Clinical Pharmacy News summary

First preventive treatment for patients with haemorrhagic stroke A regimen of perindopril, given alone or in combination with the diuretic indapamide, reduces the risk of recurrent stroke irrespective of whether blood pressure is raised or not, a new study shows...[more]

Galantamine effective in treating dementia in patients with cerebrovascular disease Galantamine (Reminyl), which is approved for the treatment of Alzheimer’s disease, improves memory, orientation and language skills of patients with cerebrovascular dementia, according to new preliminary findings...[more]

Positive results for oral cisplatin A novel, oral formulation of the anticancer drug cisplatin has an acceptable toxicity profile and is clinically bioavailable, according to the results of a phase I clinical trial...[more]

Angiotensin II inhibitors prevent diabetic nephropathy Results from three studies presented at the European Meeting on Hypertension, organised by the European Society for Hypertension, in Milan earlier this week show that angiotensin II receptor antagonists (AIIRAs) can prevent diabetic nephropathy...[more]

Lacidipine slows progression of atherosclerosis Lacidipine, a calcium channel blocker, can slow the progression of atherosclerosis more effectively than atenolol, according to the results of the European lacidipine study on atherosclerosis (ELSA)...[more]

Potential benefits of first human anti-TNF for rheumatoid arthritis Adalimumab, a tumour necrosis factor antibody being developed for the treatment of rheumatoid arthritis, reduces the signs and symptoms of the disease, say researchers...[more]

Rheumatologists urged to “think LOX not just COX” A compound ML3000, which inhibits both the 5-LOX (5-lipoxygenase) and COX (cyclo-oxygenase) pathways of the inflammatory process, is effective in improving pain scores in patients with osteoarthritis, participants at the European League Against Rheumatism meeting in Prague, Czech Republic, were told on June 15...[more]

Mixed results for abciximab in MI trials Combining the fibrinolytic drug reteplase (Rapilysin) with abciximab (ReoPro), a glycoprotein IIb/IIIa antagonist, reduces secondary complications of myocardial infarction but not mortality rates, according to trial results published this week...[more]

IBS drug fails to gain US approval The United States Food and Drug Administration has refused to grant marketing approval for tegaserod (Zelmac), Novartis’s new treatment for irritable bowel syndrome. This follows the company’s withdrawal of its marketing authorisation application in Europe last month...[more]

CHD management inadequate in primary care There is ample scope for improvement of coronary heart disease management in primary care, researchers say...[more]

First preventive treatment for patients with haemorrhagic stroke

A regimen of perindopril, given alone or in combination with the diuretic indapamide, reduces the risk of recurrent stroke irrespective of whether blood pressure is raised or not, a new study shows. This regimen is the first preventive treatment that can be used in patients with haemorrhagic stroke, where aspirin cannot be given, according to lead researcher Professor John Chalmers, University of Sydney, Australia. The results were presented at the 17th World Congress of Neurology in London this week.

In the PROGRESS study (perindopril protection against recurrent stroke study), the researchers randomly assigned 6,105 patients with a history of stroke (any type) or transient ischaemic attack within five years of the start of the study to receive either perindopril 4mg and, where indicated, indapamide 2.5mg, or placebo. The average duration to follow-up was four years, with a maximum of six years. The study included 715 patients in the United Kingdom and Republic of Ireland.

Presenting the results of the trial, Professor Stephen MacMahon, also from the University of Sydney, said that overall a 28 per cent reduction in the risk of further stroke was seen when perindopril was given alone or in combination with indapamide compared with placebo (95 per cent confidence interval, 38 per cent to 17 per cent). There was also a 26 per cent reduction in the risk of a combined secondary outcome of stroke, myocardial infarction or death from cardiovascular disease compared with placebo (34 per cent to 16 per cent). Patients given the perindopril-based regimen also had a 25 per cent reduction in the risk of developing a disability (39 per cent to 7 per cent) and a 38 per cent reduction in the risk of myocardial infarction (55 per cent to 14 per cent). The risk of dementia in those with stroke was reduced by approximately a third.

Professor Chalmers said that using a combination of perindopril and indapamide prevented one stroke, myocardial infarction or death among every 11 patients treated for five years, and when looking at stroke alone, it prevented one stroke among every 14 patients treated for five years. In a press release the researchers say that perindopril and indapamide can be used in patients who have previously suffered a cerebral haemorrhage and the combination was found to reduce the risk of a recurrent stroke among these patients by 48 per cent (67 per cent to 17 per cent). Professor Chalmers also commented that the results of the study had implications for stroke and hypertension guidelines and for regulatory authorities to extend treatment indications to include non-hypertensive patients as well as hypertensive patients.

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Galantamine effective in treating dementia in patients with cerebrovascular disease

Galantamine (Reminyl), which is approved for the treatment of Alzheimer’s disease, improves memory, orientation and language skills of patients with cerebrovascular dementia, according to new preliminary findings. It is also effective in patients with mixed dementia caused by both cerebrovascular disease and Alzheimer’s disease.

Dr Roger Bullock of the Kingshill Research Centre and colleagues enrolled 592 patients with cerebrovascular or mixed dementia, from 10 countries, in an initial six-month study of galantamine. They randomly assigned 396 patients to receive galantamine 24mg per day and 196 patients to receive placebo. After six months the study was extended and 295 of the patients who had received galatamine and 164 of those in the placebo group continued in the programme for a further six months. All these participants were given galantamine 24mg per day.

An improvement in cognitive abilities was seen in patients who received galantamine for 12 months. The cognitive ability of patients assigned placebo declined over the first six months and then subsequently improved after being switched to galantamine.

Deterioration in the ability to perform normal activities of daily living, such as bathing, dressing and doing house-work, in the placebo group was more than double that for the galantamine group. Galantamine was found to delay the emergence of behavioural symptoms in patients receiving active treatment for 12 months and alleviated such symptoms in those switched to the drug after six months.

Presenting the results this week at the 17th World Congress of Neurology in London, Dr Bullock said that galantamine was generally well tolerated and most of the side effects experienced were gastrointestinal. He told The Journal that an application for a licence for using the drug in cerebrovascular dementia might be filed in two to two and a half years time.

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Positive results for oral cisplatin

A novel, oral formulation of the anticancer drug cisplatin has an acceptable toxicity profile and is clinically bioavailable, according to the results of a phase I clinical trial.

The trial involved 29 patients with advanced tumours who received treatment with oral cisplatin at doses of up to 20mg/m² daily. The results, which were presented at the American Society for Clinical Oncology last month, showed that the oral formulation of cisplatin reached 40 to 50 per cent bioavailability. None of the patients in the study showed signs of nephrotoxicity.

The oral form of cisplatin is being developed by Ethypharm.

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Angiotensin II inhibitors prevent diabetic nephropathy

Results from three studies presented at the European Meeting on Hypertension, organised by the European Society for Hypertension, in Milan earlier this week show that angiotensin II receptor antagonists (AIIRAs) can prevent diabetic nephropathy. Nephropathy occurs in about 40 per cent of patients with diabetes.

The first, the irbesartan diabetic nephropathy trial (IDNT), presented by Dr R. Rodby of the Rush Presbyterian St Luke’s Medical Center in Chicago, United States, set out to determine whether irbesartan (Aprovel) altered the progression of nephropathy in 675 patients with type 2 diabetes.

Patients were randomised to receive irbesartan, amlodipine or placebo, which was conventional treatment. All the patients had proteinuria and slightly raised creatinine. The endpoint of the trial was a combination of doubling of serum creatinine, development of end-stage renal disease (ESRD) and death.

Patients taking irbesartan fared significantly better than those receiving amlodipine or conventional treatment. There was a 33 per cent reduction in risk (confidence interval not stated) for the time taken for the serum creatinine level to double. There was a 23 per cent reduction in risk for development of ESRD but no significant difference between the groups for all-cause mortality.

The effect of irbestartan on the development of nephropathy is thought to be independent of its effects on blood pressure.

The researchers conclude that to prevent one primary event, 15 people with diabetes and hypertension would need to be treated for three years, and 10 for prevention of doubling of creatinine levels.

The results of the IDNT were supported by those of the IRMA-II (irbesartan in patients with type II diabetes and microalbuminuria) trial. Dr H.H. Parving from the Steno Diabetes Centre in Gentofte, Denmark, presented the results on June 17.

In the IRMA-II trial, 590 patients with type 2 diabetes, hypertension and microalbuminuria were randomised to receive irbesartan 300mg, irbesartan 150mg or placebo (conventional treatment) for two years. The endpoint of the trial was the occurrence of diabetic nephropathy (defined as an increase in albumin of 30 per cent from baseline).

Irbesartan increased the time taken to develop nephropathy, and the 300mg dose was better than the 150mg dose. The risk reduction for the 300mg group was 70 per cent while that for the 150mg group was 39 per cent compared with that for patients receiving conventional therapy (confidence intervals not stated).

Dr Parving said that one case of nephropathy could be prevented for every 10 patients treated with 300mg irbesartan for two years. He recommended that patients be screened for microalbuminuria and, if present, they should be treated with irbesartan or another angiotensin II receptor antagonist.

The third trial, RENAAL (reduction of endpoints in non-insulin-dependent diabetes mellitus with the angiotensin II receptor antagonist losartan), was presented by Dr D. deZeeuw of the University of Groningen, the Netherlands. RENAAL measured the increase in time taken to double serum creatinine levels and to develop ESRD in 1,513 hypertensive patients with type 2 diabetes.

Patients were randomised to receive either conventional treatment plus losartan (Cozaar) or conventional treatment plus placebo, and were followed up for an average of 3.4 years.

Patients receiving losartan had a 16 per cent risk reduction (P=0.024) for the combined endpoint (this included death), a 25 per cent risk reduction (P=0.006) for doubling of serum creatinine and a 28 per cent risk reduction (P=0.002) for the development of ESRD. As in the IDNT, there was no difference in the mortality rate between the two groups of patients. The investigators found that protection occurred at all levels of renal function. One unexpected result was that there was a 32 per cent decrease in the number of patients admitted to hospital with congestive cardiac failure.

The RENAAL study was stopped early because of increasing evidence from the results of the HOPE (heart outcomes prevention evaluation) study, which meant that it became unethical not to give patients on conventional treatment therapy aimed at blockade of the renin-angiotensin system.

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Lacidipine slows progression of atherosclerosis

Lacidipine, a calcium channel blocker, can slow the progression of atherosclerosis more effectively than atenolol, according to the results of the European lacidipine study on atherosclerosis (ELSA).

Dr Alberto Zanchetti from the University of Milan, Italy, presented the results on June 17 at the European Meeting on Hypertension, organised by the European Society of Hypertension.

The investigators measured the thickness of the intima media of the carotid artery of 2,334 patients with hypertension aged between 45 and 75 years and repeated the measurement after four years.

The patients were treated with either 50mg atenolol daily or 4mg lacidipine (Motens). These doses could be increased, if necessary for blood pressure control, to 100mg and 6mg, respectively. Hydrochlorothiazide could be added, if required.

Blood pressure was controlled at 141/85mmHg in the atenolol group and 142/86mmHg in the lacidipine group, on average.

Intima media thickness measurements showed less progression of atherosclerosis (ie, less thickening) in the lacidipine group. The mean change in thickness for patients taking lacidipine was 0.003mm from baseline compared with 0.005mm in the atenolol group (P=0.0092). This equated to a reduction in thickening of about 22 per cent. This effect was independent of the effects of either drug on blood pressure, Dr Zanchetti said.

n Results from the INSIGHT study (international nifedipine once-daily study: intervention as a goal in hypertension treatment) support the findings of the ELSA investigators.

The INSIGHT study compared the effectiveness of nifedipine with that of co-amilozide in controlling hypertension (see PJ, June 10, 2000, p871). A subset of 242 of the INSIGHT subjects had measurement of intima media thickness of the carotid artery both at baseline and after an average of 48 months.

Dr Alain Simon, Hôpital Broussais, Paris, France, who presented the results of this sub-analysis on June 15, said that the thickness of the intima media increased significantly in the patients taking co-amilozide but not in those taking nifedipine GITS (gastrointestinal transport system, Adalat LA). However, the findings would need to be confirmed by larger trials.

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Potential benefits of first human anti-TNF for rheumatoid arthritis

Adalimumab, a tumour necrosis factor antibody being developed for the treatment of rheumatoid arthritis, reduces the signs and symptoms of the disease, say researchers. It is expected to offer patients potential benefits over existing anti-TNF therapies.

The results of three studies evaluating the efficacy and safety of adalimumab (previously known as D2E7, see PJ, July 15, 2000, p100) were presented this week at the European League Against Rheumatism meeting in Prague, Czech Republic. The first, a randomised, controlled, dose-ranging study that forms part of the phase II ARMADA Trial (anti-TNF research study programme of the monoclonal antibody D2E7 in patients with rheumatoid arthritis), showed that at all the doses tested (20mg, 40mg, 80mg), adalimumab, given subcutaneously on alternate weeks for 24 weeks, was significantly better than placebo at reducing the signs and symptoms of arthritis. Patients enrolled into the study had shown only a partial response to methotrexate treatment. All treatment arms remained on methotrexate throughout the study.

In the trial, clinical effectiveness was measured using American College of Rheumatology (ACR) criteria, a composite score that measures, along with other parameters, improvements in tender joint and swollen joint count.

Dr Edward Keystone of the centre for advanced therapeutics, Mount Sinai Hospital, Toronto, Canada, who presented the trial data at the meeting, and colleagues, found that the 40mg dose of adalimumab was most beneficial in terms of clinical effectiveness. Of the patients who received 40mg of adalimumab on alternate weeks, 65.7 per cent achieved a 20 per cent improvement in their symptoms compared with 14.5 per cent of patients who received placebo (P<0.0001). A 50 per cent improvement was seen in 53.7 per cent of patients in the 40mg group compared with 8.1 per cent in the placebo group (P<0.0001), and a 70 per cent improvement was seen in 26.9 per cent of patients in the 40mg group compared with 4.8 per cent given placebo (P<0.003). Adverse events in patients given adalimumab were comparable to those in patients given placebo, except for an increase in the rate of injection site reactions in the adalimumab group.

A total of 271 patients were enrolled in the study. All had active rheumatoid arthritis despite being treated with methotrexate, and all had failed to respond to at least one, but not more than four, disease modifying anti-rheumatic drugs before methotrexate therapy was started.

Dr Steven Fischkoff, global clinical director at Abbott Laboratories, said at a satellite symposium where the results of the trials were discussed that the company planned to submit an application for regulatory approval to European authorities within the first half of 2002. Asked whether the company expected adalimumab to have clinical benefits over the other anti-TNF agents currently on the market, he said: “So far, no study has looked at all three anti-TNF agents together. However, adalimumab is expected to offer patients potential advantages.” Since it was a fully human monoclonal antibody, patients would be expected to stay on the therapy for longer and there would be less chance of them experiencing an allergic reaction to the drug. He added that Abbott currently had no plans for direct head-to-head trials with the other anti-TNF agents.

Speaking to The Journal after the symposium, Professor Paul Emery of the rheumatology and rehabilitation research unit at the University of Leeds said that anti-TNF therapies were among the most important developments in rheumatology. “D2E7 [adalimumab] is an exciting advance,” he said. However, he commented that rationing seen with anti-TNF drugs was a problem in the United Kingdom. “Some health authorities are waiting for the National Institute for Clinical Excellence to issue guidance on these drugs before they will fund them.” He added that this should not be happening because the evidence to support their use was there.

Anti-TNF therapy binds to and neutralises TNF, thereby interrupting the inflammatory response associated with TNF accumulation in rheumatoid arthritis. Infliximab (Remicade) and entanercept (Enbrel) are currently the only anti-TNF agents licensed for the treatment of rheumatoid arthritis in the United Kingdom.

The results of other trials presented at the EULAR meeting will be published in The Journal on June 30,2001.

The Journal went to the European League Against Rheumatism meeting courtesy of Abbott Laboratories and the European Meeting on Hypertension (see p843) courtesy of Bayer

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Rheumatologists urged to “think LOX not just COX”

A compound ML3000, which inhibits both the 5-LOX (5-lipoxygenase) and COX (cyclo-oxygenase) pathways of the inflammatory process, is effective in improving pain scores in patients with osteoarthritis, participants at the European League Against Rheumatism meeting in Prague, Czech Republic, were told on June 15.

Results of several phase II studies involving ML3000 were presented at the meeting by Merckle GmbH, the company developing the drug. The data presented showed that ML3000 was effective in both osteo- and rheumatoid arthritis and had “excellent gastrointestinal tolerability”.

Stefan Laufer, professor of pharmaceutical chemistry, University of Tuebingen, Germany, speaking at a press briefing commented: “We are satisfied to see that COX-2 is not the end of the story... The data presented today make us optimistic that a treatment like ML3000, which works across the whole inflammatory process, will soon become a reality.” Professor Laufer told The Journal that pre-clinical studies comparing ML3000 with one of the COX-2 inhibitors currently on the market had shown ML3000 to have a significantly better gastrointestinal tolerability profile than the COX-2 inhibitor. He added that ML3000 was now in Phase III trials and that clinical studies to compare it with COX-2 inhibitors were planned for later this year.

Also speaking at the press briefing, Professor Kim Rainsford, chair of biomedical sciences at Sheffield Hallam University, said: “The early success and major pharmaceutical backing for the specific COX-2 inhibitors have lead to the focus being diverted from a balanced approach to minimising the inflammatory process.”

An application for marketing approval of ML3000 in the European Union is expected to be filed by Merckle early in 2002.

The Journal went to the European League Against Rheumatism meeting courtesy of Abbott Laboratories and the European Meeting on Hypertension (see p843) courtesy of Bayer

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Mixed results for abciximab in MI trials

Combining the fibrinolytic drug reteplase (Rapilysin) with abciximab (ReoPro), a glycoprotein IIb/IIIa antagonist, reduces secondary complications of myocardial infarction but not mortality rates, according to trial results published this week.

The GUSTO V (global use of strategies to open occluded coronary arteries) trial aimed to test the hypothesis that combined fibrinolytic therapy and platelet glycoprotein IIb/IIIa inhibition improves reperfusion in patients with acute MI.

The investigators randomly assigned patients to standard-dose reteplase (8,260 patients) or half-dose reteplase plus full-dose abciximab (8,328 patients). They found that, at 30 days follow-up, 488 of the patients given standard-dose reteplase had died compared with 468 of the patients on combined therapy. The statistical power of the trial meant that the investigators could show that although the combination therapy was not significantly better than reteplase, in terms of reducing mortality, it was not inferior to it.

The investigators saw fewer non-fatal reinfarctions in patients given reteplase in combination with abciximab than those given reteplase alone, and there was less need for urgent revascularisation. In addition, the researchers saw fewer major non-fatal ischaemic complications of acute MI. However, there was an increase in the rate of non-intracranial bleeding complications in the patients given combination therapy, although the absolute rates were modest, say the researchers.

The researchers comment that the question of whether combination therapy should be incorporated into practice will ultimately rest on other factors besides safety and efficacy, such as cost. But they add that if price is not a consideration then the combined therapy approach is desirable.

“The reduced morbidity and reduced need for urgent revascularisation is encouraging, even if it is partly offset by higher rates of non-intracranial bleeding,” they say (Lancet 2001;357:1905).

In an accompanying commentary on the trial (ibid, p1898), Dr Freek Verheugt of the University Medical Centre, St Radboud, the Netherlands, said: “The concept of an improvement in early patency rates leading to a decrease in mortality was not confirmed. In GUSTO V the bottom-line in current fibrinolytic reperfusion therapy seems to have been reached and speeding up reperfusion with drugs does not seem worthwhile.”

GUSTO IV trial

Results of the GUSTO IV-ACS trial, also published this week, suggest that abciximab is not beneficial as first-line treatment in patients with acute coronary syndromes who do not undergo early revascularisation.

Previous trials have shown that abciximab reduces procedure-related thrombotic complications of percutaneous coronary interventions and the risk of premature death and MI in patients with acute coronary syndromes. These benefits were seen mainly in patients undergoing early revascularisation but the GUSTO IV-ACS investigators note that many patients with acute coronary syndromes do not undergo such early procedures. They therefore conducted a randomised trial to study the effect of abciximab on patients who were not revascularised early. (Of the 7,800 patients participating in the trial, only 128 underwent percutaneous coronary intervention within 48 hours of enrolment into the trial.)

Patients, who were admitted to hospital with chest pain and either ST-segment depression or raised troponin T or I concentrations (markers of myocardial necrosis), were randomised to receive placebo (n=2,598), abciximab bolus and 24 hour infusion (n=2,590), or abciximab bolus and 48 hour infusion (n=2,612). There were 209 deaths among the patients receiving placebo, compared with 212 on 24 hour abciximab, and 238 on 48 hour abciximab. This gave an odds ratio of 1.0 (95 per cent confidence interval 0.83–1.24) for the difference between placebo and 24 hour abciximab, and 1.1 (0.94–1.39) for the difference between placebo and 48 hour abciximab.

The researchers conclude that patients with acute coronary syndromes who are not scheduled to undergo early revascularisation gain no benefit from intravenous abciximab during the first 24 or 48 hours after enrolment. They note that the findings are in contrast to earlier investigations and that the reasons for the differences are not completely understood (Lancet 2001;357:1915).

The National Institute for Clinical Excellence issued guidance on the use of glycoprotein IIb/IIIa antagonists in September last year (see PJ, October 7, 2000, p509).

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IBS drug fails to gain US approval

The United States Food and Drug Administration has refused to grant marketing approval for tegaserod (Zelmac), Novartis’s new treatment for irritable bowel syndrome (see PJ, May 26, p707). This follows the company’s withdrawal of its marketing authorisation application in Europe last month.

Novartis withdrew its application in Europe because of a disagreement between the company and the European Agency for the Evaluation of Medicinal Products about the drug’s effectiveness. Novartis says it will be resubmitting its application for marketing approval of Zelmac in Europe but does not expect the drug to reach the European market before 2003. Novartis had, however, hoped to gain approval in the US.

A spokeswoman for Novartis told The Journal on June 19 that the FDA had requested additional information about the drug before approval could be granted. A decision about whether to appeal against the FDA’s decision or to resubmit its application in the US had not yet been made.

The latest issue of the Merec Bulletin reviews IBS and the value of drug treatments available for this condition. The bulletin, which is produced by the National Prescribing Centre, concludes that current therapies are of limited value and have a poor evidence base (Merec Bulletin 2000;11:41).

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CHD management inadequate in primary care

There is ample scope for improvement of coronary heart disease management in primary care, researchers say.

Dr Adrian Brady, consultant cardiologist at Glasgow Royal Infirmary, and colleagues assessed detection and prevention of cardiac risk factors in 24,431 patients with established coronary heart disease.

Cholesterol levels had never been recorded in 44 per cent of patients. In patients who were tested, 44 per cent had a total cholesterol above 5mmol/L, yet only 16 per cent had been prescribed a statin. Aspirin was prescribed for 50 per cent of patients and b-blockers for 23 per cent of patients who had had a previous myocardial infarction. Hypertension was controlled reasonably well, apart from in patients with diabetes, and 23 per cent of patients continued to smoke, they say.

“The findings show that secondary prevention of CHD in primary care currently falls well short of the recommendations made in both the national service framework and the Scottish Intercollegiate Guidelines Network,” said Dr Brady. The study was conducted before the guidelines were published (BMJ 2001;322:1463).

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