COMMENTARY

New Antihypertensive Therapies, and Old Hypertensive Risks?

Linda Brookes, MSc

April 17, 2008

Progress With Angiotensin-Targeting Vaccines as Treatment for Hypertension

Abstract

The challenge for antihypertensive therapy is getting patients to adhere to it -- so a new vaccine in late phase 2 studies is a real promise for a better future, as is the possibility of a dual-acting angiotensin-plus endothelin-receptor antagonist, also in phase 2 studies. Then back to risks, new studies find that alcohol may be more of a risk than realized, that smoking plus high blood pressure greatly increases the risk of those rare hemorrhagic strokes, and finally that reducing blood pressure to target has a mortality benefit after a patient experiences a stroke.

Probably the greatest challenge for physicians treating high blood pressure is that for their patients, the condition is largely asymptomatic and therefore adherence to therapy is problematic. As a result, a major goal of researchers for a number of years has been to develop therapeutic vaccines that would induce relatively long-lasting reductions in blood pressure without requiring daily dosing, thus avoiding the challenge of poor adherence to antihypertensive medication regimens. The candidate vaccine that has been furthest along in development is CYT006-AngQb, a conjugate vaccine composed of modified angiotensin II covalently linked to recombinant virus-like particles derived from the RNA bacteriophage Q-beta. It is being developed by Cytos Biotechnology AG (Schlieren [Zurich], Switzerland).

In phase 1 studies, CYT006-AngQb was shown to be safe and well tolerated, and all participants receiving the vaccine mounted an angiotensin II-specific antibody response.[1] Now the phase 2a results, which were first presented at the 2007 meeting of the American Heart Association[2] and published in The Lancet,[3] have shown that immunization with the vaccine was not associated with any serious adverse events and that at the higher dose the vaccine raised antibody levels sufficiently high to significantly lower blood pressure. The trial is the first to show that vaccination against a vasoactive endogenous substance can reduce blood pressure in human beings.

The multicenter, double-blind, randomized, placebo-controlled phase 2a trial, which was carried out by researchers in Switzerland and Germany, involved 72 patients with mild-to-moderate hypertension (grade 1-2, systolic blood pressure [SBP] 140-179 mm Hg, diastolic blood pressure [DBP] 90-109 mm Hg, or both, according to World Health Organization criteria).[4] The first 36 patients were randomly assigned to receive subcutaneous injections of CYT006-AngQb 100 mcg or placebo, and the next group of 66 patients to CYT006-AngQb 300 mcg or placebo. Injections were administered at weeks 0, 4, and 12. Patients stopped taking any antihypertensive medication ≥ 2 weeks before injection of the study drug; 24-hour ambulatory blood pressure was measured before treatment and at week 14. The vaccine was apparently well tolerated, with 5 patients leaving the study, 2 in the CYT006-AngQb 100-mcg group and 3 in the 300-mcg group.

All patients were included in safety analyses. Five serious adverse events were reported (2 in the 100-mcg group, 2 in the 300-mcg group, and 1 in the placebo group); none were deemed to be treatment-related. Most side effects were transient and consisted of mild local reactions at the injection site, with a higher rate of local reactions in the active treatment group compared with the placebo group. Mild, transient influenza-like symptoms were seen in 3 patients in the CYT006-AngQb 100-mcg group, 7 in the 300-mcg group, and 0 in the placebo group.

All 48 patients who received CYT006-AngQb responded with high immunoglobulin G (IgG) titers against angiotensin II after only one injection. The antibody response was strongly boosted after the second injection, but was reversible with an average half-life of 3.2 weeks. All patients except the 5 who withdrew received a third injection, after which the antibody titers were boosted again, and reached peak levels 2 weeks after the third injection but without surpassing the level reached after the second injection. The average half-life after the third injection was 17 weeks.

Analyses excluding the study dropouts showed that in the CYT006-AngQb 300 mcg group mean ambulatory daytime blood pressure fell from baseline to week 14 by 9.0/4.0 mm Hg compared with placebo (P = .015 for SBP and P = .064 for DBP). The 300 mcg dose reduced the early morning blood-pressure surge compared with placebo (reductions at 0800 h 25/13 mm Hg; P < .0001 for ABP, P = .0035 for DBP). Changes in the 100 mcg group were not significant. The blood pressure reducing effect of CYT006-AngQb is comparable with that produced by low doses of the renin inhibitor aliskiren, the investigators note, although they stress that later-stage clinical trials will be needed to show efficacy and safety in a broader hypertensive population.

Commenting on the study in the same issue of The Lancet,[5] Ola Samuelsson, MD, and Hans Herlitz, MD (Sahlgrenska University Hospital, Göteborg, Sweden), say that "the results of this new biotherapy for hypertension are intriguing and promising, and vaccination for hypertension may turn out to be very useful in many patients." They agree that larger studies are needed to show the efficacy and safety of antibodies against angiotensin II. Drs Samuelsson and Herlitz point out that the half-life of the antibody after the second booster dose of the vaccine was, at 17 weeks, much longer than any RAAS inhibiting drug, which raises the question of whether it will be safe to inhibit the actions of circulating angiotensin II for several months without the ability to quickly reverse inhibition, which can easily be done for drugs by withdrawal of treatment. Another important safety issue, they add, is whether repeated stimulation of the immune system by booster doses of an endogenous peptide linked to a virus-like particle can cause autoimmune disease. The trial was probably too small to detect an autoimmune response, they believe, but larger trials of longer duration could also show whether the vaccine has any organ-protective effect.

Cytos has said that based on the data obtained to date, which the company regards as very promising, two phase 2 clinical studies are planned to begin in the first half of 2008. These trials will investigate optimized treatment regimens and formulations of CYT006-AngQb to explore the full potential of the vaccine.[6]

A similar antihypertensive vaccine under development by Protherics (London, UK, and Brentwood, Tennessee) is scheduled to be the focus of a phase 2a proof of concept study starting in the first half of 2008.[7] Angiotensin Therapeutic Vaccine (ATV) is a conjugate of a 12-amino acid analogue of angiotensin I (PMD3117) crosslinked to keyhole limpet hemocyanin (KLH). An earlier version of the vaccine was evaluated in phase 1 and was well tolerated and generated a prolonged antibody response, but did not affect blood pressure.[8] Protherics now have a new formulation of ATV containing a novel adjuvant, CoVaccine HT, an oil-in-water emulsion that acts by stimulating the B-cell immune response against the antigen component of the vaccine it is combined with. This results in an increase in the amount of circulating IgG synthesized against the antigen. The double-blind, placebo-controlled phase 2a study with ATV will enroll approximately 120 patients with mild-to-moderate hypertension. Patients will be given 3 intramuscular injections 21 days apart and both antibody response and effects on blood pressure will be assessed. The goal of this study will be to confirm that the new formulation increases levels of anti-angiotensin antibodies in hypertensive patients and to establish whether this results in a reduction in blood pressure. The results are expected during the first half of 2009. If they are positive, Protherics plans to outlicense further development and commercialization of the vaccine.

Research into antihypertensive vaccines is also continuing in China, at Huazhong University of Science and Technology in Wuhan. Preclinical studies with a vaccine that uses a peptide from the extracellular portion of rat angiotensin II type 1A (AT1A) receptor have been reported.[9,10] The vaccine, ATR12181, was shown to be effective in reducing blood pressure and ameliorating remodeling of target organs in spontaneously hypertensive rats.

Dual-Acting Angiotensin and Endothelin Receptor Antagonist (Dara) Compound in Second Phase 2 Study

The first and only dual-acting angiotensin II and endothelin (ET1) receptor antagonist (DARA), PS433540, the lead internal product of Pharmacopeia (Princeton, New Jersey) being developed as a potential treatment for hypertension and diabetic nephropathy, is now being investigated in a phase 2b clinical study,[11] following a phase 2a trial, results of which are expected in the second quarter of 2008.

The new randomized, double-blind, placebo and active-controlled, parallel-group phase 2b study is designed to evaluate the compound's safety and efficacy at 3 different doses in subjects with stage 1 and stage 2 hypertension. After a lead-in period, the multicenter trial is expected to randomize approximately 375 subjects aged 18-70 years with SBP ≥ 140 and < 180 mm Hg and mean seated DBP > 90 mm Hg and < 109 mm Hg. Subjects will be randomized into 5 study arms receiving PS433540 at 200, 400, or 800 mg, the angiotensin receptor blocker (ARB) irbesartan at a dose of 300 mg, or placebo. All doses will be administered once daily for 12 weeks.

The primary objective of the trial is to compare the change from baseline in mean seated SBP for each dose of PS433540 vs change with placebo. Additional study objectives include comparisons of changes in blood pressure for each dose of PS433540 vs changes with irbesartan. The principal study investigator is George L Bakris, MD (University of Chicago School of Medicine, Illinois).

The phase 2a randomized, double-blind, placebo-controlled, parallel-group study evaluated the compound's safety and efficacy in 170 subjects with stage 1 and stage 2 hypertension. Patients were randomized into 3 study arms (placebo and 2 active arms of 200 mg and 500 mg) receiving PS433540 or placebo once daily for 28 days. The primary study outcome was the change from baseline in mean 24-hour ambulatory SBP. The study is expected to be completed in May.

In phase 1, PS433540 was shown to be safe and well tolerated at a range of doses in healthy subjects. Results from a single ascending dose study indicated that the compound was well tolerated at all 6 doses administered, ranging from 20 to 1000 mg, and that the compound has a half-life that is consistent with once-daily administration. In the multiple ascending dose (MAD) study, 5 dose levels from 50 to 1000 mg did not produce any safety or tolerability issues, the company reported. In an angiotensin challenge study, 250 and 500 mg of PS433540 fully blocked the increase in blood pressure induced by administration of angiotensin II to healthy volunteers at least as well as 300 mg of irbesartan, the maximum approved dose of the ARB. Similar studies with other agents that block the renin-angiotensin system support that this result is a strong indication that PS433540 can be expected to lower blood pressure in hypertensive patients, Pharmacopeia says. Additional data from the MAD study demonstrated that PS433540 produced statistically significant, dose-dependent increases versus placebo in plasma-renin activity, as well as reductions in SBP and DBP in non-hypertensive healthy volunteers.

Pharmacopeia believes that there are sufficient preclinical and initial clinical data on angiotensin and ET1 receptor antagonists to suggest that compared with either agent alone, simultaneously blocking the actions of both angiotensin II and ET1 may provide significantly improved treatment options for several cardiovascular diseases. Pharmacopeia licensed worldwide development and commercialization rights to PS433540 from Bristol-Myers Squibb in 2006.

Effect of Alcohol Intake on Blood Pressure May Be Greater Than Previously Thought

Although people who consume a moderate amount of alcohol regularly have been reported to have lower blood pressure than nondrinkers, heavy alcohol intake has been associated with an increase in blood pressure. However, this is based mainly on evidence from observational epidemiologic studies that could not adequately control for the other effects present, such as diet, smoking, exercise, and socioeconomic status. Clinical trials in which participants were asked to drink different amounts of alcohol would obviously be difficult to implement, at least for ethical reasons and in terms of compliance. In an attempt to overcome these difficulties, a UK study has taken a different approach to evaluating the effects of alcohol on blood pressure, using a gene marker as an indication of differing alcohol intake levels. The results of this study have led University of Bristol researchers, led by Sarah J. Lewis, PhD, to conclude that alcohol intake may increase blood pressure to a much greater extent, even among moderate drinkers, than previously believed. The report of their study appears in the March issue of PLoS Medicine.[12]

The technique used by Dr. Lewis' group to evaluate the effect of alcohol consumption on blood pressure was Mendelian randomization,[13] a method that allows testing for a causal effect from observational data in the presence of confounding factors by using common genetic polymorphisms with well-understood effects on exposure patterns. In this case, a common polymorphism in aldehyde dehydrogenase 2 (ALDH2) was used as a surrogate for measuring alcohol consumption. ALDH2 encodes the major enzyme responsible for eliminating the intermediate compound, acetaldehyde, formed when alcohol is initially metabolized. A single point mutation in ALDH2 results in the ALDH*2 allele, leading to an inability to metabolize acetaldehyde and accumulation of acetaldehyde in the body after alcohol consumption. This allele is common in some Asian populations and people with this mutation suffer facial flushing after consumption of alcohol coupled with intense nausea, drowsiness, headache, and other unpleasant symptoms. People with this mutation therefore tend to drink much less than those without it.

Dr. Lewis and her colleagues hypothesized that by affecting alcohol consumption behavior this polymorphism may influence the risk of hypertension. They compared blood pressure in people who were homozygous for the ALDH2*2 allele (*2*2), as having very low levels of alcohol consumption, with people who were homozygous for the wild-type allele (*1*1), with relatively high alcohol consumption, and heterozygotes (*1*2), who tend to have moderate alcohol intake. They did this using data from 10 studies that reported an association between the ALDH2 genotype and blood pressure or hypertension. All the studies were population-based and most of the participants were Japanese. The 2 largest studies showed alcohol intake to be about 20-30 g/day in *1*1 homozygotes compared with 10-15 g/day in heterozygotes and 0-2 g/day in *2*2 homozygotes. (For comparison across all studies alcohol consumption was converted to a uniform measure of grams per day based on 1 unit = 10 mL = 7.9 g.)

The risk of hypertension among *1*1 homozygotes was found to be about around 2.5-fold higher than that among *2*2 homozygotes. Meta-analysis of 3 studies of hypertension, carried out in a total of 4219 subjects, showed an overall odds ratio of 2.42 (95% confidence interval [CI] 1.66-3.55, P = 4.8 × 10-6) for hypertension comparing *1*1 with *2*2 homozygotes. Even heterozygotes, as modest drinkers, showed about a 70% increase in hypertension risk, with an odds ratio of 1.72 (95% CI 1.17-2.52, P = .006) compared with *2*2 homozygotes.

Meta-analysis of 5 studies of blood pressure in a total of 7658 subjects showed that SBP was 7.44 mm Hg (95% CI 5.39-9.49, P < 1.1310-12) higher among *1*1 homozygotes and 4.24 mm Hg (95% CI 2.18-6.31, P = .00005) higher among heterozygotes than among *2*2 homozygotes. The group calculated that overall the effect of alcohol intake on SBP was calculated as 0.24 mm Hg/day and 0.16 mm Hg/day on DBP over the course of a lifetime.

In their report, Dr. Lewis and colleagues concede that a small proportion of the genotype differences in blood pressure that they found may have occurred through genotype differences in body mass index (BMI), but they believe that "the majority of the effect is likely to be due to independent effects of alcohol on blood pressure." They also noted that evidence that the effects of the ALDH2 genotype on blood pressure appeared to be due to differences in alcohol consumption levels rather than pleiotropic effects of ALDH2 or linkage disequilibrium was provided by the data on women, who tended not to drink and who showed no differences in blood pressure by genotype. "If either pleiotropic effects or confounding by linkage disequilibrium were operating, an effect on blood pressure would be seen in both sexes," the researchers point out. This was supported by previous studies that examined the effect of ALDH2 after adjustment for the amount of alcohol consumed and found no difference in blood pressure by genotype. Dr. Lewis and co-authors stress that "large-scale replication studies are required to confirm this finding and to improve the precision of our estimates."

Current UK and US hypertension guidelines caution that excess consumption of alcohol is associated with raised blood pressure as well as adverse effects on cardiovascular and hepatic health and advise that intake should be limited to the equivalent of approximately 2 drinks daily in most men, less in women and lighter weight persons.[14,15]

Synergistic Effect of Smoking and High Blood Pressure on Risk of Hemorrhagic Stroke

Smoking may exacerbate the increased risk of hemorrhagic stroke already faced by people with hypertension, particularly in men and in the elderly, according to a new study reported in Stroke.[16] The study authors, led by Koshi Nakamura, MD, PhD (The George Institute of International Health, Sydney, Australia), say that quitting smoking and lowering blood pressure are both known to be crucial for prevention of cardiovascular disease, but that combining the 2 could be expected to have extra beneficial effect on preventing hemorrhagic stroke. The study was based on data from the Asia Pacific Cohort Studies Collaboration (APCSC), an ongoing collaborative project that seeks to pool data from existing longitudinal studies with information on cardiovascular disease in the Asia Pacific region.[17,18]

This analysis comprises a large number of prospective cohort studies in the region and was established primarily to provide reliable evidence about the effects of a variety of modifiable risk factors, including blood pressure, lipids, BMI, and diabetes, on the risks of cardiovascular diseases and other common causes of death among populations in this region. Prospective cohort studies are eligible for inclusion in the APCSC if they include study populations from the Asia-Pacific region, recorded age, gender, and blood pressure at baseline, and vital status at the end of follow-up, and continued for ≥ 5000 person-years of follow-up. Additional data sought to include date of the baseline survey, total blood cholesterol, diabetes, height, weight, smoking habit, and any data on repeated measures of risk factors. Studies are not eligible if entry is dependent on patients having a particular medical condition or risk factor. Participants are classified as Asian if they were recruited from China, Hong Kong, Japan, Singapore, South Korea, Taiwan, or Thailand, and ANZ if they were from Australia or New Zealand.

The latest project, which was funded in part by Pfizer and the National Health and Medical Research Council of Australia, analyzed data from 41 APCSC studies (93% of the total to date), 32 of which were from Asia. For this analysis only data from people aged ≥ 20 years with information on both blood pressure and smoking status (total 563,144) were used. At the start of the study over one third (37%) of the participants were smokers and 13% were former smokers. During a median of 6.8 years follow-up, 4344 coronary heart disease (CHD) and 5906 stroke events were recorded. Dr. Nakamura and his colleagues identified a log-linear relationship between SBP and all subtypes of cardiovascular disease. The increases in risk of CHD and ischemic stroke related to a 10 mm Hg increase in SBP to both CHD and ischemic stroke were similar in smokers and nonsmokers and for all gender, age, and region subgroups, with no evidence of a threshold effect down to SBP 115 mm Hg.

Hemorrhagic stroke occurred in 746 of the 210,961 smokers and 899 of the 352,183 nonsmokers. Every 10 mm Hg increase in SBP in smokers was associated with an additional 15 percentage points increase in risk of hemorrhagic stroke compared with nonsmokers (hazard ratio [HR] 1.81 [95% CI, 1.73-1.90 vs HR 1.66 [95% CI, 1.59-1.73]), respectively; P =.003). Compared with smokers with the lowest SBP readings (≤ 120 mm Hg), smokers with the highest readings (≥ 150 mm Hg) were 9.32 times more likely to suffer a hemorrhagic stroke. For nonsmokers, being in the highest vs the lowest SBP group increased the risk of hemorrhagic stroke by 7.05 times.

Subgroup analyses showed that the synergistic effect of SBP and hemorrhagic stroke was present in most subgroups, but that it was only significant in men, in Asian study centers, and in individuals aged 65 years of age and older. The researchers believe that the gender-specific effect may have been a chance finding, since few events were reported among the smaller population of female smokers compared with male smokers. They also suggest that the regional specificity may have resulted from the difficulty in observing hemorrhagic stroke events due to a much smaller number of participants and a lower event rate of hemorrhagic stroke in ANZ participants compared with Asian participants. However, neither of these explanations can explain the age-specific significant effect, they note. Similar results were seen for every subtype of cardiovascular event when the analyses were restricting to fatal events only.

Dr. Nakamura and his colleagues point out that unlike CHD and ischemic stroke, the prevailing cause of hemorrhagic stroke is rupture resulting from fragility (including microaneurysms) of the intracerebral penetrating arteries caused by nonoptimal levels of blood pressure or amyloid angiopathy. They speculate that smoking may exacerbate the weakening of the intracranial blood vessels caused by high levels of blood pressure. However, the underlying pathophysiologic mechanism behind this interaction is unclear, and it is possible that the same synergistic effect may exist in younger people and women, the researchers admit. They acknowledge that further studies with a larger and more standardized data set are needed to determine whether there really is an interaction between blood pressure and smoking for each subtype of cardiovascular disease, the mechanism to explain the interaction, and how specific it is to demographic groups.

Treating for Hypertension May Reduce Mortality After Stroke

The results of 2 studies presented at the recent American Stroke Association's International Stroke Conference 2008, held February 20-22 in New Orleans, Louisiana, showed the benefits of aggressive antihypertensive treatment in patients with either acute ischemic or hemorrhagic stroke. High and low blood pressure levels are common following acute stroke, with up to 60% of patients being hypertensive (SBP > 160 mm Hg) and nearly 20% having relative hypotension (SBP ≤ 140 mm Hg) within the first few hours. Both conditions are associated with an adverse prognosis.

At present, the optimum management of blood pressure in the immediate post-stroke period remains unclear. Current American Heart Association/American Stroke Association guidelines[19] advise treatment in patients eligible for intravenous recombinant tissue plasminogen activator (tPA) or other acute reperfusion intervention and SBP > 185 mm Hg or DBP > 110 mm Hg or SBP > 120 mm Hg or DBP > 120 mm Hg. Recommended treatment is labetalol IV, nicardipine IV, or transdermal nitroglycerin ointment (Nitropaste), aimed at lowering blood pressure by ≥ 15% within the first day. Outside these criteria, no antihypertensive treatment is recommended. Hypertension guidelines, such as those issued by the International Society of Hypertension (ISH),[4] do not specify any treatment for the management of blood pressure in acute stroke. A number of studies previously investigated the value of reducing blood pressure in acute stroke, but showed no benefit of treatment. Only the Acute Candesartan Cilexetil Therapy in Stroke Survivors (ACCESS) study showed benefit, in this case for candesartan administered within 36 hours of stroke onset in patients with blood pressure ≥ 200/110 mm Hg.[20] However, the observed reduction in events was not associated with a reduction in blood pressure.

The United Kingdom's Control of Hypertension and Hypotension Immediately Post-Stroke (CHHIPS) pilot trial, which was funded by the National Health Service Research and Development Health Technology Assessment Program, showed that stroke patients who were treated for hypertension had lower mortality after 3 months than patients who received a placebo.[21] The trial randomized 179 patients not recently on antihypertensive treatment with a clinically suspected stroke with symptoms lasting > 60 minutes, who had had an ischemic or hemorrhagic stroke within the previous 36 hours and, and who had SBP > 160 mm Hg to treatment with lisinopril, labetalol, or a placebo.[22] Nondysphagic hypertensive patients received oral lisinopril 5, 10, or 15 mg/day, or labetalol 50, 100, or 150 mg twice daily, or placebo, for up to 14 days. Dysphagic hypertensive patients received sublingual lisinopril, 5, 10, or 15 mg/day, intravenous labetalol 50, 100, or 150 mg twice daily, or placebo, for up to 72-96 hours. The patients were similar across the 3 treatment groups with respect to age, baseline blood pressure, stroke type, time to treatment, NIHSS (National Institutes of Health Stroke Scale) score, and prevalence of dysphagia.

Lead investigator John F. Potter, DM (University of East Anglia, Norwich) reported that patients who received active treatment had greater declines in SBP during the first 24 hours compared with patients who received placebo. After 2 weeks, blood pressure declines were significantly greater in patients on active treatment than in the placebo group (decrease of 31 mm Hg vs 24 mm Hg, respectively). At 4 hours, 77% of patients on labetalol and 61% of patients on lisinopril had reached target blood pressure (SBP 145-155 mm Hg or a 15% fall in SBP). At 8 hours, 88% of the lisinopril group and 66% of the labetalol group had reached target. The fall in blood pressure was not associated with deterioration in neurologic status.

At 2 weeks, there was no difference between the active treatment group and the placebo group in terms of death and dependency, the primary outcome measure of the trial. However at 90 days after treatment began, the active treatment group had a lower mortality compared to the placebo group, with patients in the placebo group 2.2 times more likely to die.

Prof. Potter said that the preliminary results of the pilot trial are encouraging for a final phase 3 study using the same agents. Meantime, Prof. Potter and colleagues are continuing with a multicenter, prospective, randomized, open, blinded-endpoint study that is assessing whether patients already on antihypertensive therapy should have their therapy continued or discontinued within 48 hours of stroke onset and for the subsequent 2 weeks. This trial is the Continue Or Stop post-Stroke Antihypertensives Collaborative Study (COSSACS).[23]

A second trial reported in the same session at the conference has shown that early intensive treatment for hypertension in patients with acute intracerebral hemorrhage (ICH) is well tolerated and appears to slow the growth of hematomas. Elevated blood pressure is common after acute ICH and is associated with a range of poor outcomes, but the effects of early lowering of blood pressure are uncertain. The results of the vanguard phase of the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT)[24] were presented by Craig Anderson, MD, PhD (The George Institute for International Health, and The Royal Prince Alfred Hospital and University of Sydney, Australia). This pilot trial, funded by the National Health and Medical Research Council of Australia, enrolled 404 patients from 44 hospitals in Australia, China, and Korea between November 2005 and April 2007. Each patient was 18 years of age or older, had an acute ICH confirmed by a computerized tomography (CT) scan, and had elevated SBP (≥ 150 and ≤ 220 mm Hg). Each patient was able to begin blood pressure-lowering treatment in a monitored environment within 6 hours of ICH. A central randomization system was used to assign patients to either a treatment strategy of intensive blood pressure lowering (target SBP 140 mm Hg within 1 hour and for ≥ 24 hours) based on a stepped protocol of routinely available intravenous agents, or American Heart Association (AHA) guideline-based blood pressure lowering (target SBP 180 mm Hg).[25] Digital images of baseline and repeat CT (24 + 72 hours) were performed using standardized techniques were analyzed centrally.

The baseline characteristics of the randomized groups were similar. SBP was an average of 14 mm Hg lower (P < .0001) in the intensive group in the first hour and 10.8 mm Hg lower over the ensuing 24 hour. Mean proportional hematoma growth was 22.6% (95% CI -0.6 to -44.5; P = .06) lower in the intensive group compared to the guideline group (13.7% vs 36.3%, respectively), after adjustment for initial hematoma volume and time from ICH to CT. The difference in mean absolute increase between the 2 groups was not significant. The difference in "substantial" hematoma growth (> 33% or 12.5 mL) was 8% (95% CI -1 to 17, P = .05) lower in the intensively managed group (15% vs 23%, respectively), equating to a relative risk reduction of 36%. There was no evidence that early intensive blood pressure lowering increased the risks of serious adverse events or a poor outcome at 90 days. There was no statistically significant fall in clinical outcomes, although 90-day mortality was reduced from 12% in the guideline group to 10% in the intensive group and dependency from 41% to 36%, respectively. However, Prof. Anderson noted that the trial was not powered to look at clinical endpoints. He announced that a much larger trial, INTERACT 2, will begin later this year. INTERACT 2 will recruit a total of 2500 patients in Australia, New Zealand, China, the United States, and Korea.

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