In the guidelines for hypertension treatment, published in the USA in 1997, it was recommended to prescribe diuretics or beta blockers at the beginning of the treatment as first line treatment for lowering blood pressure because these drugs were tested in long-term studies and their effectiveness had been proven. However, a meta-analysis published in 1998 revealed that beta blockers are less effective than diuretics for lowering blood pressure in advanced age. It has also been proven that for patients in advanced, age beta blockers are not as effective in preventing complications, reducing mortality from ischemic heart disease, and not effective at lowering total mortality as well as mortality from cardiovascular disease.
The “LIFE-Losartan Intervention for Endpoint reduction in hypertension” study, published in “The Lancet” in 2000, gave a comparison between treatment based on the beta blocker "atenolol", and treatment based on the angiotensin receptor blocker "losartan", which involved 9,193 patients suffering from hypertension with simultaneous thickening of heart muscle wall(s). The "losartan" treatment group showed a decrease in the number of cardiovascular diseases by 13 percent, and strokes by 24.9 percent, compared to the beta blocker treatment group.
The “ASCOT – Anglo-Scandinavian Cardiac Outcomes Trial”, published in “The Lancet” in September 2005, gave a comparison between treatment based on the beta blocker "atenolol" and a diuretic, and treatment based on the calcium blocker "amlodipine" and ACEI5, which involved 19,527 patients suffering from hypertension. The calcium blocker treatment group showed a 24 percent decrease in proportion of mortality from cardiovascular diseases, a 23 percent decrease in the number of cases with injuries, and an 11 percent decrease in total mortality, compared to the beta blocker treatment group.
Soon after, “The Lancet” published a meta-analysis which convincingly showed that beta blockers are not suitable for the primary treatment of hypertension. Authors of this study showed that risk of stroke was 16 percent higher among patients with hypertension treated with beta blockers than among patients treated with other drugs.
In accordance to these results, the English Hypertension Association decided not to recommend beta blockers for the primary treatment of hypertension.
It should be noted that most of the studies that showed that beta blockers were less effective in treating hypertension, were held among the elderly population. Indeed, for the elderly group, this treatment is less effective, but in young people with a hyperdynamic state and fast pulse, treatment with beta blockers is very important for stabilizing blood pressure.
In one of the recently published meta-analyses, the authors showed that beta blockers are not effective for elderly population, but very effective for young people.
The low efficiency of beta blockers in advanced age can be explained by the mechanism that causes high blood pressure during this age. In contrast to young people, older people suffering from hypertension showed a diminished cardiac efficiency, slow pulse, high peripheral resistance, systolic hypertension, large heart muscle mass, and a high prevalence of metabolic disorders.
Beta blockers and diabetes development
In addition to the above, beta blockers also increase the risk of diabetes in patients suffering from hypertension. The “ARIC – Аtherosclerosis Risk in Communities Study” showed that treatment with beta blockers increased the risk of diabetes in patients suffering from hypertension by 28 percent, compared to patients not receiving beta blockers. In the LIFE study, "losartan" treatment reduced the risk of developing diabetes by 25 percent, compared to "atenolol" treatment.
In the ASCOT study, treatment based on calcium blockers and angiotensin converting enzyme inhibitors reduced the risk of diabetes by 30 percent, compared to treatment based on "atenolol" in conjunction with a diuretic. In our recent meta-analysis, we showed that the use of beta blockers increases the risk of developing diabetes by 20 percent. They may aggravate insulin resistance, and can therefore lead to diabetes. It is important to note that out of all the beta blockers, the main negative results are associated to "atenolol". Beta blockers are not recommended as first line treatment for elderly patients. They are desirable in young patients suffering from hypertension and tachycardia, and in patients suffering from ischemic heart disease and heart failure.
Treatment of the most senior population (over 80 years old)
Hypertension is considered a risk factor for morbidity and mortality in all age groups. Blood pressure treatments significantly reduce complications and mortality. Most studies conducted in the eighties showed the importance of lowering blood pressure, including relatively young people with high blood pressure because in those years, life expectancy was considerably less than it is today, and it was not clear whether hypertension should be treated in old age or not.
In the early nineties, studies were published that showed that among the elderly population over 60 years old, treatment with the aim of regulating blood pressure reduced the number of complications and mortality. Studies published in the nineties included patients over 60 years old, but they included only a small number of patients over 80 years old, which were very rare at the time. As life expectancy in the last 20 years has significantly increased, an important question appeared regarding whether hypertension should be treated in the oldest populations (over 80 years old) or not. These approaches are different.
According to one approach, blood pressure should not be decreased in the oldest populations with systolic hypertension, since blood vessels of these patients are less flexible, and vascular response is reduced; therefore , such patients require high blood pressure to ensure good blood flow to vital organs. This approach is based on epidemiological data that indicates a higher mortality among the oldest populations with low blood pressure.
In contrast to this approach, another one claims that high blood pressure is a risk factor for cardiovascular diseases in any age. Therefore, blood pressure should also be reduced in most elderly patients.
In 1999, “The Lancet” published a meta-analysis of a large group of patients over 80 years old, which was included in elderly patients’ studies. The results from the data obtained were that treatment for lowering blood pressure reduced stroke by 36 percent, but increased total mortality by 14 percent.
This data failed to give an answer to the question of whether treatment in most elderly patients is necessary or not.
Based on these results, researchers tried to plan a prospective study, "Hypertension in the Very Elderly Trial – HYVET", which would finally answer the question if there is any need for treating patients over 80. The study involved 1,237 patients older than 80 years with systolic blood pressure over 160 mmHg and with diastolic blood pressure over 100 mmHg. Patients received treatment with indapamide (diuretic) or perindopril (angiotensin converting enzyme inhibitor) or placebo.
After 13 months, a significant reduction in the number of strokes was found in the treatment group compared to the placebo group. However, there was no decrease in total mortality among patients receiving drugs. It’s important to note that the best results were found in the group that received “indapamide".
Based on these results, it was decided to continue the HYVET study, the results of which were published recently in the NEJM. The study involved 3,845 patients older than 80 years with systolic blood pressure 160-199 mmHg in sitting position and over 140 mmHg in standing position, and with diastolic blood pressure less than 110. About one third of patients were diagnosed with systolic hypertension. About half of the patients (1,933) received drug treatment with "indapamide" and supplemental "perindopril" if needed, and about half of patients (1,912) received placebo treatment. At the start of the study, average blood pressure was 175/90 in both groups, and it decreased by 15/6 in the treatment group compared to the control group. It’s important to note that 75 percent of patients in the treatment group needed combined treatment. The study was terminated prematurely due to unequivocal results of drug treatment benefits.
After observation for about 1.8 years, the findings were a 30 percent reduction in the number of strokes, a 39 percent reduction in fatal strokes, a 22 percent reduction in total mortality, and a 65 percent reduction of heart failure cases.
The results of the study showed that the oldest populations should be treated when systolic pressure is over 160. Research data didn’t allow to draw a conclusion on how elderly patients should be treated when systolic pressure is less than 160.
According to the study, a positive result was obtained when a diuretic was the primary treatment, and the goal of treatment was to establish blood pressure at 150/80. Though the study results answered the long-term dilemma if blood pressure should be treated in very old age, they left the question of what systolic value should be the aim and how to treat patients with systolic hypertension if the diastolic pressure is very low.
Treatment of patients in high risk groups by blocking the renin-angiotensin system (RAS)
In 2000, the NEJM published the “HOPE-The Heart Outcomes Prevention Evaluation” study, where investigators showed that the angiotensin converting enzyme inhibitor "ramipril" was effective in reducing morbidity and mortality among patients in high risk groups, independently of its effect on blood pressure.
Two large studies were published last year which tried to test effectiveness of a renin-angiotensin system (RAS) blockade in high risk populations. The ProFESS – Telmisartan to Prevent Recurrent Stroke and Cardiovascular Events – study tested the effects of "telmisartan" – an angiotensin II receptor blocker – right after stroke. The study involved 20,332 patients right after ischemic stroke. Within 15 days after a stroke, patients were randomly assigned to treatment with telmisartan 80 mg per day (10,146 patients) or placebo (10,186 patients) for an average of 2.5 years. During the observation, blood pressure was lower for 3.8/2.0 in patients who received telmisartan, compared to patients who received placebo. Despite lowering blood pressure, there was no significant reduction in number of repeated strokes and heart attacks in patients who received telmisartan.
Another study – TRANSCEND – tested the effects of treatment with telmisartan on patients with cardiovascular disease or diabetes with target organ damage that didn’t tolerate an angiotensin converting enzyme inhibitor. The study involved 5,926 patients who received treatment without a RAS blocker. Patients were randomly assigned to treatment with telmisartan 80 mg per day (2,954 patients) or placebo (2,972 patients) during 56 months. During observation, blood pressure was lower by 4.0 / 2.2 in patients who received telmisartan compared to patients who received placebo. Despite lowering blood pressure there was no significant reduction in number of primary complications in patients who received telmisartan. The last two studies have shown that treatment with telmisartan does not reduce number of strokes, and does not reduce number of cardiovascular diseases.
Combined treatment for lowering blood pressure
Reducing blood pressure is the first step in the treatment of hypertension. One of the biggest studies showed that good results were obtained from lowering blood pressure. The better the treatment lowered blood pressure, the better the results. It’s considered difficult to achieve a good balance of blood pressure with single drug treatment, therefore, in recent years, it has been recommended to use drug combinations.
RAS blockers with diuretics or calcium blockers
Beta blockers with diuretics or calcium blockers from the dihydropyridine group
Several studies have shown that a combined blockade of the RAS with angiotensin converting enzyme inhibitors and an angiotensin II receptor blocker is effective in reducing proteinuria in patients with diabetic nephropathy.
This recommendation for combined treatment has led to several studies to test the effectiveness of a combined RAS blockade, and to make sure if there is a preferred drug combination for treating hypertension.
Combined blockade of renin-angiotensin system (RAS)
The “Telmisartan or Both in patients at high risk for vascular events” (ONTARGET) study has recently been published, which tested the effectiveness of telmisartan in combination with ramipril (angiotensin converting enzyme inhibitor). The study involved 25,620 patients who were randomly assigned to either treatment with telmisartan 80 mg per day (8,542 patients), or treatment with ramipril 10 mg per day (8,576 patients), or treatment with telmisartan 80 mg in combination with ramipril 10 mg (8,502) during 56 months.
Ramipril alone lowered blood pressure by 6/4.6. Telmisartan alone lowered blood pressure by 6.9/5.2, and the combined treatment lowered blood pressure by 8.4/6.0. Despite the fact that the combined treatment of ramipril and telmisartan lowered blood pressure by more than 2.4/1.4 compared to treatment with ramipril, there was no significant reduction in the number of primary complications in patients who received combined treatment. The number of side effects such as hypotension, loss of consciousness, or renal failure was higher in patients who received combined treatment.
Authors of the work published in The Lancet presented the effects of the combined treatment with ramipril and telmisartan on urinary protein excretion and kidney function. This treatment delayed the increase in urinary protein excretion compared to treatment with ramipril alone. Despite the positive effects on urinary protein excretion, combined treatment significantly impaired kidney function compared to treatment with ramipril alone. The measured reduction of the calculated glomerular filtration was 2.82 in the group receiving ramipril compared to 6.11 ml/min/1.73m2 in the group receiving a combination of ramipril and telmisartan. The number of patients developing primary complications (dialysis, serum double creatinine or death) was higher among patients receiving the combination of ramipril and telmisartan compared to treatment only with ramipril.
Although the results of the ONTARGET study showed that combined treatment with ramipril and telmisartan is better for decreasing blood pressure and for inhibiting urinary protein excretion compared to only ramipril, it does not reduce morbidity and mortality due to cardiovascular causes and is also associated with many side effects, including the development of renal failure.
Therefore, treatment with both angiotensin converting enzyme inhibitors and angiotensin II receptor blockers should not be prescribed.
This year, the aliskiren combined with Losartan in Type 2 Diabetes and Nephropathy (AVOID) study was also published, which tested whether the addition of aliskiren (new renin inhibitor called Rasilez in Israel) to the current optimal treatment for lowering blood pressure, including losartan at maximum dose (100 mg per day), can protect kidneys in patients with diabetes and nephropathy. The study involved 599 patients who were randomly assigned to treatment with aliskiren (150 mg per day during 3 months and then 300 mg per day during 3 additional months) (301 patients) or placebo treatment (298 patients) for 6 months. The addition of aliskiren to losartan 100 mg per day lowered blood pressure by 2/1 (р=0.07) for systolic blood pressure and by 0.08 for diastolic blood pressure (and reduced urine protein excretion by 20 percent) (р˂0.001). In this study, the reduced glomerular filtration rate was 3.8 in the placebo group and only 2.4 ml/min/1.73m2 in patients who received aliskiren (р=0.07).
Although this study is relatively small and lasted only 6 months, it indicates that the combined blockade of renin-angiotensin system (RAS) with both a renin inhibitor and an angiotensin II receptor blocker can be effective.
Choosing the best combination for lowering blood pressure
This year, the Avoiding Cardiovascular events through combination therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) study was published. It tested whether an angiotensin converting enzyme inhibitor in combination with a diuretic is as effective as an angiotensin converting enzyme inhibitor in combination with a calcium blocker from the dihydropyridine group. The study involved 11,506 patients with hypertension (with systolic pressure 160 or more, or patients for lowering blood pressure) from high risk group.
High risk was determined according to the following indicators:
Minimum age of 60 with evidence of one additional cardiovascular disease or lesion of one of the target organs
Age 55-59 with evidence of two additional cardiovascular diseases or lesions of two of the target organs
Most patients (66 percent) were over 65 years old and suffered from type 2 diabetes (60 percent). They were assigned to treatment with a combination of Benazepril 20 mg and Amlodipine 5 mg during a month and then Benazepril 40 mg and Amlodipine 10 mg (5,744 patients) or with combination of Benazepril 20 mg and hydrochlorothiazide 12.5 mg during a month and then Benazepril 40 mg and hydrochlorothiazide 25 mg (5,762 patients). Before starting the study, most patients (97.2 percent) received drug treatment (medication). Average blood pressure was 145/80, and only 37.3 percent of patients had their blood pressure stabilized (less than 140/90). The combination of benazepril and amlodipine reduced blood pressure to 131.6/73.3, while that of benazepril and hydrochlorothiazide reduced blood pressure to 132.5/74.4. The average difference in pressure between the two treatment groups was 0.9/1.1 (р˂0.001). Blood pressure was stabilized throughout the study in 75.4 percent patients receiving benazepril / amlodipine and in 72.4 percent patients receiving benazepril / hydrochlorothiazide. The ACCOMPLISH study showed that combined treatment can improve blood pressure control and that the combination of an angiotensin converting enzyme inhibitor with a calcium blocker is more effective in reducing morbidity and mortality than combining an angiotensin-converting enzyme inhibitor with a diuretic.
These results can change blood pressure treatment and promote the use of the drug combination including a renin-angiotensin system (RAS) blocker and a calcium blocker from the dihydropyridine group.
The goal of treating hypertension (desirable pressure indications) is still a matter of debate.
There is disagreement about the level to which blood pressure should be reduced. However, everyone agrees that it’s necessary to lower blood pressure as soon as the diagnosis is made. One of the largest and most important studies that attempted to answer this question was the Hypertension Optimal Treatment (HOT) trial published in 1998. The study involved more than 18,000 patients suffering from hypertension which were treated to reduce diastolic blood pressure to 90, 85 or 80. After completing the observation, it turned out during several years that there was no significant difference in number of complications and mortality between patients whose goal of treatment was 90 or 80 mmHg. The only group in which lowering blood pressure to 80 reduced morbidity and mortality, was the group of patients with diabetes. In patients with diabetes, lowering diastolic pressure below 80 reduced cardiovascular morbidity and mortality by 51 percent.
Based on the HOT study, guidelines have been set to lower blood pressure below 140/90 in patients suffering from hypertension and below 130/80 among patients suffering from diabetes. In late 2002, The Lancet published the study to confirm the relationship between pressure values and morbidity and mortality among over a million people. In this article, the authors showed a direct connection between blood pressure values and mortality from strokes, ischemic heart diseases and vascular lesions starting from systolic blood pressure at 115 and diastolic blood pressure at 75.
»The authors also managed to show that starting from 115/75, any increase by 20/10 doubles the risk of death from stroke.
Based on this study, it was decided to change the recommended normal blood pressure goals in the U.S., and to determine Pre-Hypertension as blood pressure at 120-139 mmHg/ 80-89 mmHg. The conclusion was that blood pressure should be lowered to below 130/80 in patients at high risk.
Recommendations were also published by the European Hypertension and Cardiology Association in 2007. In a meta-analysis published this year in BMJ which involved 464,000 patients, the researchers concluded that any reduction in blood pressure regardless of primary blood pressure (to 110/70) significantly reduces number of complications and mortality. The researchers also found that the decrease in systolic blood pressure by 10 or diastolic blood pressure by 5 reduces risk of ischemic heart diseases by 22 percent and strokes by 41 percent. This allows us to conclude that the goal of treatment for blood pressure should be up to 110/70.
When analyzing baseline pressure test results and the blood pressure reduction achieved, it turned out that in patients with a basal systolic pressure below 130, an additional decrease in pressure led to an increase in cardiovascular mortality. According to this data, the goal of treating non-high-risk patients should be 140/90, and for patients with diabetes, or high-risk patients, 130/80.
Another study tested the advantages of lowering systolic blood pressure to a low value and involved 1,111 patients without diabetes and with systolic pressure above 150. They were randomly assigned to either goal of treatment – systolic blood pressure below 140 (553 patients – control group) or systolic blood pressure below 130 (558 patients – enhanced treatment) for 2 years in average. The study was open, and the researchers used medication as they wished. The primary goal of the study was to check the proportion of development of cardiac muscle hypertrophy (left ventricular hypertrophy, LVH) according to ECGs in 2 groups in which treatment was carried out. During observation, blood pressure decreased on average by 23/9 in the control group and by 27.3/10.4 in the enhanced treatment group. Enhanced treatment for systolic targets below 130 significantly reduced development of LVH in 82 of 483 patients (17 percent) of the control group and in 55 of 484 patients (11.4 percent) of the enhanced treatment group (р=0.013). Enhanced treatment also reduced the number of cardiovascular incidents by 50%: in the control group (9.4 percent) and 27 (4.8 percent) in the enhanced treatment group (р=0.003). This data supports an approach that seeks to reduce pressure to below 130.
Recently, the New England Journal of Medicine published results of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study which involved 4,733 patients with type 2 diabetes. They were assigned to either intensive treatment to reduce systolic blood pressure below 120 or standard treatment to reduce systolic pressure below 140 and were under observation for 4.7 years in average. The primary purpose of the study was to find out if intensive treatment can reduce number of death cases, strokes and myocardial infarctions which do not lead to death. After a year of treatment, average systolic pressure was 119.3 in the intensive treatment group and 133.5 in the standard treatment group. Despite the large differences in the values of systolic blood pressure between the 2 treatment groups there was no significant difference in number of incidents which were defined as the primary goal (annual amount 1.87 percent with intensive treatment compared to 2.09 percent with standard treatment) (р=0.20).
Proportion of annual mortality was 1.28 percent in the intensive treatment group and 1.19 percent in the standard treatment group (р=0.55). Annual number of strokes was lower in the intensive treatment group (0.32 percent) compared to the standard treatment group (0.53 percent) (р=0.001).
It’s important to note that there was a greater number of significant side effects in the intensive treatment group, including drops in blood pressure, bradycardia and increased creatinine values. The results of the ACCORD study indicate that, in patients with diabetes, systolic blood pressure should not be lowered drastically to values below 130.
The approach should be careful and the general population should strive to reduce pressure to values below 140/90, while populations at risk should strive to reduce pressure to values below 130/80.
In recent years, several important points have been identified in the treatment of hypertension:
Beta blocker treatment is less effective for reducing complications and mortality in patients suffering from hypertension without concomitant diseases. Such treatment is effective for patients after myocardial infarction or patients suffering from heart failure and tachycardia.
Treatment based on a diuretic and/or angiotensin converting enzyme inhibitor reduces the number of complications and mortality among the oldest populations. Therefore, in the older group of patients, combination medications are prescribed including diuretics such as "Tritace comb" (ACE inhibitor|thiazide) or Exforge (Angiotensin II antagonist / calcium channel blocker).
ATreatment with an angiotensin II receptor blocker reduces blood pressure and is effective in reducing morbidity and mortality in patients with hypertension. However, there is not enough evidence to claim that it reduces morbidity and mortality in high-risk populations (combination of several diseases).
AIt makes no sense to combine angiotensin converting enzyme inhibitor and angiotensin II receptor blocker, but a combination of a renin inhibitor with an angiotensin II receptor blocker is possible.
ACombined treatment given quickly in the first stage of treatment can improve blood pressure control in patients suffering from hypertension and those in a high-risk group. Combination of an angiotensin converting enzyme inhibitor or angiotensin II receptor blocker with a calcium blocker is more effective than the combination of an angiotensin converting enzyme inhibitor with diuretics both in controlling blood pressure, and with the effect on morbidity and mortality.
AThe general population should strive to reduce blood pressure to values below 140/90, while populations at high risk (having associated diseases) should strive to reduce blood pressure to values below 130/80. The ideal blood pressure goal in all patient groups is 120/80.
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