One of the mechanisms that produce the hypotensive effect of ACE inhibitors such as perindopril is the increased action of vasodilator prostaglan-dins on the kidney, which decreases hydrosaline retention and therefore increases diuresis and lowers blood pressure. NSAIDs inhibit prostaglandin synthesis and decrease renal perfusion, thus antagonizing the hypotensive effect of many antihypertensives, including ACE inhibitors. Therefore, the preferable thing to do in this patient, before increasing the medication, is to change the ibuprofen for paracetamol, which does not have this effect, and to re-evaluate it later.

An 87-year-old man with a history of hypertension and gonarthrosis. Baseline situation with full functional and cognitive autonomy that allows him to continue living alone in the community. He is receiving regular treatment with perindopril and thiazide diuretic for blood pressure control and routinely takes ibuprofen 1800 mg/day to control the symptoms derived from his gonarthrosis. After routine control, a persistent blood pressure of 190 and TAD 80 mmHg was observed. What would be the most reasonable therapeutic modification to achieve blood pressure control?

I would increase the dose of hydrochlorothiazide to 25 mg/day.

I would change ibuprofen to paracetamol to avoid the possible influence of paracetamol on the effect of hypotensives.

I would add an alpha-blocker because of the high prevalence of prostatic syndrome in males of this age.

Study population and treatment titration in the International Nifedipine GITS Study: Intervention as a Goal in Hypertension Treatment (INSIGHT).

To ascertain the baseline characteristics of the high-risk hypertensive patients entering the International Nifedipine GITS Study: Intervention as a Goal in Hypertension Treatment (INSIGHT). To determine the success of single and combination therapy in achieving target blood pressures in such a population. INSIGHT is a double-blind, prospective outcome trial comparing the efficacy of the calcium channel blocker, nifedipine GITS, and the thiazide, co-amilozide, in preventing myocardial infarction and stroke. We recruited 2996 men and 3454 women, aged 55-80 years, with blood pressure during placebo run-in >150/95 mmHg or isolated systolic blood pressure >160 mmHg from nine countries. Treatment allocation to nifedipine GITS 30 mg daily or co-amilozide (hydrochlorothiazide 25 mg/amiloride 5 mg) once daily was performed by minimization rather than randomization to balance additional risk factors. This was followed by four optional increases in treatment: dose-doubling of the primary drug, addition of atenolol 25/50 mg or enalapril 5/10 mg, and then any other hypotensive drug excluding calcium blockers or diuretics. Target blood pressure was 140/90 mmHg or a fall > or = 20/10 mmHg. Blood pressure at randomization was 172+/-15 / 99+/-9 mmHg. Thirteen per cent of the patients were previously untreated. The proportions of each additional risk factors were: smoking > 10/day, 29%; cholesterol > 6.43 mmol/l, 52%; family history of premature myocardial infarction or stroke, 21%; diabetes mellitus 20%; left ventricular hypertrophy, 10%; previous myocardial infarction, other presentations of coronary heart disease, and peripheral vascular disease, each 6%; proteinuria, 3%. Fifty-five per cent of patients had one additional risk factor, whereas 33%, 9% and 3% had two, three or more additional risk factors, respectively. The blood pressure (and falls in blood pressure) at the end of titration and at 1 year after minimization was 139+/-12 / 82+/-7 mmHg (33+/-15 / 17+/-9) in the 5226 patients still on randomized treatment The numbers requiring the four treatment increments were, respectively, 1591, 780, 597 and 294, meaning that almost 70% of patients on randomized treatment in INSIGHT are receiving only the primary drug. At one year, 69% of patients had a blood pressure < or = 140/90 mmHg. INSIGHT is one of the first double-blind comparisons of active antihypertensive treatments, requiring high-risk patients to achieve sufficient power. Despite this requirement, it is possible to achieve good blood pressure control in most patients without the addition of multiple additional treatments that may dilute any differences between the primary agents.

[Merits of paracetamol in osteoarthritic hypertensive patients].

Nonsteroidal anti-inflammatory drug (NSAID) side effects can impair quality of life in patients with osteoarthritis. Due to its particular mechanism of action, paracetamol might bypass these negative effects. To determine both the role of paracetamol in the treatment of osteoarthritis patients and optimal combination of antihypertensives and antirheumatics for these patients. A prospective clinical trial in a family practice included 110 treated hypertensives aged over 55 years: 50 controls and 60 also taking NSAIDs for osteoarthritis. This 3-month study compared two antihypertensives, lisinopril/hydrochlorothiazide fixed combination and amlodipine, with two NSAIDs, ibuprofen and piroxicam, and with paracetamol. Following clinical work-up and NSAID discontinuation for at least 3 days (run-in period of only 3-7 days), osteoarthritis subjects were randomized to 1-month periods of ibuprofen (400-600 mg t.i.d.) or piroxicam (10-20 mg o.d.) with one month of paracetamol (1000 mg t.i.d.) in the middle as a "wash-out" interval, continuing the prescribed amlodipine (5-10 mg o.d.) or lisinopril/hydrochlorothiazide fixed drug combination (10/6.25-20/12.5 mg o.d.), while control subjects (hypertensives with no osteoarthritis) were just keeping their antihypertensive therapy. Blood pressure was measured with standard mercury sphygmomanometer and with an automatic device, in standing, sitting and supine position. The intensity of arthritic pain (on a visual analogue scale from 1 to 10, where 0 means "no pain" and 10 "the worst pain you may imagine") and the patient's quality of life estimate (on a visual analogue scale from 1 to 10, where 0 means "general condition excellent" and 10 "the worst possible") were recorded. Blood pressure control was unchanged in the amiodipine group across the study periods and impaired in the lisinopril/ hydrochlorothiazide group during either ibuprofen or piroxicam, but not during paracetamol. In the amlodipine +/- ibuprofen subgroup, the reduction of the average pain intensity score throughout the study was significant (chi2 = 8.250; df 3; P = 0.037). In the lisinopril/hydrochlorothiazide +/- piroxicam subgroup, the assessed quality of life differed significantly (chi2 = 9.716; df 3; P = 0.018), while in the amlodipine +/- ibuprofen and amlodipine +/- piroxicam subgroups the changes were marginal (chi2 = 6.936; df 3; P = 0.072 and chi2 = 7146; df 3; P = 0.065, respectively).

[Evaluation of trandolapril alone or in combination with a calcium channel blocker in hypertensive patients over 60 years of age].

The efficacy and safety of trandolapril alone and in combination with a calcium channel blocker were evaluated in 13,147 hypertensive patients over 60 years old. Two patient groups were constituted. After a 2-week wash-out period, the patients in group I received monotherapy with trandolapril 2 mg/day for 4 weeks. Trandolapril was continued for another 4 weeks in responding patient, otherwise the dosage of trandolapril was doubled or another antihypertensive was added. Group 2, composed of patients previously treated with a calcium channel blocker with insufficient efficacy, was treated according to the same treatment regimen, but the calcium channel blocker was maintained throughout the study. 13,147 patients (group 1: 11,329 patients, group 2: 1,818 patients) with a mean age of 68 +/- 7 years were followed. After 4 weeks of treatment, the blood pressure measured by mercury sphygmomanometer decreased from 176 + 11/99 +/- 8 mmHg to 164 +/- 12/87 +/- 7 mmHg (p < 0.0001). This blood pressure fall was similar in group 1 (-22 +/- 12/-12 +/- 8 mmHg) and in group 2 (-21 +/- 11/-12 +/- 8 mmHg). In the pure systolic HT subgroup treated by trandolapril monotherapy, the antihypertensive effect predominantly affected the SBP (-23 +/- 12/- 4 +/- 6 mmHg). The antihypertensive effect was correlated with the initial blood pressure. In group 1, in the case of insufficient response to trandolapril monotherapy, the addition of a calcium channel blocker was the strategy which achieved the most marked antihypertensive effect (ANOVA, p < 0.0001). This bitherapy was more effective than the trandolapril+diuretic combination (-18 +/- 11/- 11 +/- 8 mmHg and -15 +/- 10/- 9 +/- 7 mmHg, respectively (p < 0.001). A total of 1,270 adverse events were reported by 996 patients (7.6%), leading to discontinuation of treatment in 372 patients (2.8%). The most frequent adverse effects were cough (2.8%), headache (0.8%), vertigo (0.8%) and nausea (0.5%). Only one minor equivalent of angioneurotic oedema was reported. In conclusion, trandolapril is effective and well tolerated in elderly hypertensive patients. In the case of pure systolic HTA, its action is essentially exerted on SBP. The combination of trandolapril+calcium channel blocker appears to be the most effective strategy in the case of incomplete blood pressure control by trandolapril alone.

[Hypertension in the elderly: particularities and precautions].

Hypertension is very common and inadequately controlled among the elderly. The HYVET study showed that antihypertensive therapy significantly reduces total mortality and cardiovascular events in people aged 80 years and older. The therapeutic goal for patients aged from 60 to 80 years is systolic blood pressure (SBP) less than 140 mmHg and a diastolic blood pressure (DBP) less than 90 mmHg, without orthostatic hypotension. For patients older than 80 years, the aim is keep SBP < 150 mmHg. This goal also depends on comorbidities, iatrogenic risk, and life expectancy. The choice of treatment must be adapted to the patient's clinical situation, taking into account any cardiovascular diseases, organ damage, and comorbidities. All of the principal antihypertensive drugs can be used in the elderly, with a preference for thiazide diuretics or calcium channel blockers for those with systolic hypertension. Generally, no more than three antihypertensive drugs should be prescribed for octogenarians (including a thiazide diuretic). Particular attention must be paid to the renal risk (estimated by glomerular filtration rate), especially for nephrotoxic and multiple drugs. Blood levels of potassium, sodium, and creatinine must be monitored in patients receiving diuretics or renin angiotensin system blockers, particularly during acute events (e.g., fever, infection, dehydration, and diarrhea). Cognitive function should be assessed in patients with hypertension older than 80 years, with the MMSE (Mini-Mental-State-Examination) to assess the risk of poor adherence, in view of the increased risk of dementia.

Alpha blocker

Contraindications There is only one compelling indication for alpha blockers, which is for benign prostatic hyperplasia. Patients who need alpha blockers for BPH, but have a history of hypotension or postural heart failure, should use these drugs with caution, as it may result in an even greater decrease in blood pressure or make heart failure even worse. The most compelling contraindication is urinary incontinence and overall fluid retention. To combat such fluid retention, patients can take a diuretic in combination with the alpha-blocker. In the absence of compelling indications or contraindications, patients should take alpha blockers as a step 4 therapy to reduce blood pressure, but only if the use of ACE inhibitors, angiotensin-II receptor blockers, calcium channel blockers, or thazide diuretics (in full dose or in combinations) have not been efficacious.

[Influence of some parameters on the blood pressure reduction under treatment: experience from the Hypertension Optimal Treatment Study].

The HOT study is the largest controlled therapeutic trial conducted to date in hypertension. This international, prospective, randomised trial is designed to determine the optimal blood pressure to be obtained during treatment, in order to achieve optimal reduction of complications and cardiovascular mortality. The HOT study is conducted according to the PROBE methodology (Prospective Randomised Open Blinded Endpoints. It has three objectives: 1) to evaluate the relationship between the development of major cardiovascular events and the DBP target level (DBP < or = 90, DBP < or = 85 or DBP < or = 80 mmHg. 2) to evaluate the relationship between the development of major cardiovascular events and real DBP observed, 3) to determine whether low-dose acetylsalicylic acid (75 mg/day) provides an additional benefit in terms of cardiovascular morbidity and mortality in treated hypertensive subjects. Between April 1992 and October 1994, 18,790 patients, between the ages of 50 and 80 years (26 countries), were randomised to these 3 target DBP groups and several parameters likely to influence the blood pressure fall were identified. The reduction of DBP was all the more pronounced the higher the baseline DBP. For a baseline DBP equal to 100 mmHg, the mean fall was 18 mmHg and for a baseline DBP equal to 110 mmHg, the mean fall was 27 mmHg. Advanced age was also found to be a factor promoting reduction of DBP, which increased after the age of 65 years. Analysed in relation to the type of treatment, this more marked reduction in the elderly showed that monotherapy with a calcium channel blocker was very effective on DBP and especially after the age of 75 years. The data of the study also showed that SBP decreased in parallel to DBP, but to an even greater extent. Thus, a 10 mmHg reduction of DBP induces a reduction of SBP by approximately 20 mmHg. This reduction of SBP related to the level of DBP was even more marked the higher the baseline SBP and the higher the target DBP objective. Thus 80% of patients in the DBP < or = 80 mmHg group had an SBP < or = 150 mmHg during treatment. Among the other factors, weight appeared to clearly influence reduction of DBP, as the reduction of DBP was more marked the lower the patient's weight. In contrast, the body mass index was poorly correlated with the reduction in blood pressure. The blood pressure reduction, regardless of weight, was more marked when a stricter blood pressure objective was adopted (DBP < or = 80 mmHg). Finally, in the particular case of elderly subjects, treatment with a calcium channel blocker appeared to be very effective in reducing the blood pressure.

Antihypertensive drug

In the United States, the JNC8 (Eighth Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure) recommends thiazide-type diuretics to be one of the first-line drug treatments for hypertension, either as monotherapy or in combination with calcium channel blockers, ACE inhibitors, or angiotensin II receptor antagonists. There are fixed-dose combination drugs, such as ACE inhibitor and thiazide combinations. Despite thiazides being cheap and effective, they are not prescribed as often as some newer drugs. This is because they have been associated with increased risk of new-onset diabetes and as such are recommended for use in patients over 65 where the risk of new-onset diabetes is outweighed by the benefits of controlling systolic blood pressure. Another theory is that they are off-patent and thus rarely promoted by the drug industry.

Antihypertensive drug

Thiazide diuretics are effective, recommended as the best first-line drug for hypertension, and are much more affordable than other therapies, yet they are not prescribed as often as some newer drugs. Chlorthalidone is the thiazide drug that is most strongly supported by the evidence as providing a mortality benefit; in the ALLHAT study, a chlorthalidone dose of 12.5 mg was used, with titration up to 25 mg for those subjects who did not achieve blood pressure control at 12.5 mg. Chlorthalidone has repeatedly been found to have a stronger effect on lowering blood pressure than hydrochlorothiazide, and hydrochlorothiazide and chlorthalidone have a similar risk of hypokalemia and other adverse effects at the usual doses prescribed in routine clinical practice. Patients with an exaggerated hypokalemic response to a low dose of a thiazide diuretic should be suspected to have hyperaldosteronism, a common cause of secondary hypertension.

[Management of hypertension in the very elderly].

The prevalence of hypertension in persons aged 80 years or older is about 70%. Recent studies in this population show the benefits of antihypertensive therapy, especially for stroke prevention. Accurate determination of blood pressure requires the use of ambulatory measurement methods or self-measurement at home because the frequency of "white coat" hypertension increases with age. It is essential to distinguish patients with sustained hypertension, who need antihypertensive drugs, from those with white coat hypertension, for whom treatment is not justified and may be dangerous because of the risk of hypotension. The objective of antihypertensive treatment is to decrease blood pressure to less than 140/90 mmHg for those aged 60 to 80 years and to decrease systolic pressure to less than 150 mmHg in those older than 80 years, without orthostatic hypotension. Any class of antihypertensive drugs can be used to start treatment, although in the absence of specific indications due to concomitant diseases, thiazide diuretics or calcium channel blockers are preferred for initial treatment. Most often, very elderly hypertensive patients will require two antihypertensive drugs for adequate blood pressure control. Generally their regimen should not include more than 3 antihypertensive drugs (including a thiazide diuretic).

Management of hypertension

Elderly Treating moderate to severe hypertension decreases death rates and cardiovascular morbidity and mortality in people aged 60 and older. The recommended blood pressure goal is advised as <150/90 mm Hg, with thiazide diuretic, CCB, ACEI, or ARB being the first-line medication in the United States. In the revised UK guidelines, calcium-channel blockers are advocated as first line, with targets of clinic readings <150/90, or <145/85 on ambulatory or home blood pressure monitoring. There are no randomized clinical trials addressing the goal blood pressure of hypertensives over 79 years old. A recent review concluded that antihypertensive treatment reduced cardiovascular deaths and disease, but did not significantly reduce total death rates. Two professional organizations have published guidelines for the management of hypertension in persons over 79 years old.

The evolution of low-dose diuretic therapy: the lessons from clinical trials.

Safe and effective antihypertensive therapy became available in the 1950s with the introduction of thiazide diuretics. Prior to that time, we did have agents that lowered blood pressure but they often needed to be given parenterally and were too poorly tolerated to be used for the treatment of any but those with life-threatening elevations of blood pressure. When thiazide diuretics-first chlorothiazide and then hydrochlorothiazide-became available, it was possible to lower blood pressure in most hypertensives and assess whether that reduction would lead to a reduction in cardiovascular morbidity and mortality. The results of 17 large trials have now made it clear that antihypertensive therapy with regimens based on diuretics and beta blockers reduces cardiovascular events and saves lives. When first introduced, thiazide diuretics were prescribed at doses we now know are excessively high (100-200 mg of hydrochlorothiazide/day), and we have learned that much lower doses, even as little as 12.5 mg of hydrochlorothiazide, are effective. These lower doses will reduce blood pressure and do so with considerably less in the way of metabolic effects. This article will trace the development of antihypertensive therapy and review how data from clinical trials have influenced the recommendations of the Joint National Committees on the Detection, Evaluation and Treatment of Hypertension.

Hydrochlorothiazide versus calcium channel blockers: what is the best add-on to a renin-angiotensin system blocker for treating hypertension in patients with renal disease?

Hypertension remains an important problem that increases the risk of cardiovascular disease and is a leading cause of mortality worldwide. Achieving long-term control of arterial hypertension, which has an estimated prevalence of 28% in the US adult population, would translate into a significant reduction in cardiovascular events. Specific causes can be identified and treated for certain forms of secondary hypertension, but often it is multifactorial. Therefore, it makes sense to attain blood pressure control by addressing more than one pressor mechanism. Several clinical studies have demonstrated that combination antihypertensive therapy is more effective than monotherapy, and a review of currently published data suggests that approximately 75% of hypertensive individuals will require some form of combination therapy to achieve target blood pressure (BP) goals. To this end, the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of Blood Pressure (JNC 7) has recommended that antihypertensive therapy should start with two drugs when a patient presents with systolic blood pressure (SBP) more than 20 mm Hg above target levels, diastolic blood pressure (DBP) more than 10 mm Hg above target levels, or both. This review attempts to analyze the current evidence in published medical literature to answer the question of whether hydrochlorothiazide or a calcium channel blocker is a better add-on to a renin-angiotensin system blocker for treating hypertension in patients with renal disease.

Hypertension

Medications Several classes of medications, collectively referred to as antihypertensive medications, are available for treating hypertension. First-line medications for hypertension include thiazide-diuretics, calcium channel blockers, angiotensin converting enzyme inhibitors (ACE inhibitors), and angiotensin receptor blockers (ARBs). These medications may be used alone or in combination (ACE inhibitors and ARBs are not recommended for use in combination); the latter option may serve to minimize counter-regulatory mechanisms that act to restore blood pressure values to pre-treatment levels. Most people require more than one medication to control their hypertension. Medications for blood pressure control should be implemented by a stepped care approach when target levels are not reached.

Antihypertensive drug

Which type of medication to use initially for hypertension has been the subject of several large studies and resulting national guidelines. The fundamental goal of treatment should be the prevention of the important endpoints of hypertension, such as heart attack, stroke and heart failure. Patient age, associated clinical conditions and end-organ damage also play a part in determining dosage and type of medication administered. The several classes of antihypertensives differ in side effect profiles, ability to prevent endpoints, and cost. The choice of more expensive agents, where cheaper ones would be equally effective, may have negative impacts on national healthcare budgets. As of 2018, the best available evidence favors low-dose thiazide diuretics as the first-line treatment of choice for high blood pressure when drugs are necessary. Although clinical evidence shows calcium channel blockers and thiazide-type diuretics are preferred first-line treatments for most people (from both

[Comparative Efficacy of the Influence of Fixed Combinations of Antihypertensive Drugs That Block the Renin-Angiotensin-Aldosterone System, With Thiazide Diuretics on the Parameters of Ambulatory Blood Pressure Monitoring].

to compare effects of fixed-dose combinations of antihypertensive drugs that block renin-angiotensin-aldosterone system (RAAS) with hydrochlorothiazide (HCT) on parameters of ambulatory blood pressure monitoring (ABPM). Patients (n=50; 25 women, 25 men aged 40-75 years) with stage II essential hypertension who received no antihypertensive therapy for 12 weeks were randomized to receive once daily fixed-dose combinations of either valsartan/HCT (Val/HCT - group I) or quinapril/HCT (Quin/HCT - groupII) in starting doses of 80/12.5 or 10/12.5 mg, respectively. If target BP (<140 and 90 mm Hg) was not achieved after 2 weeks, doses were increased to 160/12.5 and 20/12.5 mg, respectively. Patients in whom target BP was not achieved after another 2 weeks were excluded from the study. Follow - up after achieving target BP was 12 weeks. Both combinations significantly (p<0.001) reduced office systolic and diastolic BP (SBP and DBP), however, BP decrease in group I was significantly (p<0.01) greater (-42.0+/-2,7 /-22.2+/-1.2 mm Hg) than in group II (-26,4+/-2,1/-6.6+/-0.4 mm Hg). Significant reduction of day- and night-time BP (p<0.001) observed in both groups was also more pronounced (p<0.01) in group I. In both groups we recorded significant (p<0.01) decreases of BP variability and morning BP rise. Variability of DBP at night (-3.3+/-0.2 mm Hg), magnitude and speed of morning DBP surge (-20.9+/-0.3 mm Hg and -3.4+/-0.2 mm Hg/hour, respectively) in group I decreased significantly (p<0.05) greater compared with same parameters in group II (-2.5+/-0.2 mm Hg, -17.7+/-0.3 mm Hg, -2.6+/-0.2 mm Hg/hour, respectively). Fixed-dose combinations of RAAS blockers and HCT provided reliable reduction of BP, BP variability, morning BP rise, and high percentage of achievement of target BP. Val/HCT combination was more effective in terms of reducing SBP, DBP and pulse BP levels at routine measurement, and day- and night-time SBP and DBP, night-time DBP variability, and rate of morning DBP rise.

Management of hypertension

The best first-line medication is disputed, but the Cochrane collaboration, World Health Organization, and US guidelines support low-dose thiazide-based diuretic as first-line treatment. The UK guidelines emphasise calcium channel blockers (CCB) in preference for people over the age of 55 years or people of African or Caribbean descent, with angiotensin-converting enzyme inhibitors (ACE-I) used as a first line for younger people. In Japan, starting with any one of six classes of medications, including CCB, ACEI/ARB, thiazide diuretics, beta-blockers, and alpha-blockers, is deemed reasonable, while in Canada and Europe all of these except alpha-blockers are recommended as options. Compared to placebo, beta-blockers have a greater benefit in stroke reduction, but no difference on coronary heart disease or all-cause mortality. However, three-quarters of active beta-blocker treatments in the randomised controlled trials included in the review used atenolol, and none used the newer

Antihypertensive drug

Patient factors The choice between the drugs is to a large degree determined by the characteristics of the patient being prescribed for, the drugs' side effects, and cost. Most drugs have other uses; sometimes the presence of other symptoms can warrant the use of one particular antihypertensive. Examples include: Age can affect the choice of medications. Current UK guidelines suggest starting patients over the age of 55 years first on calcium channel blockers or thiazide diuretics. Age and multi-morbidity can affect the choice of medication, the target blood pressure and even whether to treat or not. Anxiety may be improved with the use of beta blockers. Asthmatics have been reported to have worsening symptoms when using beta blockers. Benign prostatic hyperplasia may be improved with the use of an alpha blocker. Chronic kidney disease. ACE inhibitors or ARBs should be included in the treatment plan to improve kidney outcomes regardless of race or diabetic status.

Antihypertensive drug

Antihypertensives are a class of drugs that are used to treat hypertension (high blood pressure). Antihypertensive therapy seeks to prevent the complications of high blood pressure, such as stroke and myocardial infarction. Evidence suggests that reduction of the blood pressure by 5 mmHg can decrease the risk of stroke by 34%, of ischaemic heart disease by 21%, and reduce the likelihood of dementia, heart failure, and mortality from cardiovascular disease. There are many classes of antihypertensives, which lower blood pressure by different means. Among the most important and most widely used medications are thiazide diuretics, calcium channel blockers, ACE inhibitors, angiotensin II receptor antagonists (ARBs), and beta blockers.

Long-term blood pressure control in older Chinese patients with isolated systolic hypertension: a progress report on the Syst-China trial.

This report on the ongoing double-blind placebo-controlled Syst-China trial investigated whether antihypertensive drug treatment based mainly on a calcium entry blocker and a converting enzyme inhibitor, would be suitable for maintaining long-term blood pressure (BP) control in older Chinese patients (average age: 67 years) with isolated systolic hypertension (systolic pressure 160-219 mm Hg and diastolic pressure < 95 mm Hg). Active treatment consisted of nitrendipine (10- 40 mg/day) with the possible addition of captopril (12.5- 50 mg/day) and hydrochlorothiazide (12.5-50 mg/day), as necessary to reduce systolic pressure to a level of 150 mm Hg or lower and by at least 20 mm Hg. Matching placebos were used in the control group. This progress analysis was restricted to BP control up to 3 years of follow-up. The placebo (n = 1134) and active treatment n = 1245) groups had similar characteristics at enrolment. The sitting BP averaged 170/86 mm Hg. Systolic pressure fell (P < 0.001) on average 8 mm Hg more on active treatment than on placebo and diastolic pressure 3 mm Hg more. Fewer patients remained on monotherapy in the placebo than in the active treatment group (P < 0.001); on placebo the second and third line medications were started more frequently (P < 0.001). This progress report showed that significant BP reduction can be achieved and maintained in older Chinese patients treated with a calcium antagonist, associated with a converting-enzyme inhibitor and a thiazide, as necessary. Whether this BP reduction would result in a clinically meaningful decrease of cardiovascular complications is still under investigation.

Amiloride

minimal efficacy. For people with resistant hypertension, already taking a thiazide diuretic, an angiotensin converting enzyme inhibitor (ACE-i) or an angiotensin II receptor blocker (ARB), and a calcium channel blocker, the addition of amiloride (or spironolactone) was better at reducing blood pressure than adding a beta-blocker (bisoprolol) or an alpha-1 blocker (doxazosin). When combined with hydrochlorothiazide, the addition of amiloride had positive effects on blood pressure and blood sugar tolerance. Amiloride may therefore be useful for preventing the metabolic side effects of thiazide diuretics, allowing for the use of higher thiazide doses (in line with how they were originally studied).

How far should we lower blood pressure in the elderly.

In the last few years several large intervention trials have addressed the treatment of hypertension in the elderly and how far blood pressure should be lowered in such patients. The positive results of intervention against high blood pressure in the elderly has resulted in a positive attitude towards treatment and today this is an accepted and highly effective medical intervention. Both stroke and coronary morbidity have been shown to be positively affected as has total mortality. The specific issue, how far to lower blood pressure in the elderly was probably best addressed in the Hypertension Optimal Treatment (HOT) stduy in which about a third of the patients, i.e. >6,000 patients, were > or =65 years of age. In most of the early intervention studies of antihypertensive treatment in elderly patients diuretics or beta-blockers or the two in combination were used as the therapy by which blood pressure was lowered. However, novel therapies, in particular calcium antagonists, have shown benefits of the same magnitude as the older therapies, e.g. in the STONE trial, the Syst-Eur study, the Syst-China study and the STOP-Hypertension-2 study. In the latter study a regimen based on either of two ACE inhibitors was also shown to be equally effective as conventional treatment, based on diuretics and/or betablockers, in the elderly. These trials will be briefly reviewed here as will the SCOPE study which is an ogoing trial in which hypertensive patients aged 70-89 years are being treated with an angiotensin II receptor antagonist under double-blind and placebo-controlled conditions. It can be concluded that a wealth of information, based on large intervention trials, has been accumulated during the last decade. It is quite obvious that the elderly hypertensive patients benefit from antihypertensive treatment to at least the same extent as the young and middle-aged. It appears that blood pressure ought to be lowered down to normotensive values also in the elderly in order to minimize their risk if cardiovascular complications, although more studies would be welcome to address this issue specifically in the elderly.

Blood pressure-lowering efficacy of monotherapy with thiazide diuretics for primary hypertension.

Hypertension is a modifiable cardiovascular risk factor. Although it is established that low-dose thiazides reduce mortality as well as cardiovascular morbidity, the dose-related effect of thiazides in decreasing blood pressure has not been subject to a rigorous systematic review. It is not known whether individual drugs within the thiazide diuretic class differ in their blood pressure-lowering effects and adverse effects. To determine the dose-related decrease in systolic and/or diastolic blood pressure due to thiazide diuretics compared with placebo control in the treatment of patients with primary hypertension. Secondary outcomes included the dose-related adverse events leading to patient withdrawal and adverse biochemical effects on serum potassium, uric acid, creatinine, glucose and lipids. We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2014, Issue 1), Ovid MEDLINE (1946 to February 2014), Ovid EMBASE (1974 to February 2014) and ClinicalTrials.gov. We included double-blind, randomized controlled trials (RCTs) comparing fixed-dose thiazide diuretic monotherapy with placebo for a duration of 3 to 12 weeks in the treatment of adult patients with primary hypertension. Two authors independently screened articles, assessed trial eligibility, extracted data and determined risk of bias. We combined data for continuous variables using a mean difference (MD) and for dichotomous outcomes we calculated the relative risk ratio (RR) with 95% confidence interval (CI). We included 60 randomized, double-blind trials that evaluated the dose-related trough blood pressure-lowering efficacy of six different thiazide diuretics in 11,282 participants treated for a mean duration of eight weeks. The mean age of the participants was 55 years and baseline blood pressure was 158/99 mmHg. Adequate blood pressure-lowering efficacy data were available for hydrochlorothiazide, chlorthalidone and indapamide. We judged 54 (90%) included trials to have unclear or high risk of bias, which impacted on our confidence in the results for some of our outcomes.In 33 trials with a baseline blood pressure of 155/100 mmHg, hydrochlorothiazide lowered blood pressure based on dose, with doses of 6.25 mg, 12.5 mg, 25 mg and 50 mg/day lowering blood pressure compared to placebo by 4 mmHg (95% CI 2 to 6, moderate-quality evidence)/2 mmHg (95% CI 1 to 4, moderate-quality evidence), 6 mmHg (95% CI 5 to 7, high-quality evidence)/3 mmHg (95% CI 3 to 4, high-quality evidence), 8 mmHg (95% CI 7 to 9, high-quality evidence)/3 mmHg (95% CI 3 to 4, high-quality evidence) and 11 mmHg (95% CI 6 to 15, low-quality evidence)/5 mmHg (95% CI 3 to 7, low-quality evidence), respectively.Direct comparison of doses did not show evidence of dose dependence for blood pressure-lowering for any of the other thiazides for which RCT data were available: bendrofluazide, chlorthalidone, cyclopenthiazide, metolazone or indapamide.In seven trials with a baseline blood pressure of 163/88 mmHg, chlorthalidone at doses of 12.5 mg to 75 mg/day reduced average blood pressure compared to placebo by 12.0 mmHg (95% CI 10 to 14, low-quality evidence)/4 mmHg (95% CI 3 to 5, low-quality evidence).In 10 trials with a baseline blood pressure of 161/98 mmHg, indapamide at doses of 1.0 mg to 5.0 mg/day reduced blood pressure compared to placebo by 9 mmHg (95% CI 7 to 10, low-quality evidence)/4 (95% CI 3 to 5, low-quality evidence).We judged the maximal blood pressure-lowering effect of the different thiazides to be similar. Overall, thiazides reduced average blood pressure compared to placebo by 9 mmHg (95% CI 9 to 10, high-quality evidence)/4 mmHg (95% CI 3 to 4, high-quality evidence).Thiazides as a class have a greater effect on systolic than on diastolic blood pressure, therefore thiazides lower pulse pressure by 4 mmHg to 6 mmHg, an amount that is greater than the 3 mmHg seen with angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs) and renin inhibitors, and the 2 mmHg seen with non-selective beta-blockers. This is based on an informal indirect comparison of results observed in other Cochrane reviews on ACE inhibitors, ARBs and renin inhibitors compared with placebo, which used similar inclusion/exclusion criteria to the present review.Thiazides reduced potassium, increased uric acid and increased total cholesterol and triglycerides. These effects were dose-related and were least for hydrochlorothiazide. Chlorthalidone increased serum glucose but the evidence was unclear for other thiazides. There is a high risk of bias in the metabolic data. This review does not provide a good assessment of the adverse effects of these drugs because there was a high risk of bias in the reporting of withdrawals due to adverse effects. This systematic review shows that hydrochlorothiazide has a dose-related blood pressure-lowering effect. The mean blood pressure-lowering effect over the dose range 6.25 mg, 12.5 mg, 25 mg and 50 mg/day is 4/2 mmHg, 6/3 mmHg, 8/3 mmHg and 11/5 mmHg, respectively. For other thiazide drugs, the lowest doses studied lowered blood pressure maximally and higher doses did not lower it more. Due to the greater effect on systolic than on diastolic blood pressure, thiazides lower pulse pressure by 4 mmHg to 6 mmHg. This exceeds the mean 3 mmHg pulse pressure reduction achieved by ACE inhibitors, ARBs and renin inhibitors, and the 2 mmHg pulse pressure reduction with non-selective beta-blockers as shown in other Cochrane reviews, which compared these antihypertensive drug classes with placebo and used similar inclusion/exclusion criteria.Thiazides did not increase withdrawals due to adverse effects in these short-term trials but there is a high risk of bias for that outcome. Thiazides reduced potassium, increased uric acid and increased total cholesterol and triglycerides.

[Perspectives on treatment of hypertension in elderly patients].

Hypertension increases in prevalence with age. Population-based studies suggest that more than 50% of people over the age of 65 years may have chronic hypertension, defined as blood pressure (BP) > or = 140/90 mmHg. Hypertension, especially systolic hypertension, is the most common, powerful, however treatable risk factor for cardiovascular morbidity and mortality in the elderly. Large randomised trials have demonstrated that treating elderly and even very old persons (age > 80 years) is highly efficacious. A recent meta-analysis, comparing active treatment with placebo in isolated systolic hypertension demonstrated highly significant benefits: stroke was reduced by 30%, coronary heart disease events by 23%, all cardiovascular events by 26%, and cardiovascular deaths by 13%. The classic strategy of an initial thiazide or thiazide-like diuretic therapy has been verified by the most recent trials. Furthermore it is not appropriate to limit the choice of initial drugs for hypertensive older individuals to a single class of agents, since so many older people have other medical problems that affect this decision and reaching the target blood pressure is the determinant factor for cardiovascular risk reduction. Therefore single drug therapy with long-acting (dihydropyridine-type) calcium-antagonists, beta-blockers, angiotensin-converting-enzyme-inhibitors or angiotensin-receptor-blockers is justified with respect to individual efficacy and comorbidity. If a combination of antihypertensive drugs is needed to reach blood pressure goal, thiazides remain the cornerstone. First line therapy with an alpha-blocker is no longer recommended, even for men with hypertension and benign prostatic hypertrophy. Today, recommended blood pressure goals are the same for younger individuals and the elderly.

Alpha-1 blocker

In patients with neurogenic hypertension who fail in achieving blood pressure control with angiotensin converting enzyme inhibitors (ACEi), Angiotensin receptor blockers (ARB) and calcium channel blockers (CCB), alpha- and beta- adrenergic receptor blockers constitute the main treatment options. This is supported by studies that show surprisingly though consistently that neither alpha- nor beta-blocker mono- therapy reduces sympathetically mediated blood pressure reactivity to acute experimental stressors. Studies of combined oral alpha- and beta-blockade using an alpha-blocker (e.g., doxazosin or terazosin) in combination with a nonlipophilic beta-blocker with more reliable bioavailability (e.g., betaxolol, bisoprolol, atenolol and others) have shown a larger antihypertensive effect. This approach also enables separate titration of alpha- and beta-blocking effects. In these studies, doxazosin was prescribed at the low dose of 1–2 mg.

Efficacy and safety of lercanidipine versus hydrochlorothiazide as add-on to enalapril in diabetic populations with uncontrolled hypertension.

Angiotensin-converting enzyme inhibitors plus dihydropyridine calcium channel blockers or low-dose thiazide diuretics are considered first-line therapies in hypertensive diabetic patients as glucose metabolism is not relevantly affected. Most diabetic patients require at least two different drug classes to achieve the recommended target blood pressure of 130/85 mmHg. This controlled clinical trial investigated the calcium channel blocker lercanidipine versus hydrochlorothiazide (HCTZ) as add-on in diabetic patients with uncontrolled hypertension on enalapril monotherapy. Overall, 174 patients (18-80 years old, well-controlled diabetes type 1 or 2, mild to moderate hypertension) were included in a 2-week placebo run-in followed by 4 weeks on enalapril 20 mg. Subsequently, 135 non-responders (90 mmHg < or = mean sitting diastolic blood pressure < or = 109 mmHg) were randomized to 20 weeks of double-blind add-on therapy to enalapril with either lercanidipine 10 mg (n = 69) or HCTZ 12.5 mg (n = 66). The primary study objective was to prove non-inferiority of lercanidipine add-on versus HCTZ add-on in reducing sitting diastolic blood pressure; response rates and tolerability data were also observed. Both add-on treatments clearly decreased diastolic blood pressure to a greater extent than enalapril monotherapy (mean +/- SD changes at study end: lercanidipine, -9.3 mmHg; HCTZ, -7.4 mmHg); non-inferiority of lercanidipine versus HCTZ was formally proven. Blood pressure response rates reached 69.6% on enalapril plus lercanidipine as compared with 53.6% on enalapril plus HCTZ (difference between treatments, P > 0.05). Blood pressure of 130/85 mmHg or less was achieved in 30.4% of patients on lercanidipine add-on and in 23.2% of those randomized to HCTZ add-on (P > 0.05). Both treatment regimens were well tolerated. Lercanidipine add-on showed comparable efficacy to HCTZ add-on in diabetic patients with hypertension badly controlled on angiotensin-converting enzyme inhibitor monotherapy. The blood pressure response rates seemed to be somewhat higher following enalapril plus lercanidipine than enalapril plus HCTZ.

Management of hypertension in the elderly patient.

Hypertension in the elderly is associated with increased occurrence rates of sodium sensitivity, isolated systolic hypertension, and 'white coat effect'. Arterial stiffness and endothelial dysfunction also increase with age. These factors should be considered in selecting antihypertensive therapy. The prime objective of this therapy is to prevent stroke. The findings of controlled trials show that there should be no cut-off age for treatment. A holistic program for controlling cardiovascular risks should be fully discussed with the patient, including evaluation to exclude underlying causes of secondary hypertension, and implementation of lifestyle measures. The choice of antihypertensive drug therapy is influenced by concomitant disease and previous medication history, but will typically include a thiazide diuretic as the first-line agent; to this will be added an angiotensin inhibitor and/or a calcium channel blocker. Beta blockers are not generally recommended, in part because they do not combat the effects of increased arterial stiffness. The hypertension-hypotension syndrome requires case-specific management. Drug-resistant hypertension is important to differentiate from faulty compliance with medication. Patients resistant to third-line drug therapy may benefit from treatment with extended-release isosorbide mononitrate. A trial of spironolactone may also be worthwhile.

Antihypertensive drug

However, ACE inhibitors (and angiotensin II receptor antagonists) should not be a first-line treatment for black hypertensives without chronic kidney disease. Results from the ALLHAT trial showed that thiazide-type diuretics and calcium channel blockers were both more effective as monotherapy in improving cardiovascular outcomes compared to ACE inhibitors for this subgroup. Furthermore, ACE inhibitors were less effective in reducing blood pressure and had a 51% higher risk of stroke in black hypertensives when used as initial therapy compared to a calcium channel blocker. There are fixed-dose combination drugs, such as ACE inhibitor and thiazide combinations. Notable side effects of ACE inhibitors include dry cough, high blood levels of potassium, fatigue, dizziness, headaches, loss of taste and a risk for angioedema. Angiotensin II receptor antagonists

Adult hypertension: reducing cardiovascular morbidity and mortality.

(1) Since our last review of treatments for arterial hypertension in 1999 (Prescrire International no.41), many new data have been published and new antihypertensive drugs have appeared on the market. (2) The working definition of hypertension is unchanged, namely blood pressure of at least 160/95 mm Hg in the general population, and at least 140/80 mm Hg in patients with diabetes and a history of stroke; these figures must be found on several occasions using a standardised method, with the patient at rest. (3) The goals of antihypertensive therapy are to reduce mortality and cardiovascular events, and not simply to drive blood pressure below a fixed (and often controversial) threshold. (4) Some drug and non drug interventions have a positive risk-benefit balance in the long term. (5) When antihypertensive drug therapy is needed, trials based on clinical endpoints show that it is best to start treatment with a single drug. (6) New data support the use of certain thiazide diuretics (chlortalidone, or hydrochlorothiazide if chlortalidone is not available) as first line treatment for most hypertensive patients, including non diabetic adults, diabetic adults, elderly subjects (over 65 years), and stroke patients. Some betablockers and angiotensin-converting-enzyme inhibitors (ACE inhibitor) are second-line alternatives. (7) Assessment of other antihypertensive drugs has also progressed since 1999, including indapamide (thiazide-like diuretic), amlodipine, diltiazem and verapamil (calcium channel blockers), lisinopril (ACE inhibitor), and losartan and valsartan (angiotensin II antagonists). However, these drugs are not as thoroughly evaluated as thiazide diuretics, betablockers and some ACE inhibitors.

The older patient with hypertension: care and cure.

Hypertension is one of the most important clinical conditions affecting older people. Its prevalence in this group of subjects is above 60% and continues to grow. Isolated systolic hypertension accounts for the majority of cases as systolic blood pressure increases with advancing age, while diastolic blood pressure remains unchanged or even decreases. Nowadays hypertension is a well established risk factor for stroke and cardiovascular disease among older people and its treatment is considered mandatory. The general recommended blood pressure goal in uncomplicated hypertension is less than 140/90 mmHg, even if this target in older people is based mainly on expert opinion. All patients should receive nonpharmacological treatment, in particular reduction in excess body weight when body mass index is greater than 26 kg/m(2) and dietary salt restriction. Older patients with hypertension may also benefit from smoking cessation, physical activity and alcohol restriction. In relation to drug therapy, a low-dose thiazide diuretic could be a good first step. Other first-line drugs are long-acting calcium channel blockers, generally dihydropyridines, and angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers. The HYVET study showed a specific protective effect of indapamide with or without perindopril in people older than 80 years. Since monotherapy normalizes blood pressure in only 40-50% of cases, a combination of two or more drugs is often required. Moreover the addiction of a second drug may reduce the dose-related adverse effects of the first one. Finally, compliance with treatment should always be achieved by giving complete information to patients and simplifying the drug regimen as much as possible.

Chlortalidone

Medical use High blood pressure Chlortalidone is considered a first-line medication for treatment high blood pressure. Some recommend chlortalidone over hydrochlorothiazide. A meta-analysis of randomized controlled trials found that chlortalidone is more effective than hydrochlorothiazide for lowering blood pressure, while the two drugs have similar toxicity. Trials of chlortalidone for high blood pressure found that lower doses of chlortalidone (e.g., 12.5 mg daily in ALLHAT study) had maximal blood pressure lowering effect and that higher doses did not lower it more. Chlortalidone, like other thiazides, appears effective in people with kidney disease. Chlortalidone and other thiazide diuretics are effective for lowering high blood pressure in persons with chronic kidney disease, although the risk of adverse effects is higher in these persons.

Guidelines for management of hypertension: report of the third working party of the British Hypertension Society.

Use non-pharmacological measures in all hypertensive and borderline hypertensive people. Initiate antihypertensive drug therapy in people with sustained systolic blood pressures (BP) >/=160 mm Hg or sustained diastolic BP >/=100 mm Hg. Decide on treatment in people with sustained systolic BP between 140 and 159 mm Hg or sustained diastolic BP between 90 and 99 mm Hg according to the presence or absence of target organ damage, cardiovascular disease or a 10-year coronary heart disease (CHD) risk of >/=15% according to the Joint British Societies CHD risk assessment programme/risk chart. In people with diabetes mellitus, initiate antihypertensive drug therapy if systolic BP is sustained >/=140 mm Hg or diastolic BP is sustained >/=90 mm Hg. In non-diabetic hypertensive people, optimal BP treatment targets are: systolic BP <140 mm Hg and diastolic BP <85 mm Hg. The minimum acceptable level of control (Audit Standard) recommended is <150/<90 mm Hg. Despite best practice, these levels will be difficult to achieve in some hypertensive people. In diabetic hypertensive people, optimal BP targets are; systolic BP <140 mm Hg and diastolic BP <80 mm Hg. The minimum acceptable level of control (Audit Standard) recommended is <140/<90 mm Hg. Despite best practice, these levels will be difficult to achieve in some people with diabetes and hypertension. In the absence of contraindications or compelling indications for other antihypertensive agents, low dose thiazide diuretics or beta-blockers are preferred as first-line therapy for the majority of hypertensive people. In the absence of compelling indications for beta-blockade, diuretics or long acting dihydropyridine calcium antagonists are preferred to beta-blockers in older subjects. Compelling indications and contraindications for all antihypertensive drug classes are specified. For most hypertensives, a combination of antihypertensive drugs will be required to achieve the recommended targets for blood pressure control. Other drugs that reduce cardiovascular risk must also be considered. These include aspirin for secondary prevention of cardiovascular disease, and primary prevention in treated hypertensive subjects over the age of 50 years who have a 10-year CHD risk >/=15% and in whom blood pressure is controlled to the audit standard. In accordance with existing British recommendations, statin therapy is recommended for hypertensive people with a total cholesterol >/=5 mmol/L and established vascular disease, or 10-year CHD risk >/=30% estimated from the Joint British Societies CHD risk chart. Glycaemic control should also be optimised in diabetic subjects. Specific advice is given on the management of hypertension in specific patient groups, ie, the elderly, ethnic subgroups, diabetes mellitus, chronic renal disease and in women (pregnancy, oral contraceptive use and hormone replacement therapy). Suggestions for the implementation and audit of these guidelines in primary care are provided.

Interaction between antihypertensives and NSAIDs in primary care: a controlled trial.

Non-steroidal anti-inflammatory drugs (NSAIDs) may increase blood pressure (BP) and blunt the effects of many antihypertensives. It seems that NSAIDs and the antihypertensive drugs differ in their propensity to such an interaction. To determine the extent of the interaction between two antihypertensives and three NSAIDs. A prospective clinical trial in a family practice included 88 treated hypertensives aged over 55 years; 39 controls and 49, also taking NSAIDs for osteoarthritis. During this 3-month study, two antihypertensives, lisinopril/hydrochlorothiazide and amlodipine, were compared with three NSAIDs: ibuprofen, acetaminophen, and piroxicam. BP was measured with standard mercury sphygmomanometer and with an automatic device, in standing, sitting, and supine position. The average starting blood pressure in the study group was 149.3A+/-9.8/88.6A+/-6.8 mm Hg. In the lisinopril/hydrochlorothiazide subgroup, both ibuprofen and piroxicam elevated systolic BP by 7.7-9.9% (p<0.001), which, during the acetaminophen period, decreased by 6.9-9.4% to 0.3-0.9% above baseline (p<0.001), increasing again by 7.0-7.7% (p<0.001) during the second exposition to these drugs. In the amlodipine subgroup, ibuprofen or piroxicam increased BP by 1.1-1.6% (p>0.290) only, and there were no significant shifts in the follow-up periods. Analogous deviations were observed with both measurement devices, in all the examinee's positions. In the control group, BP did not change appreciably. Piroxicam and ibuprofen markedly blunt the effects of antihypertensive drugs while acetaminophen is almost inert. Lisinopril/hydrochlorothiazide combination is much more affected by this interaction than amlodipine (ClinicalTrials.gov #NCT00631514).