Intensive Blood Pressure Reduction Research Articles

The International Stroke Conference 2008 New Orleans, Louisiana February 20-22, 2008

The International Stroke Conference 2008 New Orleans, Louisiana February 20-22, 2008

Management of cardiovascular risk with RAS inhibitor/CCB combination therapy

Hypertension is a significant risk factor for cardiovascular disease (CVD), including stroke, myocardial infarction, kidney disease and heart failure. Considerable research has been undertaken to delineate the differential effects of various classes of antihypertensive agents in delaying or preventing cardiovascular morbidity and mortality. Although possible benefits may result from specific agents or classes of agents in certain high-risk subgroups, prompt and intensive blood pressure (BP) reduction to target levels remains the most crucial factor in this benefit. Despite this, the BP remains above the target level in a large majority of patients, reinforcing the need for improved treatment paradigms. Among antihypertensive agents, inhibitors of the renin-angiotensin system--angiotensin-II receptor blockers and angiotensin-converting enzyme inhibitors--and long-acting dihydropyridine calcium channel blockers (DHP-CCBs) have been shown to provide safe, effective and well-tolerated BP control. These agents have also been proven as effective as, and in some cases superior to, other classes of agents in reducing cardiovascular morbidity and mortality. As the majority of high-risk patients require at least two and possibly even three medications to achieve the target BP, combination therapy with these two classes of drugs is a rational approach to therapy. Whether fixed-dose combination therapy with a renin-angiotensin system inhibitor plus a DHP-CCB affords greater clinical benefit compared with other combination regimens remains to be determined in large, prospective clinical trials. Meanwhile, such a combination offers effective, convenient, well-tolerated control of the most important modifiable risk factor for CVD.

Intensive blood pressure reduction may reduce hematoma growth after ICH

Intensive blood pressure reduction may reduce hematoma growth after ICH

Should We Be Treating Blood Pressure More Aggressively and Earlier After Acute Stroke?

Should We Be Treating Blood Pressure More Aggressively and Earlier After Acute Stroke?

Intensive blood pressure reduction in acute cerebral haemorrhage trial (INTERACT): a randomised pilot trial

There is much uncertainty about the effects of early lowering of elevated blood pressure (BP) after acute intracerebral haemorrhage (ICH). Our aim was to assess the safety and efficiency of this treatment, as a run-in phase to a larger trial. Patients who had acute spontaneous ICH diagnosed by CT within 6 h of onset, elevated systolic BP (150-220 mm Hg), and no definite indication or contraindication to treatment were randomly assigned to early intensive lowering of BP (target systolic BP 140 mm Hg; n=203) or standard guideline-based management of BP (target systolic BP 180 mm Hg; n=201). The primary efficacy endpoint was proportional change in haematoma volume at 24 h; secondary efficacy outcomes included other measurements of haematoma volume. Safety and clinical outcomes were assessed for up to 90 days. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00226096. Baseline characteristics of patients were similar between groups, but mean haematoma volumes were smaller in the guideline group (12.7 mL, SD 11.6) than in the intensive group (14.2 mL, SD 14.5). From randomisation to 1 h, mean systolic BP was 153 mm Hg in the intensive group and 167 mm Hg in the guideline group (difference 13.3 mm Hg, 95% CI 8.9-17.6 mm Hg; p<0.0001); from 1 h to 24 h, BP was 146 mm Hg in the intensive group and 157 mm Hg in the guideline group (10.8 mm Hg, 95% CI 7.7-13.9 mm Hg; p<0.0001). Mean proportional haematoma growth was 36.3% in the guideline group and 13.7% in the intensive group (difference 22.6%, 95% CI 0.6-44.5%; p=0.04) at 24 h. After adjustment for initial haematoma volume and time from onset to CT, median haematoma growth differed between the groups with p=0.06; the absolute difference in volume between groups was 1.7 mL (95% CI -0.5 to 3.9, p=0.13). Relative risk of haematoma growth >or=33% or >or=12.5 mL was 36% lower (95% CI 0-59%, p=0.05) in the intensive group than in the guideline group. The absolute risk reduction was 8% (95% CI -1.0 to 17%, p=0.05). Intensive BP-lowering treatment did not alter the risks of adverse events or secondary clinical outcomes at 90 days. Early intensive BP-lowering treatment is clinically feasible, well tolerated, and seems to reduce haematoma growth in ICH. A large randomised trial is needed to define the effects on clinical outcomes across a broad range of patients with ICH. National Health and Medical Research Council of Australia.

The Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial: Results of the Vanguard Phase

A number of observational studies have shown that the risk of a poor outcome after acute intracerebral hemorrhage, including early death, is greater among patients who present with higher blood pressure (BP). For every 1–2 mm Hg increase in systolic BP there is approximately a 1% increase in death and dependency. However, the effects associated with early lowering of BP are less clear. This article discusses results from the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial [INTERACT].

Advances in hemorrhagic stroke therapy: conventional and novel approaches

Treatments for spontaneous intracerebral, thrombolytic-induced and intraventricular hemorrhages (IVH) are still at the preclinical or early clinical investigational stages. There has been some renewed interest in the use of surgical evacuation surgery or thrombolytics to remove hematomas, but these techniques can be used only for specific types of brain bleeding. The STICH (Surgical Trial in Intracerebral Haemorrhage) clinical trials should provide some insight into the potential for such techniques to counteract hematoma-induced damage and subsequently, morbidity and mortality. More recently, clinical trials (ATACH [Antihypertensive Treatment in Acute Cerebral Hemorrhage] and INTERACT [Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial]) have begun testing whether or not regulating blood pressure affects the well-being of hemorrhage patients, but the findings thus far have not conclusively demonstrated a positive result. More promising trials, such as the early stage CHANT (Cerebral Hemorrhagic And NXY-059 Treatment) and the late stage FAST (Factor VIIa for Acute Hemorrhagic Stroke Treatment), have addressed whether or not manipulating oxidative stress and components of the blood coagulation cascade can achieve an improved prognosis following spontaneous hemorrhages. However, CHANT was halted prematurely because although it showed that the spin trap agent NXY-059 was safe, it also demonstrated that the drug was ineffective in treating acute ischemic stroke. In addition, the recombinant activated factor VII FAST trial recently concluded with only modestly positive results. Despite a beneficial effect on the primary end point of reducing hemorrhage volume, controlling the coagulation cascade with recombinant factor VIIa did not decrease the mortality rate. Consequently, Novo Nordisk has abandoned further development of the drug for the treatment of intracerebral hemorrhaging. Even though progress in hemorrhage therapy that successfully reduces the escalating morbidity and mortality rate associated with brain bleeding is slow, perseverance and applied translational drug development will eventually be productive. The urgent need for such therapy becomes more evident in light of concerns related to uncontrolled high blood pressure in the general population, increased use of blood thinners by the elderly (e.g., warfarin) and thrombolytics by acute ischemic stroke patients, respectively. The future of drug development for hemorrhage may require a multifaceted approach, such as combining drugs with diverse mechanisms of action. Because of the substantial benefit of factor VIIa in reducing hemorrhage volume, it should be considered as a prime drug candidate included in combination therapy as an off-label use if the FAST trial proves that the risk of thromboembolic events is not increased with drug administration. Other promising drugs that may be considered in combination include uncompetitive NMDA receptor antagonists (such as memantine), antioxidants, metalloprotease inhibitors, statins and erythropoietin analogs, all of which have been shown to reduce hemorrhage and behavioral deficits in one or more animal models.

1100 INTERACT (intensive blood pressure reduction in acute cerebral haemorrhage trial): rationale, design, and early results

1100 INTERACT (intensive blood pressure reduction in acute cerebral haemorrhage trial): rationale, design, and early results

Intensive blood pressure reduction is beneficial in patients with impaired cardiac function coexisting with chronic renal insufficiency.

Both in CHF (congestive heart failure) and CRI (chronic renal insufficiency), blood pressure reduction is beneficial for preservation of cardiac and renal function. However, it is uncertain how much blood pressure reduction is appropriate in patients with both CHF and coexisting CRI. In the present study, we examined whether intensive blood pressure reduction is more beneficial in these patients than the usually accepted level of reduction. Thirty-five men and 21 women of average age 63+/-5 years suffering from both CHF and CRI were selected from 316 patients attending the Kidney Disease Center of Saitama Medical School Hospital. All participants had an ejection fraction (EF) of less than 55% as determined by echocardiography. Renal function was evaluated by 24-h creatinine clearance (GFR), and a GFR of less than 50 ml/min was regarded as indicating renal insufficiency. Patients were divided into 2 groups according to the target blood pressure: in group I, blood pressure (BP) was lowered to less than 120/75 mmHg and in group II, blood pressure was lowered to less than 130/80 but more than 121/76 mmHg. The daily doses of basic antihypertensive agents were amlodipine 5 to 20 mg, benazepril 2.5 to 5 mg, guanabenz 2 to 8 mg and furosemide 20 to 60 mg. At the end of a 2-year follow-up period, the BP in group I was controlled at the level of 118+/-4/73+/-3 mmHg with good maintenance of EF (46+/-4 to 60+/-4%) and GFR (44+/-4 to 40+/-3 ml/min). In group II, BP was maintained at 128+/-4/81+/-2 mmHg, accompanied by a reduction of EF (46+/-4 to 42+/-3%) and a significant reduction of GFR (44+/-3 to 35+/-3 ml/min). These results suggest that intensive blood pressure reduction might be beneficial in cases complicated by cardiorenal failure.

Racial Differences in the Effectiveness of Nonpharmacologic Treatment of Hypertension

To the Editor: Hypertension is responsible for much morbidity and mortality,1 in particular cerebrovascular and cardiovascular disease. Intensive treatment of hypertension reduces the incidence of stroke and cardiovascular events and decreases cardiovascular mortality compared with less intensive blood pressure reduction.2 Antihypertensive drugs are efficacious in reducing blood pressure, but their use is associated with a variety of side effects,3 and adherence to medication is often poor. A nonpharmacologic approach is generally recommended in the initial treatment of mild hypertension or as an adjunct to pharmacologic therapy in patients with more severe or resistant hypertension. Several trials have shown favorable changes in blood pressure with diet modification, weight reduction, sodium restriction, and physical exercise.4,5 We wished to investigate possible racial differences in effectiveness …

UKPDS and the old

Diabetes is common in the old, defined here as aged 80 plus; in Melton Mowbray 11–14% of octogenarians had diabetes1. What are the implications of the landmark United Kingdom Prospective Diabetes Study (UKPDS) for them? UKPDS showed that intensive glycaemic control with sulphonylurea or insulin reduced microvascular endpoints; there was an approximately 25% risk reduction of microvascular endpoints at l0 years reducing the risk from 11.4 to 8.6%2. Approximately half of these patients were aged over 65 at l0 years study duration and there were very broad inclusion criteria. Unfortunately, 50% of elderly diabetic subjects are dead within five years of census, 3 and 40% of subjects newly diagnosed by glucose tolerance test are also dead within 5 years. Several studies have now shown that improved glycaemic control leads to improved cognitive function4-7 and improved glycaemic control leads to improved quality of life, 4, 8, 9 although there is one contradictory study10. Thus as a geriatrician I still aim for glycaemic control as good as I can reasonably and safely achieve, but my justification is cognitive function and quality of life. The UKPDS Hypertension in Diabetes embedded study11 is of major interest since intensive blood pressure reduction significantly reduced many adverse endpoints such as heart failure, stroke (fatal and non-fatal), microvascular disease and diabetes related death; the Kaplan-Meier plots appear to show that many of these differences are apparent at 4 to 5 years. These findings are particularly relevant to the old diabetic person not only because of the relatively short time to derive benefit, but also because these are the co-morbid conditions that affect the British diabetic retiree. Dornan's comparison of elderly/old subjects known and not known to have diabetes12 showed that the diabetic person was significantly more likely to have had a previous stroke, cognitive impairment, congestive cardiac failure, neuropathy and blind registration. Other studies have similarly shown that the elderly diabetic person is at increased risk of dementia, 13 which is presumably predominantly vascular in origin14. As the authors of UKPDS pointed out, one should also look at the Systolic Hypertension in the Elderly Program (SHEP) study:15 elderly subjects with systolic blood pressure greater than 160 mm Hg were randomised to active treatment with a thiazide diuretic, or to placebo; this study had 650 octogenarians (8% diabetic) and a 5 year follow up. There are subgroup analyses of diabetic subjects16 and old subjects, 7 but not old diabetic subjects. In SHEP, treatment of octogenarians reduced more strokes than treatment of younger subjects15.17 The absolute benefit of antihypertensive treatment was greater in the diabetic than in the non-diabetic group;16 in the diabetic group active treatment significantly reduced major cardiovascular events, and all coronary heart disease events. However, SHEP accepted only about 1% of subjects referred and excluded subjects receiving insulin, so one wonders how generalisable are the results. The Systolic Hypertension in Europe Trial (Syst-Eur)18 had 441 octogenarians (24% diabetic);18 treatment with a long acting calcium channel blocking agent aimed to reduce systolic BP to<150 mm Hg. The study was terminated after a median follow-up of 2 years because a significant result had been obtained. Subgroup analysis of diabetic subjects19 shows a greater absolute benefit from treatment than in the non-diabetic subjects; in the diabetic group active treatment significantly reduced cardiovascular death, all cardiovascular events and strokes. Subgroup analysis of old subjects17 reveals a non-significant decrease in strokes. Treatment also reduced the incidence of dementia20. Diabetic patients were included in Syst-Eur if their diabetes was controlled, i.e. insulin treatment was not an exclusion criterion. There are two worries regarding antihypertensive treatment in the old: although it decreases strokes, there is a non-significant increase in mortality;17 however, given the greater absolute benefit of treating diabetic subjects, this may be even less applicable to the diabetic octogenarian. Secondly, the subjects in these trials may be fitter than the patient in your clinic. Given the comorbidity of the old diabetic person, a study of diabetes in frail old folk is required, but unlikely to happen. However, HYVET is an ongoing placebo controlled trial of antihypertensive therapy in octogenarians; its inclusion criteria are broad and its pilot study recruited 1284 subjects so that one anticipates a large diabetic subgroup; other outcomes of interest such as falls, quality of life and confusion will be assessed. treat as per SHEP or Syst-Eur targets (e.g. systolic BP <150 mm Hg); conclude that there is limited data on treating run of the mill octogenarians, and await new data or enter the patient into HYVET. At present, I cautiously treat as per SHEP and Syst-Eur but I am very wary of inducing postural hypotension. Thus the importance of UKPDS is to direct our attention to the old diabetic subject's blood pressure, which will hopefully improve disability free survival.