Effect of three months' treatment with irbesartan on blood and pulse pressure of hypertensive type 2 diabetic patients: open, observational study in 31,793 patients

OBJECTIVES: In hypertensive diabetics the cardiovascular risk is substantially increased. Therefore, an effective reduction of both blood pressure and pulse pressure is of particular importance for these patients. The aim of the prospective observational study in hypertensive type 2 diabetics was to assess the effect of a switch from the previous antihypertensive therapy to the angiotensin-II-receptor antagonist irbesartan (alone or in combination with HCTZ) on the reduction of blood pressure and pulse pressure, the reduction of diabetic nephropathy (microalbuminuria), and tolerability. METHODS: 8714 general practitioners included 31,793 type 2 diabetics aged at least 18 years in an open observational study. After inclusion in to the study the patients received irbesartan 300 mg as monotherapy or in combination with hydrochlorothiazide 12.5 mg (HCTZ). Main outcome measures for efficacy were the reduction of systolic (SBP) and diastolic (DBP) blood pressures, reduction of pulse pressure, and blood pressure responder (reduction in DBP > or = 10 mmHg or diastolic < 90 mmHg), diastolic normalization (DBP < 90 mmHg) and overall normalization rates (SBP < 140 mmHg and DBP < 90 mmHg) after 3 months. Further outcome measures included the reduction of microalbuminuria or proteinuria, and adverse events (AEs) as a measure of tolerability. RESULTS: Thirty-eight per cent of patients received irbesartan 300 mg and 61% irbesartan in combination with HCTZ. Mean systolic blood pressure was reduced by 22.5 mmHg, diastolic blood pressure by 10.7 mmHg (baseline values: 160.2 and 93.2 mmHg). Pulse pressure fell on average by 11.6 mmHg. 83.4% of the patients were responders, with an overall normalization rate of 42.7% (SBP < 140 mmHg and DBP < 90 mmHg), respectively 73.8% (DBP < 90 mmHg). The antihypertensive benefit was achieved irrespective of the previous medication. Mean albuminuria decreased by about 27.7 mg/L. Only 0.3% of patients experienced adverse events. CONCLUSIONS: In type 2 diabetics with hypertension and either uncontrolled or no previous antihypertensive therapy a change to treatment with irbesartan or irbesartan/HCTZ for 3 months resulted in a distinct reduction of systolic and diastolic blood pressures, with concomitant effective reductions of pulse pressure and microalbuminuria.     

Clinical implication of morning blood pressure surge in hypertension

Cardiovascular events occur most frequently in the morning. The morning surge in blood pressure may be associated with hypertensive target organ damage and subsequent cardiovascular risk in hypertensive patients. In our prospective study on elderly hypertensive patients, the morning blood pressure surge (defined as the increase from the lowest blood pressure during sleep to the average of the first 2 h after waking) was significantly associated with silent hypertensive cerebrovascular disease and subsequent stroke risk. This association was independent of age and 24-h ambulatory blood pressure levels. In addition, even after controlling for these factors and status of silent cerebrovascular disease, the contribution of the morning blood pressure surge remained significant, and a 10 mmHg increase in systolic morning blood pressure surge increase the stroke risk by 22%. A related factor is orthostatic hypertension, which might be associated with increased sympathetic activity, and which is significantly associated with an increase in morning blood pressure surge and ambulatory blood pressure variability. A possible implication is that, in addition to strict blood pressure control, antihypertensive medication that targets exaggerated morning blood pressure may achieve more effective prevention of cardiovascular events in hypertensive patients.     

Current treatment of patients with hypertension: therapeutic implications of INSIGHT

When planning treatment for patients with hypertension, current guidelines emphasise the importance of risk stratification, based on blood pressure, the presence of end-organ damage and other cardiovascular risk factors. Because the beneficial effect of antihypertensive therapy seems to be linked to the degree of blood pressure reduction, guidelines recommend reducing blood pressure below 140/90mm Hg, with a lower target in patients who are young or who have diabetes mellitus (with or without nephropathy) or non-diabetic nephropathy. Blood pressure reduction can be achieved with several classes of drugs, including diuretics, beta-blockers, ACE inhibitors, angiotensin II antagonists and calcium channel antagonists. Calcium channel antagonists have been shown to reduce the risk of stroke and major cardiovascular events. However, it is still controversial whether different treatment regimens based on different drug classes can offer advantages beyond similar degrees of blood pressure control in preventing cardiovascular morbidity and mortality. The International Nifedipine GITS Study: Intervention as a Goal in Hypertension Treatment (INSIGHT) was a controlled clinical trial aimed at comparing the efficacy of a long-acting calcium channel antagonist, nifedipine gastrointestinal-transport-system (GITS), versus co-amilozide, a combination of the diuretics hydrochlorothiazide (HCTZ) and amiloride, on morbidity and mortality in high-risk hypertensive patients. Nifedipine GITS and HCTZ/amiloride were equally effective at reducing blood pressure and the risk of primary outcomes (a composite of death from any cardiovascular or cerebrovascular cause, non-fatal stroke, myocardial infarction and heart failure). Results from other studies indicate that there may be greater benefits for stroke and smaller benefits for coronary artery disease with calcium channel antagonist-based regimens than with diuretic or beta-blocker-based regimens. However, there is at present insufficient evidence to recommend a specific drug choice based on patient risk profile. Thus, the choice of antihypertensive drug(s) should be according to efficacy and tolerability. In addition to the reductions in cardiovascular risk, two substudies of INSIGHT showed that nifedipine GITS was able to prevent the progression of intima media thickness in the common carotid artery and slow the progression of coronary calcification. The clinical significance of this effect in the prevention of cardiovascular events still remains to be established.     

Triple Combination Therapy for Global Cardiovascular Risk: Atorvastatin,Perindopril, and Amlodipine

Statins, angiotensin-converting enzyme (ACE) inhibitors, and calcium channel blockers (CCBs) have markedly changed the clinical progression of patients with coronary artery disease (CAD). The goal of this paper is to review the rationale and evidence for combining these three drug classes in hypertensive patients with hypercholesterolemia or CAD. Data sources include a literature search for publications on the use of a statin combined with various antihypertensive drugs in patients with hypertension and hypercholesterolemia or stable CAD. Hypercholesterolemia and hypertension constitute major physiological risk factors of ischemic heart disease. Current guidelines recommend a global approach to risk management, using agents that address as many risk factors as possible. Dual combination therapies are an important component of guideline-recommended therapy in hypertension. Our review of the literature indicates that triple therapy with a statin, ACE inhibitor, and CCB is associated with a significant reduction in major cardiovascular events. For example, a post hoc analysis in 1056 patients with stable CAD participating in the EUROPA trial indicated that the addition of perindopril to a CCB and a lipid-lowering agent was associated with a 46 % reduction in the composite of cardiovascular death, myocardial infarction, and resuscitated cardiac arrest (p = 0.023). In addition, single pill formulations are known to result in better adherence to the treatment. Single-pill formulations that combine a statin, an ACE inhibitor, and a CCB appear to offer an effective approach to the management of global cardiovascular risk.     

Effect of three months’ treatment with irbesartan on blood and pulse pressure of hypertensive type 2 diabetic patients: open,observational study in 31 793 patients

ABSTRACT

Objectives: In hypertensive diabetics the cardiovascular risk is substantially increased. Therefore, an effective reduction of both blood pressure and pulse pressure is of particular importance for these patients. The aim of the prospective observational study in hypertensive type 2 diabetics was to assess the effect of a switch from the previous antihypertensive therapy to the angiotensin-II-receptor antagonist irbesartan (alone or in combination with HCTZ) on the reduction of blood pressure and pulse pressure, the reduction of diabetic nephropathy (microalbuminuria), and tolerability.

Methods: 8714 general practitioners included 31?793 type 2 diabetics aged at least 18 years in an open observational study. After inclusion in to the study the patients received irbesartan 300?mg as monotherapy or in combination with hydrochlorothiazide 12.5?mg (HCTZ). Main outcome measures for efficacy were the reduction of systolic (SBP) and diastolic (DBP) blood pressures, reduction of pulse pressure, and blood pressure responder (reduction in DBP ≥ 10 mmHg or diastolic < 90 mmHg), diastolic normalization (DBP < 90 mmHg) and overall normalization rates (SBP < 140 mmHg and DBP < 90 mmHg) after 3 months. Further outcome measures included the reduction of microalbuminuria or proteinuria, and adverse events (AEs) as a measure of tolerability.

Results: Thirty-eight per cent of patients received irbesartan 300?mg and 61% irbesartan in combination with HCTZ. Mean systolic blood pressure was reduced by 22.5?mmHg, diastolic blood pressure by 10.7?mmHg (baseline values: 160.2 and 93.2?mmHg). Pulse pressure fell on average by 11.6?mmHg. 83.4% of the patients were responders, with an overall normalization rate of 42.7% (SBP < 140?mmHg and DBP < 90?mmHg), respectively 73.8% (DBP < 90?mmHg). The antihypertensive benefit was achieved irrespective of the previous medication. Mean albuminuria decreased by about 27.7?mg/L. Only 0.3% of patients experienced adverse events.

Conclusions: In type 2 diabetics with hypertension and either uncontrolled or no previous antihypertensive therapy a change to treatment with irbesartan or irbesartan/HCTZ for 3 months resulted in a distinct reduction of systolic and diastolic blood pressures, with concomitant effective reductions of pulse pressure and microalbuminuria.     

Importance of blood pressure variability in the assessment of cardiovascular risk and benefits of antihypertensive therapy

Although there is no doubt regarding the relationship between short-term blood pressure variability (BPV) and cardiovascular events in the hypertensive population, to date, the association between long-term BPV and target organ damage is unknown. Rothwell et al. recently published a post-hoc analysis of two large randomized trials, Anglo Scandinavian Cardiac Outcomes Trial Blood Pressure Lowering Arm (ASCOT-BLPA) and the Medical Research Council (MRC), aimed at demonstrating whether drug effects on short-term and long-term BPV explain the differences of antihypertensive treatment in stroke prevention. Analysis found that short-term and long-term BPV was lower in hypertensive patients treated with amlodipine with regards to atenolol. The amlodipine group showed a lower risk of stroke and coronary events with respect to subjects assigned to atenolol. Interestingly, the lower stroke risk detected in hypertensive patients treated with amlodipine was abolished after adjusting by within-individual BPV. Taking into account these findings, the authors concluded that the opposite effect of calcium channel blockers and β-blockers on BPV explains the disparity in the risk of stroke of patients under antihypertensive treatment. Therefore, to effectively prevent cerebrovascular events, blood pressure-lowering agents need both to reduce mean blood pressure and its short-term and long-term variability.     

Perindopril: a review of its use in patients with or at risk of developing coronary artery disease

Perindopril (Coversyl) is a prodrug ester of perindoprilat, an ACE inhibitor. This agent has shown pharmacodynamic effects beyond those responsible for lowering blood pressure (BP), including the improvement of endothelial function and the normalisation of vascular and cardiac structure and function. Perindopril has a well established role in the treatment of patients with hypertension or heart failure. In the EUROPA trial, once-daily perindopril 8 mg prevented cardiovascular events in patients with stable coronary artery disease (CAD) without any apparent heart failure receiving standard recommended therapy. In the ASCOT-BPLA trial, a calcium channel antagonist +/- perindopril regimen demonstrated significant cardiovascular benefits compared with a conventional beta-blocker +/- diuretic regimen in patients with hypertension who were at risk of developing cardiovascular events. These trials demonstrate that while perindopril, in addition to standard recommended therapy, has a potential role in preventing cardiovascular events in hypertensive patients, its role in the management of patients with stable CAD is clearly established.     

Amélioration des composantes systolique et pulsée de la pression artérielle,de la rigidite artérielle et de l’hypertrophie ventriculaire gauche chez des patients hypertendus traités par l’association perindopril/indapamide. L’étude REASON

Improving the systolic and pulse pressure components of blood pressure, arterial stiffness and left ventricular hypertrophy in hypertensive patients treated with the perindopril/indapamide combination. The REASON Study.It is now well established, particularly in elderly patients, that systolic blood pressure (SBP) levels represent a more reliable predictor than diastolic blood pressure of hypertension-related morbidity and mortality including coronary heart disease, stroke, heart failure, renal insufficiency and cardiovascular death. Adequate control of SBP has therefore become a major objective of antihypertensive therapies. Indeed, despite the recent focus on the systolic blood pressure component in the latest guidelines, systolic hypertension is frequently neglected in clinical practice. Furthermore, several observational studies have suggested that pulse pressure (PP) may be a superior predictor of cardiovascular complications than mean arterial pressure (MAP) levels in certain populations and in elderly patients in particular. Finally, pulse pressure is a marker of large artery stiffness; in risk assessment and risk reduction strategies, pulse pressure and arterial stiffness are strongly associated with vascular alterations and are therefore more closely related to cardiovascular risk. The REASON Study was initiated from these observations.     

Arterial 'prehypertension': a useful concept for drug companies, useless for patients

(1) Elevated blood pressure is an independent and progressive cardiovascular risk factor. The risk starts to increase above a threshold of 115/75 mmHg. (2) The threshold values for blood pressure with practical implications for patients' health have been determined from clinical trial results. These are, for example, 160/95 mmHg in patients without diabetes and complications of hypertension, and 140/80 mmHg in patients with diabetes or a history of stroke. (3) A prospective cohort analysis confirmed the progressive nature of the relation between blood pressure and the risk of cardiovascular events: after about 12 years the incidence of cardiovascular events was 7% when blood pressure was less than 120/80 mmHg and 12% when it was between 130/85 and 140/90 mmHg. However, patients with these moderately elevated blood pressure values were also more likely to be diabetic. (4) The only trial involving patients with systolic pressure values between 130 and 139 mmHg, levels referred to by some as 'prehypertension', was not designed to determine either the clinical benefits or the adverse effects of treatment with candesartan. Two years after withdrawal of this antihypertensive drug, there was no statistically significant difference in the proportion of patients requiring antihypertensive treatment (threshold 160/100 mmHg). (5) In practice, 'prehypertension' is not a useful concept for patient management. The blood pressure thresholds above which the risk-benefit balance for some treatments becomes positive, in terms of morbidity or mortality, remain at 160/95 mmHg for patients without diabetes or complications and 140/80 mmHg for patients with diabetes or a history of stroke.     

Epidemiology of hypertension in the elderly.

Epidemiological studies confirm that hypertension, particularly systolic hypertension, is a major cardiovascular and cerebrovascular risk factor in the elderly. Clinical trials convincingly demonstrate the benefits of treating both diastolic hypertension in persons up to age 80 years, and isolated systolic hypertension in persons over age 60. The European Working Party on Hypertension in the Elderly (EWPHE) trial showed that reducing elevated blood pressure resulted in a 27% reduction in overall cardiovascular mortality, as well as significant reductions in severe congestive heart failure, strokes and deaths from myocardial infarction. The Systolic Hypertension in the Elderly Program (SHEP) also reported a 36% reduction in the incidence of stroke and decreases in cardiovascular events, including myocardial infarctions, when hypertension was treated. Additional EWPHE data suggest that the optimal level of systolic blood pressure control is between 146 and 158mm Hg, while patients in the SHEP trial with isolated systolic hypertension derived benefits at an average treated systolic blood pressure of 143mm Hg. Elderly study populations comply well with antihypertensive treatment, and blood pressure can be safely lowered with simple drug regimens. Nonpharmacological treatment is recommended for initial treatment of mild diastolic hypertension and isolated systolic hypertension, and as adjuvant treatment with medication. Since all antihypertensive agents can lower blood pressure in the elderly, therapy should be chosen based on its potential for side effects, drug interactions and effects on concomitant disease states.     

Therapeutic strategies for hypertension treatment in patients with selected cardiovascular diseases

Patients with hypertension and concomitant cardiovascular (CVD) conditions are at high risk for developing deleterious CVD-related clinical sequelae. The selection of therapeutic strategies for hypertension management in patients with cardiovascular diseases is an important first step in normalizing blood pressure (BP) levels (<140/90 mmHg). The ultimate goal of BP normalization for this high-risk group of hypertensive patients is target-organ protection. This review will discuss the management of hypertension in patients with selected CVD conditions (congestive heart failure, coronary artery disease, renal insufficiency/end-stage renal disease) and will incorporate both nondrug and drug therapies. Nondrug therapy, including weight reduction, physical activity, restriction of dietary sodium and alcohol intake are effective strategies for lowering BP. If these measures are not adequate, then the addition of drug therapy is needed in order to provide gradual BP normalization. Drug regimens may include a single antihypertensive agent with up-titration of the dose, or a combination of antihypertensive agents at a lower dose of each agent. The availability of different classes of antihypertensive agents enables therapeutics strategies to be implemented in the management of hypertension that provide maximum target-organ protection for each entity of CVD. Thus, aggressive hypertension management is crucial for delaying/preventing target organ damage and subsequent CVD clinical events.     

Impact of increased heart rate on clinical outcomes in hypertension: implications for antihypertensive drug therapy

Thirty-eight studies have been published to date on the association between elevated heart rate and mortality. After adjustment for other risk factors, only two studies for all-cause mortality and four studies for cardiovascular mortality reported an absence of association between heart rate and mortality in male populations. This relationship has been found to be generally weaker among females. Most of these studies investigated samples of general populations. The four studies performed in hypertensive men found a positive association between heart rate and all-cause mortality (hazard ratios ranging from 1.9 to 2.0) or cardiovascular mortality (hazard ratios ranging from 1.3 to 1.7). In spite of this evidence, elevated heart rate remains a neglected cardiovascular risk factor in both genders. The pathogenetic mechanisms connecting high heart rate, hypertension, atherosclerosis and cardiovascular events have also been explicated in many studies. Elevated heart rate is due to an increased sympathetic and decreased parasympathetic tone. This altered balance of the autonomic nervous system tone could explain the increase in events with the increased heart rate. However, it has also been proved that blood flow changes associated with high heart rate favour both the formation of the atherosclerotic lesion and the occurrence of the cardiovascular event. Reduction of heart rate in hypertensive patients with increased heart rate could be an additional goal of antihypertensive therapy. Several trials retrospectively showed the beneficial effect of cardiac-slowing drugs, such as beta-adrenoceptor antagonists (beta-blockers) and non-dihydropyridine calcium channel antagonists, on mortality, notably in patients with coronary heart disease, but no published data are available in patients with hypertension free of coronary heart disease. Other antihypertensive drugs that have been shown to reduce the heart rate are centrally acting drugs and angiotensin II receptor antagonists, but their bradycardic effect is rather weak. The f-channel antagonist ivabradine is a selective heart rate-lowering agent with no effect on blood pressure. Although it has not been proven in existing trials, it would seem reasonable to recommend antihypertensive agents that decrease the heart rate in hypertensive patients with a heart rate higher than 80-85 beats per minute. Since the fast heart rate per se causes cardiovascular damage, all drugs that lower the heart rate have the potential of further reducing cardiovascular events in patients with elevated heart rate. Unfortunately, lowering of the heart rate is not a clinically recognised goal. Prospective trials investigating whether treatment of high heart rate can prevent cardiovascular events, notably in hypertensive patients, are warranted.     

Antihypertensive drugs: diuretics and betablockers are the best assessed

(1) In trials involving hypertensive non diabetic patients under 65, some diuretics and betablockers have prevented strokes, without conferring protection from coronary events or death. In one trial captopril had an effect comparable to that of diuretics or betablockers in terms of overall cardiovascular prevention, but was a little less effective in preventing strokes. (2) In trials involving hypertensive subjects over 65, some diuretics and betablockers have reduced the risk of stroke, coronary events, heart failure, and death. In one trial a diuretic was superior to a betablocker in terms of preventive efficacy and adverse effects. Nitrendipine, in combination with other antihypertensive drugs, prevented strokes in one trial. (3) In a trial involving hypertensive diabetic patients, captopril and atenolol reduced the risk of stroke, heart failure and worsening of retinal disease, without preventing coronary events or death. In two trials coronary events were more frequent on dihydropyridine than on an angiotensin-coverting-enzyme (ACE) inhibitor. (4) In one trial a diuretic reduced the risk of relapse after stroke, even in patients without severe hypertension.     

Angiotensin-converting enzyme inhibitors and coronary heart disease prevention.

A number of large randomised controlled trials have shown that angiotensin-converting enzyme (ACE) inhibitors, compared with placebo or other blood pressure-lowering drugs, improve coronary heart disease outcomes (fatal and non-fatal myocardial infarction, and coronary revascularisation) in diverse patient groups, e.g. in primary and secondary prevention, those with and without left ventricular dysfunction, and among hypertensive and non-hypertensive subjects. An updated meta-regression analysis which included five major trials in patients with established coronary artery disease (CAD) (EUROPA, INVEST, ACTION, PEACE and CAMELOT) concluded that ACE inhibitor (ACE-I) therapy has clear benefits in secondary prevention, but there are important and unexplained differences between trials in clinical outcome, baseline cardiovascular risk, blood pressure changes and trial design which deserve further discussion of the underlying mechanisms and clinical interpretation. For example, in placebo-controlled trials the biggest (2022%) reductions in primary end points (including mortality) have been observed with perindopril and ramipril, whereas trials using trandolapril and quinapril had no effect on survival or recurrent CAD events. This review summarises and compares the major findings of these recent trials, and provides further analysis of the underlying mechanisms and clinical significance of secondary CAD prevention with ACE-I therapy.     

How can hypertensive patients be better treated? The contribution of combination therapy

Recent studies demonstrated that target blood pressure (BP) in treated hypertensive patients should be below 140 mmHg for systolic blood pressure (SBP) and below 90 mmHg for diastolic blood pressure (DBP). However, population studies from several countries have demonstrated that in clinical practice the proportion of controlled hypertensive patients is less than 30%. In order to elucidate these questions in France we analysed a large population of 145,000 subjects examined at the Centre d'Investigations Préventives et Cliniques in Paris (IPC). Among those with high BP at the time of their IPC visit, only 20% received an antihypertensive treatment. Among those receiving an antihypertensive treatment, less than 27% (24% in men and 30% in women) presented with BP values less than 140 mmHg for SBP and less than 90 mmHg for DBP. This analysis also showed that 72% of hypertensive patients presented with at least one modifiable associated cardiovascular risk factor and that more than 30% of hypertensive men and more than 25% of hypertensive women presented with at least two associated risk factors. The use of combination therapies could help to increase the percentage of well-controlled hypertensive subjects. It has been shown that in order to reach this BP level, combination therapy should be used in more than two-thirds of the treated subjects. The trandolapril-verapamil combination is the first fixed combination of an angiotensin-converting enzyme inhibitor and a non-dihydropyridine calcium-channel blocker. Administered once daily, this combination reduces BP more than a classic monotherapy. The effects of the trandolapril-verapamil combination on risk factors are either neutral (metabolic parameters), or even beneficial (reduction in heart rate).     

Discordant effects of beta-blockade on central aortic systolic and brachial systolic blood pressure: considerations beyond the cuff

The role of beta-blockers in uncomplicated hypertension has been challenged recently. Compared with other antihypertensives, beta-blockers are less effective for preventing cardiovascular events in patients with uncomplicated hypertension. Moreover, a recent meta-analysis of placebo-controlled clinical trials concluded that atenolol is not more efficacious than placebo for preventing cardiovascular events in patients with hypertension. Although these agents lower blood pressure measured conventionally over the brachial artery with a blood pressure cuff, they do not exert a commensurate effect on blood pressure in the central aorta. Central aortic blood pressure and aortic augmentation index are strong predictors of left ventricular hypertrophy, an independent risk factor for cardiovascular events. Emerging data are illuminating the antihypertensive paradox whereby antihypertensive agents may elicit discordant effects on central and peripheral blood pressure and hemodynamics. Vasodilatory antihypertensives, such as renin-angiotensin-aldosterone system inhibitors and calcium channel blockers, elicit reductions in central aortic blood pressure equal to or greater than that in the brachial artery. Conversely, beta-blockers lower central aortic blood pressure to a lesser degree even when blood pressure measured by sphygmomanometry is reduced substantially. Given the strong relationship between central aortic blood pressure and target organ damage, the effectiveness of beta-blockers may be overestimated in practice on the basis of conventional blood pressure measurements alone. Differences in central and peripheral blood pressure may account for the lack of cardiovascular protection afforded by beta-blockers in clinical trials and could account for a portion of the apparent "benefit beyond blood pressure" reduction with other classes of antihypertensive agents. Future studies should aim to better clarify the role of central aortic blood pressure in the treatment of hypertension. In the meantime, the effects of antihypertensive drugs on blood pressure "beyond the brachial blood pressure cuff" should be considered when prescribing antihypertensive agents for a patient.     

Prevention of cardiovascular events in elderly people

BACKGROUND AND OBJECTIVE: Cardiovascular disease has been identified as the leading cause of morbidity and mortality in developed countries. Given the increase in life expectancy and the development of cardiovascular preventive measures, it has become increasingly important to detect and prevent cardiovascular diseases in the elderly. We reviewed the scientific literature concerning cardiovascular prevention to assess the importance of cardiovascular preventive measures in old (> or =65 years of age) individuals. METHODS: We undertook a systematic search for references relating to prevention of cardiovascular disease in the elderly, mainly ischaemic stroke, coronary artery disease and heart failure, on the MEDLINE database 1962-2005. For cardiovascular prevention by drugs or surgery, emphasis was placed on randomised controlled trials, review articles and meta-analyses. For cardiovascular prevention by lifestyle modification, major cohort studies were also considered. RESULTS: Stroke, coronary heart disease and heart failure were found to be the main targets for cardiovascular prevention in published studies. Antihypertensive treatment has proven its efficacy in primary prevention of fatal or nonfatal stroke in hypertensive and high-risk patients >60 years of age, particularly through treatment of systolic hypertension. Systolic blood pressure reduction is equally important in the secondary prevention of stroke. Similarly, in nonvalvular atrial fibrillation, an adjusted dose of warfarin with a target International Normalized Ratio (INR) of between 2 to 3 prevents ischaemic stroke in elderly patients with an acceptable haemorrhagic risk but is still under prescribed. Antiplatelet agents are indicated in elderly patients with nonembolic strokes. Few large-scale studies have investigated the effect of HMG-CoA reductase inhibitors (statins) on stroke prevention in old individuals. To date, the largest trials suggest a beneficial effect for stroke prevention with use of statins in high-risk elderly subjects < or =82 years of age. Carotid endarterectomy is indicated in carotid artery stenosis >70% and outcomes are even better in elderly than in younger patients. However, medical treatment is still the first-line treatment in asymptomatic elderly patients with <70% stenosis. In ischaemic heart disease, different trials in elderly individuals have shown that use of statins, antithrombotic agents, beta-adrenoceptor antagonists and ACE inhibitors plays an important role either in primary or in secondary cardiovascular prevention. Hormone replacement therapy has been used to treat climacteric symptoms and postmenopausal osteoporosis and was thought to confer a cardiovascular protection. However, controlled trials in elderly individuals changed this false belief when it was found that there was no benefit and even a harmful cardiovascular effect during the first year of treatment. Smoking cessation, regular physical activity and healthy diet are, as in younger individuals, appropriate and effective measures for preventing cardiovascular events in the elderly. Finally, antihypertensive treatment and influenza vaccination are useful for heart failure prevention in elderly individuals. CONCLUSIONS: Cardiovascular prevention should be more widely implemented in the elderly, including individuals aged > or =75 years, and this might contribute to improved healthy status and quality of life in this growing population.     

Perindopril: the evidence of its therapeutic impact in hypertension

INTRODUCTION: Effective antihypertensive therapy reduces the risk of cardiovascular and cerebrovascular disease and death. Perindopril, a long-acting angiotensin-converting enzyme (ACE) inhibitor, is an established antihypertensive agent administered as a once-daily tablet. AIMS: To review recent evidence for the use of perindopril in the treatment of hypertension. EVIDENCE REVIEW: Evidence shows that perindopril alone or in combination with other antihypertensive agents can achieve clinically significant reductions in blood pressure after 12 weeks of treatment. There is strong evidence from large randomized studies that perindopril-based therapy reduces the risk of cardiovascular outcomes, including mortality, in patients with coronary artery disease and those who have had a prior stroke or transient ischemic attack. There is also some evidence that these effects are greater than those achieved by blood pressure reduction alone, suggesting other drug-related effects including improvements in endothelial function. Recent results have also shown that an amlodipine ± perindopril regimen prevented more major cardiovascular events than an atenolol-based regimen in patients with hypertension, as a result of better control of blood pressure. Economic evidence from one major study shows that, for most patients, the incremental cost per quality-adjusted life-year gained with perindopril 8 mg was lower than the threshold value of €20 000 (73-92% of patients) in Europe or ￡20 000 (94% of patients) in the UK. CLINICAL VALUE: There is strong evidence supporting the use of perindopril-based therapy for the treatment of hypertension and reduction in the risk of cardiovascular disease, stroke, and death in a wide range of patients with stable coronary artery disease or hypertension.     

Reducing the risk of stroke in elderly patients with hypertension: a critical review of the efficacy of antihypertensive drugs

The risk of ischaemic or haemorrhagic stroke is increased in patients with hypertension, with a linear relationship between elevation of blood pressure and stroke risk being seen even in normotensive individuals. In elderly subjects it has been shown that systolic blood pressure (SBP) elevation in particular is the most important risk predictor for stroke. This is also the rationale for treating elevated SBP in the elderly. Several clinical trials have repeatedly shown the benefits of blood pressure control for prevention of stroke and also for dementia, both of the multi-infarct and Alzheimer subtype. Remaining research questions involve the proper and evidence-based choice of drug treatment in the elderly hypertensive patient. In spite of the introduction of many newer antihypertensive drugs, use of thiazide diuretics is still one of the best treatment choices, as this class of drugs is well proven and cost effective. Another question concerns when and how to treat patients >80 years of age. An ongoing randomised clinical trial, the Hypertension in the Very Elderly trial, is currently trying to evaluate risks and benefits of antihypertensive treatment in this age category.