to ACE inhibitors for its anti-proteinuric effect and it inhibits renal disease progression in patients with diabetic nephropathy.

The IDNT study suggested that the ARB might be superior to calcium antagonists in patients with diabetic nephropathy. Irbesartan and amlodipine were associated with a  risk reduction in the doubling of serum creatinine, ESRD, and death. Therefore, ARBs are well-established to inhibit the progression of diabetic nephropathy.

The IRMA study with the ARB irbesartan showed that the renoprotective effect of ARBs may be independent of blood pressure lowering. In patients with mild diabetic nephropathy associated with microalbuminuria, the incidence of diabetic nephropathy was reduced in a dose-dependent fashion with irbesartan, although the blood pressure reduction in both irbesartan groups and placebo group was similar. Blood pressure reduction was higher than recommended, at an average of 133-144 mm Hg SBP. A clear linear relation has been shown between level of mean arterial blood pressure and decrease in glomerular filtration rate. Thus, blood pressure must be lowered below 130/80 mm Hg or more to inhibit the progression of renal disease. Although ACE inhibitors and ARBS are preferred treatment in patients with diabetic nephropathy, there is no data to show whether antihypertensive agents affecting the renin-angiotensin system are superior to the other classes of AHA when blood pressure is tightly controlled.

 

Beyond blood pressure lowering

Ramipril significantly decreased myocardial infarction and cardiovascular death in patients with diabetes, despite small reductions in blood pressure, in the MICRO-HOPE study. Thus, ACE inhibitors might possess a beneficial effect beyond blood pressure lowering on the cardiovascular system in diabetic patients.

In the CAPPP study that compared captopril to diuretics and beta blockers, captopril was more effective in reducing the primary endpoint of myocardial infarction, stroke, and cardiovascular death. This was mostly attributed to reduction of cardiac death.

In the ABCD study, the ACE inhibitor significantly reduced the incidence of fatal and non-fatal myocardial infarction, compared to the calcium antagonist nisoldipine. Cardiovascular mortality and total mortality were significantly reduced with losartan compared to atenolol in the LIFE study in patients with diabetes. In the STOP Hypertension-2 study, the ACE inhibitor significantly reduced MI compared to calcium antagonist. In the UKPDS, there was no difference between captopril and atenolol for cardioprotective effect in diabetic patients. Hence, when ACE inhibitors are more effective than beta blockers for cardioprotection in diabetic patients is not conclusive, although there are no reports of the beta blocker being better.

In the IDNT study that reported the renoprotective effects were greater with irbesartan compared to amlodipine, the cardiovascular outcomes were nearly the same with the ARB and calcium antagonist. Detailed analysis shows that non-fatal myocardial infarction reduction was reduced by 41% with amlodipine compared with placebo. Thus, it remains controversial whether ACE inhibitor and ARB are better than calcium antagonists for cardioprotection.

Results of several clinical trials suggested that an ACE inhibitor and ARB might be more effective to inhibit the incidence of coronary arterial diseases than a calcium antagonist, diuretics and beta blockers, but discrepant results have been shown. Thus, the superiority of renin angiotensin blockade remains controversial.

In the HOPE study, the benefit was only partly attributed to the modest reduction of 3-4 mm Hg in office blood pressure. However, the 24-hour blood pressure reduction was underestimated, because of the more pronounced nighttime blood pressure reduction. The effect of ramipril might be attributable to the moderate reduction in nocturnal blood pressure. In the Syst-Eur study, office blood pressure was poorly related to CV events, but 24-hr blood pressure and especially nighttime blood pressure were more tightly related to CV events. Thus, aggressive control of office blood pressure and tight control of blood pressure are very important to prevent CV events.

Diurnal blood pressure pattern in diabetic patients show that the lack of a fall in nighttime blood pressure was related to the presence of microalbuminuria in contrast to diabetic patients with a nighttime blood pressure reduction. Patients with type 1 diabetes and higher nighttime blood pressure had increasing amounts of microalbuminuria, suggesting that nighttime blood pressure should be tightly controlled, even in diabetic patients with normal levels of blood pressure and microalbuminuria, for both cardioprotection and renoprotection.

To achieve target blood pressure, most hypertensive patients with diabetic nephropathy require several antihypertensive agents. In the RENAAL study, about 80% of patients required losartan and a diuretic to achieve target blood pressure levels.

Several clinical studies have demonstrated that all patients with diabetes and especially those with renal insufficiency should have their blood pressure lowered to less than 130/80 mm Hg and in most patients this will require 3 or more agents.

The anithypertensive cocktail for patients with hypertension and diabetes should include an ACE inhibitor or an ARB, plus a diuretic and calcium antagonist for cardioprotection and renoprotection.

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