Morbidity and mortality on combination versus monotherapy: a posthoc analysis of the Systolic Hypertension in Europe trial.

BACKGROUND: The current literature supports the immediate use of combinations of antihypertensive drugs in terms of ease of use and adherence, but the key issue whether combination therapy is more effective than monotherapy in the prevention of cardiovascular complications remains unproven. METHODS: We analysed the double-blind (median follow-up 2.0 years) and open follow-up (6.0 years) phases of the Systolic Hypertension in Europe trial. Patients were 60 years or more with an entry systolic/diastolic blood pressure (BP) of 160-219/less than 95 mmHg. Antihypertensive treatment started immediately after randomization in the active-treatment group, but only after completion of the double-blind trial in control patients. Treatment consisted of nitrendipine (10-40 mg/day) with the possible addition of enalapril (5-20 mg/day). We adjusted our analyses for sex, age, history of cardiovascular complications, baseline systolic BP and previous antihypertensive treatment. RESULTS: During the double-blind trial, adding enalapril to nitrendipine (n = 515), compared with the equivalent combination of placebos (n = 559), decreased systolic BP by a further 9.5 mmHg and reduced all cardiovascular events by 51% (P = 0.0035) and heart failure by 66% (P = 0.032), with similar trends for stroke (-51%; P = 0.066) and cardiac events (-44%; P = 0.075). Over the whole duration of follow-up, combination therapy (n = 871), compared with nitrendipine monotherapy (n = 1552), decreased systolic BP by 3.1 mmHg and reduced total mortality (-32%; P = 0.023), with similar trends for all cardiovascular events (-23%; P = 0.081) and stroke (-42%; P = 0.054). CONCLUSION: Despite the limitations of a posthoc analysis, but congruent with the stronger BP reduction, our results suggest that combination therapy with nitrendipine plus enalapril might improve outcome over and beyond the benefits seen with nitrendipine monotherapy.

'Beyond blood pressure' means multiple risk factor intervention, not pleiotropic antihypertensive drugs.

PURPOSE OF REVIEW: We examined the role of blood pressure-lowering compared with class-specific properties of antihypertensive drugs in cardiovascular prevention. RECENT FINDINGS: We reviewed recently published trials and meta-regression analyses. SUMMARY: From 150,000 to 180,000 randomized patients followed up from 3 to 5 years were required to demonstrate a 10-15% benefit 'beyond blood pressure lowering' of newer antihypertensive drugs, such as calcium channel blockers or angiotensin-converting enzyme inhibitors in the prevention of cause-specific cardiovascular complications. Assuming an absolute risk of new-onset diabetes mellitus on older drugs of approximately 10% over 5 years and a relative benefit on the newer drugs of approximately 30%, about 100 patients would have to be treated for 5 years with the newer agents to avert approximately three iatrogenic cases of diabetes. Whether or not new-onset diabetes is associated with increased risk is uncertain. In most patients, optimization of treatment at acceptable tolerance requires rotation through and combination of several drug classes. Combination of different classes of antihypertensive drugs not only enhances the blood pressure-lowering efficacy, but likely decreases the risk of metabolic adverse effects as well. True benefit beyond blood pressure lowering in hypertensive patients comes from multiple risk factor intervention.

Progress in cardiovascular diseases: cognitive function in essential hypertension.

Essential hypertension has rather recently become recognized as a major factor in the development of the 2 main types of dementia, that is, no longer merely vascular dementia but Alzheimer disease as well. The relationship between high blood pressure (BP) and the dementias is quite a complicated one, given a wide variability in temporal courses. The interval between the respective manifestations of hypertension and cognitive deterioration may vary from a few years to several decades. Moreover, temporal relationships may be obscured because of the observation that BP tends to fall in the face of imminent Alzheimer disease. Although the cause-and-effect sequence of this relationship has not been established, it may suggest that a low BP in this phase of life could be equally harmful as hypertension in the preceding period. Individual monitoring of BP and drug titration in the hypertensive elderly may well become mandatory in the highest age group. The question whether some antihypertensive drug categories might act more effectively in preventing cognitive deterioration than others, irrespective of their antihypertensive potential, remains. A modest meta-analysis on our part seems to suggest that suppression of the renin-angiotensin-aldosterone system (RAAS) would fail to offer such protection, in contrast to certain dihydropyridine (DHP) calcium-channel blockers. Unfortunately, recently published comparative prospective megatrials (Anti-hypertensive and Lipid-lowering Treatment to Prevent Heart Attack Trial and Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm) failed to carry any record on the mental status of the study populations, thereby missing a golden opportunity to resolve the above issue. Consequently, there remains an urgent need for further blinded long-term comparative hypertension trials, including follow-up evaluation of cognitive functions in relation to the course of BP.

Prognostic significance of electrocardiographic voltages and their serial changes in elderly with systolic hypertension.

The aim of the present study was to assess the prognostic value of ECG voltages at baseline and their serial changes during follow-up in a large prospective study with standardized follow-up and strictly defined end points. Patients who were 60 years old or older, with systolic blood pressure of 160 to 219 mm Hg and diastolic pressure <95 mm Hg, were randomized into the double-blind placebo-controlled Systolic Hypertension in Europe trial. Active treatment consisted of nitrendipine, which could be combined with or replaced by enalapril, hydrochlorothiazide, or both. At the end of the double-blind part of the trial (median follow-up, 2.0 years), follow-up was extended and all patients received active study drugs (median total follow-up, 6.1 years). Electrocardiography was performed at baseline and yearly thereafter. Electrocardiographic left ventricular mass was prospectively defined as the sum of 3 voltages (RaVL+SV1+RV5), which averaged 3.1+/-1.0 mV. The adjusted relative hazard rate, associated with a 1 mV higher sum at baseline, amounted to 1.10 and 1.15 for all-cause and cardiovascular mortality and to 1.21 and 1.18 for strokes and cardiac events, respectively (P< or =0.01 for all). A 1-mV decrease in electrocardiographic voltages during follow-up independently predicted a lower incidence of cardiac events (relative hazard rate: 0.86; P< or =0.05), but not of stroke or mortality. In conclusion, electrocardiographic voltages at baseline and their serial changes during follow-up predict subsequent events in older patients with systolic hypertension.

Dementia and antihypertensive treatment.

PURPOSE OF REVIEW: We present an updated overview on the long-term effects of hypertension on the occurrence of cognitive dysfunction and overt degenerative or vascular dementia later in life. The preventative effects of antihypertensive treatment in this regard are examined, with a focus on placebo-controlled, double-blind, randomized prospective trials. RECENT FINDINGS: The stereotypical straightforward linear relationship between mid-life hypertension and dementia later in life can no longer be considered strictly invariable. Successfully treated hypertensive patients who are still at risk for clinical dementia late in life may ultimately fare better in the presence of a slightly elevated rather than low systolic blood pressure. The mechanisms underlying this 'J-curve' phenomenon are currently being explored. Recently completed prospective randomized antihypertensive trials (Syst-Eur 2, PROGRESS and SCOPE) have yielded variable results, and merit cautious interpretation. SUMMARY: The incidence and prevalence of dementia are increasing exponentially worldwide, particularly in those older than 70 years. Because hypertension predisposes to dementia, therapeutic blood pressure titration should be maintained over the years, and intensified beyond 70 years in order to avoid over-treatment in the latter period.

Effects of immediate versus delayed antihypertensive therapy on outcome in the Systolic Hypertension in Europe Trial.

BACKGROUND: To assess the impact of immediate versus delayed antihypertensive treatment on the outcome of older patients with isolated systolic hypertension, we extended the double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial by an open-label follow-up study lasting 4 years. METHODS: The Syst-Eur trial included 4695 randomized patients with minimum age of 60 years and an untreated blood pressure of 160-219 mmHg systolic and below 95 mmHg diastolic. The double-blind trial ended after a median follow-up of 2.0 years (range 1-97 months). Of 4409 patients still alive, 3517 received open-label treatment consisting of nitrendipine (10-40 mg daily) with the possible addition of enalapril (5-20 mg daily), hydrochlorothiazide (12.5-25 mg daily), or both add-on drugs. Non-participants (n = 892) were also followed up. RESULTS: Median follow-up increased to 6.1 years. Systolic pressure decreased to below 150 mmHg (target level) in 2628 participants (75.0%). During the 4-year open-label follow-up, stroke and cardiovascular complications occurred at similar frequencies in patients formerly randomized to placebo and those continuing active treatment. These rates were similar to those previously observed in the active-treatment group during the double-blind trial. Considering the total follow-up of 4695 randomized patients, immediate compared with delayed antihypertensive treatment reduced the occurrence of stroke and cardiovascular complications by 28% (P = 0.01) and 15% (P = 0.03), respectively, with a similar tendency for total mortality (13%, P = 0.09). In 492 diabetic patients, the corresponding estimates of long-term benefit (P < 0.02) were 60, 51 and 38%, respectively. CONCLUSIONS: Antihypertensive treatment can achieve blood pressure control in most older patients with isolated systolic hypertension. Immediate compared with delayed treatment prevented 17 strokes or 25 major cardiovascular events per 1000 patients followed up for 6 years. These findings underscore the necessity of early treatment of isolated systolic hypertension.