Presenter: Ajay K Gupta, MD, MSc (International Centre for Circulatory Health NHLI, Imperial College, London, United Kingdom)

The latest analysis of the results from the blood pressure lowering-arm of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT-BPLA) has shown that a regimen based on a calcium channel blocker (CCB) (amlodipine), with or without addition of an angiotensin converting enzyme (ACE) inhibitor (perindopril), reduced the risk of new-onset diabetes by 34% in hypertensive patients, compared with a regimen based on a beta-blocker (atenolol) with or without a thiazide-type diuretic, bendroflumethiazide.^[1]

The ASCOT investigators believe that this finding has implications for the future role of beta-blockers and diuretics in the management of patients with hypertension and suggest that physicians adopt what they refer to as "the ASCOT strategy, an evidence-based strategy for combining CCBs and ACE inhibitors," to get their patients to currently recommended target blood pressures. "By so doing, they know that they will reduce the risk of new-onset diabetes by almost one third," the investigators say. On the basis of the results of this most recent analysis, the ASCOT investigators have also developed a new risk score model that can be used to identify those hypertensive patients at highest risk of new-onset diabetes.

ASCOT-BPLA: Main Study

The multicenter, prospective, randomized, controlled ASCOT-BPLA study was designed to compare a newer, CCB-based antihypertensive regimen with the most commonly prescribed combination antihypertensive regimen at the time, a beta-blocker plus a thiazide diuretic, in a population of over 19,000 hypertensive adults at moderate risk of developing cardiovascular disease. ASCOT-BPLA was supported mainly by Pfizer (New York, NY), with additional funding by Servier Research Group (Paris, France).

Patients enrolled in ASCOT were aged 40 to 79 years, had hypertension (screening and baseline blood pressure ≥ 160/100 mm Hg untreated or ≥ 140/90 mm Hg treated with ≥ 1 drugs), no previous myocardial infarction (MI) or current coronary heart disease (CHD), and ≥ 3 other cardiovascular risk factors, such as male gender, age ≥ 55 years, smoking, or diabetes mellitus.^[2] Diabetes at baseline was defined as:

• Fasting plasma glucose (FPG) ≥ 7 mmol/L (126 mg/dL) and/or random glucose ≥ 11.1 mmol/L (200 mg/dL);
  
  
• Self-reported diabetes and receiving dietary or drug therapy; or
  
  
• Presence of both impaired fasting glucose (IFG) (≥ 6 mmol/L) and glucosuria in absence of the above 2 criteria.

Patients were assigned either to amlodipine 5 to 10 mg, adding perindopril 4 to 8 mg as required, or to atenolol 50 to 100 mg, adding bendroflumethiazide 1.25 to 2.5 mg and potassium as required (atenolol-based regimen). Blood pressure targets were < 140/90 mm Hg for patients without diabetes and < 130/80 mm Hg for patients with diabetes.

The BPLA study was stopped prematurely in December 2004 after a median follow-up of 5.5 years on the recommendation of the data and safety monitoring board, at which time the patients on the amlodipine-based regimen showed a 10% reduction in the primary endpoint of fatal CHD and nonfatal MI compared with those on the atenolol-based regimen, although this difference did not reach statistical significance.^[3] Patients on the amlodipine based regimen experienced an 11% reduction in total mortality, a 23% reduction in fatal and nonfatal strokes, and a 24% reduction in cardiovascular death, compared with patients taking the beta-blocker-based regimen.

Analysis of New-Onset Diabetes

An analysis of new-onset diabetes, a prespecified tertiary endpoint of the main trial, was carried out in the 14,120 patients enrolled in ASCOT-BPLA who did not have diabetes at baseline: 7046 in the atenolol-based treatment group and 7074 in the amlodipine-based treatment group. Other baseline characteristics did not differ between these 2 groups.

New-onset diabetes was diagnosed according to the 1999 WHO criteria (FPG ≥ 7.0 mmol/L [126 mg/dL] or 2-hr plasma glucose level ≥ 11.1 mmol/L [200 mg/dL]).^[4]

Compared with patients on the atenolol-based regimen, patients allocated to the amlodipine-based regimen were found to be 34% less likely to develop new-onset diabetes. A total of 799 (11.4%) patients in the atenolol-based treatment group developed new-onset diabetes compared with only 587 (8.0%) in the amlodipine-based treatment group. Patients who received the atenolol-based regimen were at increased risk of new-onset diabetes irrespective of all other diabetes risk factors (eg, increased weight, blood glucose at study entry, and initial blood pressure level).

Risk Factors

Antihypertensive therapy with amlodipine, with or without perindopril, was the strongest protective factor among baseline predictors of new onset diabetes (Table 1). This protective effect was mainly due to the ACE inhibitor, since the effect of amlodipine on risk of new-onset diabetes was neutral, Dr. Gupta commented. Four other protective risk factors were also identified (Table 1).

Table 1. Protective Factors

Factor	HR	95% CI	P
Amlodipine ? perindopril	0.66	0.59-9,71	< .001
HDL-cholesterol (per mmol/L)	0.72	0.58-0.89	.002
Total cholesterol (per mmol/L)	0.89	0.84-0.94	< .001
Age ≥ 55 yrs (per 5 yrs)	0.94	0.90-0.98	.006
Alcohol intake (units/wk)	0.99	0.99-1.00	.017

CI = confidence interval; HDL = high-density lipoprotein; HR = hazard ratio.

"One of the most important risk factors for developing new-onset diabetes was being allocated to the beta-blocker plus or minus diuretic treatment strategy," Dr. Gupta said. FPG was the strongest risk factor at baseline, followed by body mass index (BMI) and triglyceride levels (Table 2).

Table 2. Risk Factors*

Factor	HR	95% CI
FPG (per mmol/L > 5 mmol/L)?	5.80	5.34-6.43
BMI (per 5-unit increase)	1.49	1.38-1.62
Triglyceride (per mmol/L)	1.12	1.07-1.17
SBP (per 10 mm Hg)	1.07	1.04-1.10
Use of non-CAD medication (Y/N)	1.25	1.11-1.40

*For all comparisons, P < .001
^?Baseline risk = FPG ≤ 5 mmol/L. BMI >35 kg/m² given similar risk; hazard ratio per 5-unit increase from baseline.
BMI = body mass index; CI = confidence interval; FPG = fasting plasma glucose; HR = hazard ratio.

Dividing the patient population into quartiles based on these factors showed that risk of new-onset diabetes increased with risk score, the patients with the highest score (4th quartile) having an almost 20-fold higher risk than the patients in the lowest (1st) quartile (Table 3). Within each quartile, the patients taking the atenolol-based regimen were at higher risk than those on the amlodipine-based regimen. Comparison of the observed numbers of events with the expected probabilities of the development of diabetes predicted using the risk score showed no difference.

Table 3. New-Onset Diabetes According to Risk Quartiles

	1st Quartile	2nd Quartile	3rd Quartile	4th Quartile
Hazard ratio	1	2.5	5.0	19.0
(95% CI)		(1.8-3.5)	(3.7-6.8)	(14.3-25.4)

CI = confidence interval; HR = hazard ratio

Dr. Gupta believes that this risk model "is robust, has an excellent discriminative ability, and could potentially play an important role in clinical practice." The designated discussant at the World Cardiology Congress, Jos?L. Zamorano Gomez, MD, PhD (University Clinic San Carlo, Madrid, Spain), agreed that the risk score obtained by combining the most important risk factors for new-onset diabetes "makes it possible to calculate in advance a risk score which was extremely good at discriminating between risk groups presented in quartiles."

Implications for Treatment of Hypertension

Dr. Gomez also pointed out that, although the ASCOT analysis and other trials seem to indicate that amlodipine has a neutral effect with respect to development of new-onset diabetes, it is unlikely that the 34% difference in the 2 ASCOT treatment groups was entirely due to the ACE inhibitor in the "amlodipine plus or minus perindopril group," because not all patients in this group received perindopril. "Consequently, a certain proportion of the final effect must be due to the atenolol plus or minus diuretic group, particularly atenolol," he stated. Dr. Gomez believes that now that the risk of new-onset diabetes with these drugs has been demonstrated, preventing new-onset diabetes should be regarded in the same light as a "compelling indication" in hypertension management guidelines.

Commenting separately on the latest data, Neil Poulter, MD, MSc (Imperial College, London, UK), Secretary of the ASCOT Executive Committee, said: "These findings have critically important implications for many thousands of people. Hypertension already increases the risk of diabetes 2-3 times. Now we know that the commonly used combination of a beta-blocker plus or minus diuretic significantly increases the risk compared with a new combination, amlodipine plus or minus perindopril. Physicians should think carefully before using the beta-blocker-based strategy to treat hypertension."

The main results of ASCOT reported in 2005^[3] prompted a review of guidelines for the management of hypertension in the United Kingdom by the National Institute for Health and Clinical Excellence (NICE), working with the British Hypertension Society. The resulting joint guideline, published in June 2006,^[5] included the recommendation that beta-blockers should no longer be preferred initial therapy for hypertension, relegating them to fourth line. Although the greater risk of new-onset diabetes with beta-blockers was acknowledged, the guideline also pointed out that most clinical trials upon which the recommendation was based used atenolol, and other beta-blockers might not carry the same risk. The guideline retained diuretics as a first-line option in patients aged ≥ 55 years, although reports of ongoing discussions had indicated that diuretics would also be removed as recommended first-line drugs.

Commenting in Barcelona on the UK guideline, Peter S. Sever, MD, PhD (Imperial College, London), Co-chairman of the ASCOT Executive Committee, said, "We know from other trials, including Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT),^[6] that diuretics are metabolically unfriendly, that they increase fasting plasma glucose, and they are not lipid friendly and there is no doubt that they do contribute to the diabetes." He stressed that "the evidence for not including a diuretic at least in your first and second choice and replacing it with a CCB and an ACE inhibitor is very strong. Why would you want to increase the risk, even if it is not as great as for a beta-blocker, if you have alternative therapies that are now available in generic formulations, so that there is no cost issue as there was before?"

Prof. Sever stressed the increased risk hypertensive patients face if they have diabetes. Regardless of the presence of other risk factors such as hypertension, dyslipidemia, or smoking, or how many risk factors are present, "in a patient with diabetes the overall risk is enhanced dramatically," he said. "A patient with hypertension and diabetes is at equivalent risk to a hypertensive patient who has already had an MI and is nondiabetic. We regard it as the equivalent to secondary prevention in patients with diabetes -- we have to assume they have got established cardiovascular disease," he added.

The ASCOT Strategy

Prof. Sever and his colleagues urge physicians to adopt "the ASCOT strategy," ie, combining CCBs and ACE inhibitors for treatment of hypertension, with the addition of a statin, based on evidence from the lipid-lowering arm of the ASCOT study (ASCOT-LLA), for which over 10,000 patients in the blood pressure lowering study also received atorvastatin 10 mg or placebo daily.^[7] "We know from ASCOT-BPLA that this combination will reduce cardiovascular mortality and all-cause mortality, reduce the incidence of MI, and reduce stroke incidence compared with the more conventional and widely used beta-blocker/thiazide combination therapy," said Prof. Sever. "We also know from ASCOT-LLA that most hypertensives will benefit from addition of a statin. The risk reductions were greater than one third for MI and about one quarter for stroke."

Another crucial management strategy to get blood pressure to target is to get a fast, early reduction, according to Prof. Sever.

"We know, from unpublished data from ASCOT, that the early and rapid reductions in blood pressure were associated with dramatic reductions in event rates, MI, and stroke. So with good blood pressure control, the addition of lipid lowering with statins and the preference for the so-called 'newer strategy' of CCB and ACE inhibitors, with all that package -- the ASCOT strategy -- we can confidently say that in hypertensive patients we can reduce the incidence of MI and stroke by nearly two thirds. Out in the real world the majority of hypertensives are poorly controlled, often on inappropriate treatment, and the vast majority are not receiving statins. This is the sort of package that will deliver cardiovascular protection if it was adopted more widely in coronary care."

Although the overall ASCOT population was mainly (95%) white, Prof. Sever believes the strategy based on the ASCOT findings can be applied to other ethnic groups, including black and Asian patients. "These populations are at very real risk of developing new-onset diabetes and we see no reason why our results should not be applied to other ethnic groups," he said.

References

1. Gupta A. Determinants of new-onset diabetes among hypertensive patients randomised in the ASCOT-BPLA Trial. Presented at the World Congress of Cardiology 2006, September 2-6, 2006, Barcelona, Spain: Clinical trial update I, September 6, 2006.
2. Sever PS, Dahl? B, Poulter NR, et al; ASCOT investigators. Rationale, design, methods and baseline demography of participants of the Anglo-Scandinavian Cardiac Outcomes Trial. J Hypertens. 2001;19:1139-1147.
3. Dahl? B, Sever PS, Poulter NR, for the ASCOT investigators. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomized controlled trial. Lancet. 2005;366:895-906.
4. WHO. Department of Non-Communicable Disease Surveillance. WHO 1999 criteria for diagnosis of diabetes mellitus. Geneva: World Health Organization; 1999: 1-59.
5. NICE clinical guideline 34. Hypertension: management of hypertension in adults in primary care (partial update of NICE clinical guideline 18). London: National Institute for Health and Clinical Excellence; 2006. Available at www.nice.org.uk/CG018.
6. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin converting enzyme inhibitor or calcium channel blocker vs diuretic. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002;288:1981-1997.
7. Sever PS, Dahl? B, Poulter NR, et al; ASCOT investigators. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial -- Lipid Lowering Arm (ASCOT-LLA): a multicentre randomized controlled trial. Lancet. 2003;361:1149-1158.

Several presentations at the 2006 World Cardiology Congress (WCC) in Barcelona reported new data on aliskiren, the oral renin inhibitor that is pending approval for the treatment of hypertension in the United States and Europe. The data, from phase 3 clinical trials with the drug alone and in combination with other antihypertensive drug classes, further support its use as a very effective new approach to control of high blood pressure. In addition, information about new and ongoing clinical trials for other cardiovascular therapeutic indications was revealed at WCC 2006.

Aliskiren

Aliskiren is the first in a new class of potent, orally effective renin inhibitors. The compound is conceptually elegant in that whereas all of the other drugs act by inhibiting certain aspects of the ultimate step in the renin-angiotensin system (RAS), ie, angiotensin II, aliskiren targets the first and rate-limiting step -- namely, renin.

Although the biologic activity of aliskiren actually increases renin production, the activity of the renin produced is inhibited, and thus its capacity to form angiotensin I, as measured by plasma renin activity (PRA), is reduced. By contrast, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and thiazide diuretics all increase both plasma renin concentration and activity, leading to increased production of angiotensin I, which is then available for conversion to angiotensin II. In addition, renin inhibitors do not affect kinin metabolism and hence would not be expected to cause dry cough or angioneurotic edema, both characteristic side effects of ACE inhibitors.

Since 2002, aliskiren has been developed solely by Novartis (Basel, Switzerland). Throughout the clinical development program, aliskiren has consistently shown reductions in blood pressure of > 10 mm Hg as monotherapy and additive reductions when aliskiren is given in combination with other antihypertensive drugs. It provides both smooth 24-hour blood pressure control and long-term control, with tolerability comparable to that seen with placebo at doses within the expected therapeutic dose range, and it has been well tolerated when used with other cardiovascular drugs. The most commonly reported adverse events for aliskiren have been diarrhea, headache, and nasopharyngitis. No pharmacokinetic interactions have been identified when aliskiren has been used in conjunction with other drugs commonly administered to patients with hypertension.

Phase 3 trials with aliskiren are ongoing in the United States, Europe, and Japan. The first regulatory submission for aliskiren was made by Novartis in the United States. In April of this year, the US Food and Drug Administration (FDA) accepted for review the new drug application (NDA) for aliskiren as a treatment for hypertension both as monotherapy and in coadministration with other antihypertensive agents, and in September the European Medicines Agency followed suit for the same therapeutic applications. The submissions were based on data from > 7800 patients who had received aliskiren in 44 clinical trials. The trade name for aliskiren, pending approval, will be Rasilez, and if it is approved, this direct renin inhibitor will be the first example of what is expected to be the first new class of antihypertensive medications to become available for over 10 years.

Following the first presentation of clinical data on aliskiren at the annual meetings of the American Society of Hypertension^[1] and the European Society of Hypertension^[2] earlier this year, the latest data presented at the WCC provided additional support for 3 potential regimens in which once-daily aliskiren provides:

• Consistent and sustained blood pressure lowering over 12 months of treatment, providing sustained 24-hour blood pressure control, with no rebound high blood pressure seen after discontinuation of therapy;
  
  
• Additive blood pressure reductions when combined with the diuretic hydrochlorothiazide (HCTZ) or with the ACE inhibitor ramipril;
  
  
• The same antihypertensive efficacy, when combined with amlodipine, with a lower incidence of edema than would occur with an equipotent, higher dose of amlodipine.

Aliskiren Alone or in Combination With Hydrochlorothiazide

A study of aliskiren alone and in combination with HCTZ in hypertensive patients showed that aliskiren reduces blood pressure effectively and can maintain its blood pressure-lowering effect over 1 year of therapy.^[3]

Domenic Sica, MD, and colleagues investigated aliskiren alone and in combination with HCTZ in a 12-month, open-label study that included a final 1-month, randomized, placebo-controlled withdrawal period. A total of 1955 adults aged ≥ 18 years with uncomplicated mild to moderate hypertension (mean sitting diastolic blood pressure [DBP] 90-109 mm Hg) were randomized to aliskiren 150 mg (n = 1178) or 300 mg (n = 773) once daily, after washout and a 2- to 4-week drug-free period. Dose titration (aliskiren 150 mg uptitrated to 300 mg) or addition of HCTZ (12.5 mg titrated to 25 mg if required) to aliskiren 300 mg was permitted in patients who did not achieve blood pressure control (<140/90 mm Hg) after 2 months.

A total of 1625 patients (83%) completed the open-label treatment period up to Month 11. At this point, 261 patients who had remained on aliskiren monotherapy were randomized to either continued aliskiren (n = 132) or placebo (n = 129) during a 4-week double-blind withdrawal phase.

At the end of the open-label treatment period, reductions in DBP and systolic blood pressure (SBP) in the aliskiren monotherapy groups and the aliskiren/HCTZ groups were similar (Table 1).

Table 1. Changes in Mean Sitting DBP and Mean Sitting SBP (?SEM) at Endpoint of Open-Label Treatment

Treatment Group	n	Change From Baseline (mm Hg)
		msDBP	msSBP
By initial assigned treatment:
Aliskiren 150 mg	1162	-12.4 ? 0.2	-17.5 ? 0.4
Aliskiren 300 mg	766	-13.3 ? 0.3	-18.8 ? 0.5
By final treatment received:
Aliskiren monotherapy	1060	-13.3 ? 0.3	-17.4 ? 0.5
Aliskiren/HCTZ combination	668	12.1 ? 0.3	-18.7 ? 0.5

HCTZ = hydrochlorothiazide; msDBP = mean sitting diastolic blood pressure; msSBP = mean sitting systolic blood pressure.

During the withdrawal period, patients on placebo had a gradual increase in mean sitting blood pressure that appeared to plateau after 3 weeks (Table 2). In the patients who remained on aliskiren, blood pressure reductions were maintained at levels similar to those seen at Month 11. At the end of the withdrawal period, there was a statistically significant difference in blood pressure between the aliskiren and placebo groups (5.99/3.87 mm Hg; P < .0001).

Table 2 Changes in Mean Blood Pressure During Withdrawal Period From Month 11

	Change vs Month 11 Baseline (mm Hg)
	Aliskiren		Placebo
	msDBP	msSBP	msDBP	msSBP
Week 1	0.3	1.3	2.5	3.2
Week 2	0.3	0.3	4.2	4.7
Endpoint	1.2	1.7	5.0	7.4

msDBP = mean sitting diastolic blood pressure; msSBP = mean sitting systolic blood pressure.

Twenty-four hour ambulatory blood pressure monitoring (ABPM) showed a clear separation between aliskiren and placebo at most hourly time points, showing that reductions in blood pressure with aliskiren were sustained throughout the 24-hour dosing period. "The blood pressure response numbers are quite comparable to monotherapy with an ACE inhibitor or an ARB," Dr. Sica said.

In a second study, data on the effects of aliskiren treatment and treatment withdrawal on plasma renin concentrations and PRA in these patients were presented by James Pool, MD (Baylor College of Medicine, Houston, Texas).^[4] PRA and renin concentration were measured in plasma samples from a subset of patients at selected centers (297 during the open-label period and 26 during the withdrawal period).

Sustained reductions in PRA from baseline were similar with aliskiren as monotherapy and in combination therapy. These reductions in PRA were maintained during long-term (12 months) treatment with both monotherapy and combination therapy (Table 3), indicating that aliskiren effectively suppresses PRA even when used in combination with drugs that increase PRA.

Table 3. Mean Percentage Change From Baseline in PRA and Renin Concentration

Open-label treatment:	PRA		Renin Concentration
	Aliskiren n = 138	Aliskiren/HCTZ n = 159	Aliskiren n = 100	Aliskiren/HCTZ n = 131
Month 6	-73.2	-65.3	+148	+390
Endpoint	-68.0	-65.4	+176	+411
Withdrawal period:	Aliskiren n = 15	Placebo n = 11	Aliskiren n = 11	Placebo n = 9
Wk 1	-70.5	-61.7	+267	+56.5
Wk 2	-68.4	-60.2	+154	+19.9
End	-76.1	-55.9	+82.8	-1.6

HCTZ = hydrochlorothiazide; PRA = plasma renin activity.

Renin concentrations increased in patients taking aliskiren during the open-label treatment period, but this rise was more marked in the patients on aliskiren plus HCTZ. During the withdrawal period, PRA remained suppressed in patients who continued on aliskiren despite renin levels that remained above baseline levels. In the patients who switched to placebo, PRA remained > 50% below baseline levels even 4 weeks after withdrawal of therapy, although renin concentration returned almost to baseline levels by study endpoint, suggesting continued renin inhibition with aliskiren beyond the drug's plasma half-life.

Comments

"This study has opened up a whole series of scientific questions, such as what it is that is actually occurring that allows this drug to continue to suppress PRA a month after it has been withdrawn," said Dr. Pool. "I think it is going to open up a new concept of how we can reverse some of the undesirable effects that diuretics have on the renin angiotensin system," he suggested.

Dr. Sica believes that aliskiren may be one of the first drugs with an effect related to tissue compartmentalization and not to plasma levels. "That is new and very novel and may speak well for issues of end-organ protection," he predicted. "We still have a lot to learn about the drug - it has to distinguish itself - but we have good reasons to believe that it may be different," he said, adding:

"For example, if you give an ACE inhibitor and an ARB and look at renal protection, the duration of time that you expose the kidney to the drug is almost totally dependent on the plasma level. Once the drug has disappeared from the plasma compartment there is little likelihood that there is going to be any residual effect on renal function parameters. However, we see aliskiren remaining in the kidney for weeks, suggesting there may be an immediate effect in the plasma but a more prolonged effect in the tissue. That has not yet been borne out with data, but on this basis I would rather block this axis completely and for a prolonged period of time rather than an on-off time each day. . . . Our gain in changes in renal failure progression rates with ACE inhibitors and ARBs has not been great. We can do better, but it is going to take drugs with fundamentally different pharmacology. Although this was not a primary aspect of the study, it will probably have to be critically evaluated, and it may be one of the most important findings."

There was no evidence of dose-dependent side effects during open-label treatment with aliskiren alone or with HCTZ. During the withdrawal period, adverse rates were similar in patients on aliskiren (15.9%) and placebo (14.7%). The most commonly reported adverse events were diarrhea, back pain, headache, dizziness, and nasopharyngitis. Dr. Sica believes that the safety and tolerability of aliskiren will probably be similar to that of ARBs.

Aliskiren Plus Amlodipine in the Treatment of Hypertension

Adding aliskiren to the calcium channel blocker amlodipine provides significant additional blood pressure lowering without increasing the incidence of the edema associated with doubling the amlodipine dose, according to a study reported by Mark Munger, PharmD (College of Pharmacy, University of Utah, Salt Lake City).^[5]

The effects of adding aliskiren 150 mg to amlodipine 5 mg in patients with inadequate blood pressure control on this treatment were compared with continuing amlodipine 5 mg monotherapy or increasing the dose to 10 mg in a 6-week, randomized, parallel-group study. A total of 762 patients with mild-to-moderate hypertension (mean sitting DBP 95-109 mm Hg untreated or < 110 mmHg if treated) underwent 2 weeks' washout followed by 4 weeks of single-blind treatment with amlodipine 5 mg once daily. The 545 patients whose DBP remained between 90 and 110 mm Hg on this regimen were randomized to double-blind treatment with amlodipine 5 mg monotherapy, amlodipine 10 mg, or aliskiren 150 mg plus amlodipine 5 mg for 6 weeks.

Aliskiren 150 mg/amlodipine 5 mg treatment produced significantly greater reductions in mean sitting DBP and SBP between baseline and study endpoint (Week 6), the primary efficacy measure of the study, than the reduction with amlodipine 5 mg (P < .0001) (Table 4). The reductions with combination treatment compared with amlodipine 10 mg were comparable for DBP and nonsignificantly greater with combination treatment for mean sitting SBP. Blood pressure reductions were evident in all groups after 1 week of treatment. After 3 weeks, reductions in blood pressure were significantly (P < .0001) greater with combination treatment than with amlodipine 5 mg. Rates of blood pressure control (< 140/90 mm Hg) and responder rates (percentage of patients with mean sitting DBP < 90 mm Hg and/or 10-mm Hg reduction from baseline) were significantly greater in the amlodipine 10 mg and combination treatment groups compared with amlodipine 5 mg.

Table 4. Efficacy Measures and Adverse Events

	Aliskiren 150 mg/ Amlodipine 5 mg	Amlodipine
		5 mg	10 mg
msDBP (mean change mm Hg)	-8.46*	-4.84	-8.04*
msSBP (mean change mm Hg)	-10.98*	-4.96	-9.63*
Responder rate (%)	64.2*	45.2	59.9*
Blood pressure control rate (%)	42.8*	22.6	37.9*
Overall adverse events (%)?	31.6	28.5	30.9
Edema (%)	2.1	3.4	11.2?

msDBP = mean sitting diastolic blood pressure. msSBP = mean sitting systolic blood pressure.
*P < .005 vs amlodipine 5 mg
^?P < .001 vs combination
^?Significance not tested

Aliskiren in Combination With Ramipril in Patients With Hypertension and Diabetes

The results of a substudy that compared the effects of 8 weeks of treatment with aliskiren, ramipril, or both drugs in combination were presented by Charles Kilo, MD (Washington University School of Medicine, St Louis).^[6] Renin system blockade is beneficial in the management of hypertension in patients with diabetes, but monotherapy is often insufficient to achieve the stringent blood pressure control required in this population, Dr. Kilo noted.

A total of 256 adult male or female patients with type 1 or 2 diabetes and hypertension (mean sitting DBP > 95 and < 109 mm Hg) who were participating in a larger study of diabetes and hypertension were randomized in double-blind fashion to treatment with aliskiren 150 mg, ramipril 5 mg, or aliskiren/ramipril 150/5 mg once daily for 4 weeks. This was followed by a further 4 weeks of forced titration to aliskiren 300 mg, ramipril 10 mg, or aliskiren/ramipril 300/10 mg, respectively.

Aliskiren 300 mg was superior to ramipril 10 mg in lowering mean sitting SBP (mean treatment difference 2.7 mmHg, P = .012) and noninferior in lowering mean sitting DBP. The aliskiren/ramipril combination provided significant additional blood pressure lowering (4.6/2.1 mm Hg), for an overall reduction of 16.6/12.8 mm Hg. Renin concentration increased significantly in all treatment groups compared with baseline, with a greater increase in the aliskiren group (115%) than in the ramipril group (68%), and the largest increase seen with combination therapy (315%). Consistent with the reactive rise in renin concentration, PRA increased by 111% in the ramipril group, but was reduced by 68% in the aliskiren group. When combination therapy was administered, aliskiren counteracted the ramipril-induced increase in PRA, leading to an overall reduction of 44%.

The combination of aliskiren and ramipril was well tolerated and appeared to reduce the incidence of ACE inhibitor-induced cough.

Further studies should be carried out to determine whether the combination of aliskiren and ramipril provides additional antiatherogenic and anti-inflammatory benefits, Dr. Kilo and his colleagues believe. Angiotensin II is atherogenic and proinflammatory, Dr. Kilo explained, so by blocking it with aliskiren, the effects of congestive heart failure, left ventricular hypertrophy, endothelial dysfunction, and new-onset diabetes can be reduced. "Aliskiren has multibeneficial effects," he said. "It is the best drug so far to treat hypertension, because you are treating it at the beginning of the RAS pathway." It would be most effective to use aliskiren with an ACE inhibitor rather than using it with an ARB, but it would still be better than either alone," Dr. Kilo declared.

Pooled Analysis of Trials in Hypertension

An analysis of pooled data from 7 randomized, double-blind, multicenter studies that evaluated the antihypertensive efficacy and safety of aliskiren as monotherapy or in combination with other antihypertensive drugs was presented by Matthew R Weir, MD (University of Maryland School of Medicine, Baltimore).^[7] The results of the analysis showed that aliskiren monotherapy effectively and dose-dependently lowers blood pressure, with effects independent of age or gender and placebo-like tolerability. The 150-mg and 300-mg doses of aliskiren consistently provided additional blood pressure reductions when added to other antihypertensive agents without compromising tolerability.

Data were used from 7 randomized, double-blind, multicenter studies, 5 of which were placebo controlled (2 with active controlled arms) and 2 of which were active controlled trials. They involved a total of 7060 patients (mean age 50.2-59.8 years; 50.2%-72.5% men; 77.4% white) with mild-to-moderate hypertension (mean sitting SBP 150.6-156.6 mm Hg, mean sitting DBP 99.0-99.6 mm Hg). Duration of active treatment, with aliskiren given at doses of 75-600 mg alone or in combination with valsartan, HCTZ, ramipril, or amlodipine, was 6-8 weeks after a washout period of 1-2 weeks and a single-blind placebo period of 2-4 weeks.

In the placebo-controlled studies, aliskiren lowered mean sitting DBP and mean sitting SBP from baseline in a dose-dependent manner up to 300 mg compared with placebo. The effect of 600 mg was not markedly greater than that of 300 mg. Reductions in DBP from baseline with aliskiren monotherapy, the studies' primary endpoint, were 7.2-10.3 mm Hg (75-mg dose), 7.8-10.3 mm Hg (150-mg dose), 10.3-12.3 (300-mg dose), and 11.5-12.5 mm Hg (600-mg dose) (Table 5).

Table 5. Change in Mean Sitting DBP (mm Hg) With Aliskiren Monotherapy vs Placebo

Study Group	Study
	Aliskiren/ Irbesartan	Japanese Monotherapy	Aliskiren Monotherapy	Aliskiren/ Valsartan	Aliskiren/ HCTZ
Placebo	-6.3	-3.3	-4.9	-8.6	-6.9
Aliskiren 75 mg	-	-7.2*	-	-10.3	-8.7*
Aliskiren 150 mg	-9.3*	-7.8*	-10.3*	-10.3	-8.9*
Aliskiren 300 mg	-11.8*	-10.7*	-11.1*	-12.3*	-10.3*
Aliskiren 600 mg	-11.5*	-	-12.5*	-	-

DBP = diastolic blood pressure; HCTZ = hydrochlorothiazide
*P < .05 vs placebo.

Reductions from baseline in mean sitting SBP were 8.6-12.1 mm Hg (75 mg), 8.7-13.0 mm Hg (150 mg), 14.1-15.7 mm Hg (300 mg), and 15.8 mm Hg (600 mg).

Responder rates (percentage of patients with mean sitting DBP < 90 mm Hg and/or 10-mm Hg reduction from baseline) were significantly higher for all aliskiren doses compared with placebo (Table 6).

Table 6. Responder Rates (%) With Aliskiren Monotherapy vs Placebo

Study Group	Study
	Japanese Monotherapy	Aliskiren Monotherapy	Aliskiren/ Valsartan	Aliskiren/ HCTZ
Placebo	27.8	36.2	48.3	45.8
Aliskiren 75 mg	47.8*	-	59.9*	51.9*
Aliskiren 150 mg	48.2*	59.3*	59.3*	51.9*
Aliskiren 300 mg	63.7*	63.3*	68.0*	-63.9*
Aliskiren 600 mg	-	69.3*	-	-

HCTZ = hydrochlorothiazide
*P < .05 vs placebo.

Aliskiren 75-600 mg demonstrated comparable antihypertensive efficacy in men and women, both in patients aged < 65 years and those ≥ 65 years of age.

Addition of aliskiren 150-300 mg to other classes of antihypertensive drugs (diuretic, ACE inhibitor, ARB, or CCB) was associated with additional, mainly significant reductions in blood pressure (Table 7). No substantial additional blood pressure-lowering effect was seen with aliskiren added to valsartan, but this may have been due to the lower numbers (< 100) in this study, and more studies are needed to determine the effect of aliskiren in combination with ARBs, Dr. Weir commented.

Table 7. Change in Mean Sitting SBP (mm Hg) From Baseline With Addition of Aliskiren to Other Classes of Antihypertensive Drugs

Antihypertensive Drug	Monotherapy	Combination Therapy
		Aliskiren 150 mg	Aliskiren 300 mg
Ramipril 10 mg	-12.0		-16.6?
Valsartan 160 mg	-15.5	-16.6
Valsartan 320 mg	-16.5		-18.0
HCTZ 12.5 mg	-13.9	-17.6*	-19.8*
HCTZ 25 mg	-14.3	-19.5*	-21.2*
Amlodipine 5 mg	-5.0	-11.0?

HCTZ = hydrochlorothiazide; SBP = systolic blood pressure.
*P < .05
^?P < .0001 vs monotherapy

In placebo-controlled studies of aliskiren, tolerability of doses up to 300 mg once daily did not differ significantly from that of placebo (Table 8). Over the dose range of 75-600 mg, treatment-emergent adverse events were reported by 39.8% of aliskiren-treated patients compared with patients receiving placebo. The incidence of discontinuations due to an adverse event with aliskiren was low and similar to that seen with placebo. The most common adverse events with aliskiren, reported by ≥2% of patients, were headache, nasopharyngitis, and diarrhea. Headache showed a trend toward reduction in incidence with increase in dose. The incidence of diarrhea with aliskiren was significantly higher than with placebo overall (P < .05), due mainly to the effect of the 600-mg dose (9.5%; P < .0001 vs placebo) that was not seen with the 150- or 300-mg doses. Tolerability was not affected by addition of other agents to aliskiren.

Table 8. Rates of Adverse Events With Aliskiren Monotherapy

	Placebo n = 781	Aliskiren 75 mg n = 478	Aliskiren 150 mg n = 774	Aliskiren 300 mg n = 768	Aliskiren 600 mg n = 296	All aliskiren n = 2316
Any SAE	0.6%	0.6%	0.4%	0.5%	0.3%	0.5%
Any AE	40.2%	40.4%	37.5%	40.2%	43.9%	39.8%
Discontinuations due to AE	3.5%	1.7%	1.6%	2.6%	1.7%	1.9%
Adverse events reported by ≥2% of patients for aliskiren monotherapy overall:
Headache	8.7%	6.5%	5.4%*	5.7%*	5.1%	5.7%?
Nasopharyngitis	5.8%	7.1%	4.3%	3.8%	1.7%?	4.4%
Diarrhea	1.2%	1.3%	1.3%	2.3%	9.5%?	2.6%*

SAE = serious adverse event.
*P < .05
^?P < .01
^?P < .0001 vs placebo

Overall, > 95% of adverse events with aliskiren were mild or moderate in severity, and most were considered not to be related to study treatment. The incidence of laboratory abnormalities with aliskiren was similar to the incidence seen with placebo.

Dr. Weir expressed the hope that the mechanism of action will provide opportunities for risk reduction in cardiovascular and renal disease progression. The mechanism of action, however, remains to be determined. "We are still trying to fully understand the mechanism of action of ACE inhibitors, which we have had for 25 years, and ARBs, which we have had for > 11 years," he pointed out. "Now that we have renin inhibitors to use in clinical practice, he said, "I expect to see an evolution of scientific understanding." Dr. Weir believes that incremental attenuation of the RAS may prove to be more beneficial in some patients than in others. "Using ABPM and other surrogate measures such as proteinuria, we may be better able to explore the types of RAS inhibition that we use and ultimately the dose, because the dose response for vascular protection for these types of drugs might be quite a bit different from the dose response for office-based blood pressure determinations that we have traditionally used," he suggested. There may be ethnic differences in the response to renin inhibitors, and these are being studied along with the impact of dietary salt and potassium, Dr. Weir noted.

Clinical Trial Program

The cardiovascular outcome program with aliskiren, called "ASPIRE HIGHER," conducted by Novartis, includes 2 key studies, scheduled to begin in 2007, that aim to define the role of direct renin inhibition in primary and secondary prevention. Aliskiren in Visceral Obesity AT risk patients Outcomes Research (AVIATOR) is a prehypertension study to determine whether aliskiren delays the time to first major cardiovascular event in approximately 15,000 high-risk subjects. The ALiskiren Trial in Type 2 Diabetic nephropathy (ALTITUDE) will enroll approximately 6000 subjects to determine whether aliskiren delays the time to diabetic complications. Both these studies are scheduled to report results between 2011 and 2013.

A mega-trial program will address the long-term effects of decreasing PRA. The first studies, which will enroll 300-500 patients each, are scheduled to start in 2007 and will determine effects of aliskiren on surrogate markers of target organ damage. The first study, Aliskiren in the Evaluation of Proteinuria in Diabetes (AVOID), will compare the effects of aliskiren 300 mg with placebo over 6 months in patients with type 2 diabetes with proteinuria who have already treated with an ARB. The primary endpoint is percent reduction in urinary albumin/creatinine ratio. Aliskiren in Left Ventricular Hypertrophy (ALLAY) compares aliskiren 300 mg with losartan and the combination of both agents over 9 months in patients with left ventricular hypertrophy (LVH). The end point is LV mass by MRI. Both of these studies are expected to report results in late 2007. A post myocardial infarction trial of aliskiren in combination is due to start in 2006.

Aliskiren is in phase 2 trials to determine its role in the treatment of heart failure. The Aliskiren Observation of Heart Failure Treatment (ALOFT) study is evaluating the efficacy and safety of aliskiren 150 mg vs placebo in addition to standard therapy over 12 weeks in adults (aged ≥18 years) with hypertension and stable heart failure. The study aims to recruit 280 hypertensive patients with New York Heart Association class II-IV congestive heart failure and brain natriuretic peptide (BNP) > 150 pg/mL. The primary endpoint will be the reduction in BNP. Investigators report that early studies with aliskiren in heart failure suggest that it might be effective as part of triple-drug therapy, in combination with an ACE inhibitor and an ARB, or even as part of a 4-drug regimen consisting of aliskiren, ACE inhibitor, ARB, and aldosterone antagonist.

Other Renin Inhibitors in Development

Aliskiren is believed to have a 5-year lead over the next generation of renin inhibitors being developed by the pharmaceutical industry. The company responsible for the early development of aliskiren, Speedel (Basel, Switzerland), has another renin inhibitor, SPP635, in phase 1, with results expected to be announced in late 2006. A renin inhibitor also in phase 1 is being developed jointly by Actelion (Allschwil, Switzerland) and Merck (Whitehouse Station, New Jersey). Other companies have renin inhibitors at the preclinical stage.

References

1. Brookes L. New data on first-in-class oral renin inhibitor, aliskiren. Medscape Conference Coverage of the American Society of Hypertension 21st Annual Scientific Meeting and Exposition; May 16-20, 2006; New York, NY. Medscape Cardiology. 2006. Available at: http://www.medscape.com/viewprogram/5431.
2. Uresin Y, Taylor AA. Renin inhibitor aliskiren in combination with ACE inhibitor in diabetic patients with hypertension. Presented at the European Meeting on Hypertension; June 12-16, 2006; Madrid, Spain. [See Medscape Conference Coverage at http://www.medscape.com/viewprogram/5705.]
3. Sica D, Gradman A, Lederballe O, et al. Aliskiren, a novel renin inhibitor, is well tolerated and has sustained BP-lowering effects alone or in combination with HCTZ during long-term (52 weeks) treatment of hypertension. Eur Heart J. 2006;25(suppl):121.  P797.
4. Pool J, Gradman A, Kolloch R, et al. Aliskiren, a novel renin inhibitor, provides long-term suppression of the renin system, when used alone or in combination with hydrochlorothiazide in the treatment of hypertension. Eur Heart J. 2006;25(suppl):119.  P790.
5. Munger MA, Drummond W, Essop MR, et al. Aliskiren as add-on to amlodipine provides significant additional blood pressure lowering without increased oedema associated with doubling the amlodipine dose. Eur Heart J. 2006;25(suppl):117. : P784.
6. Kilo C, Taylor A, Tschoepe D, et al. Aliskiren, a novel renin inhibitor for treatment of hypertension, enhances renin system suppression by reducing plasma renin activity alone or in combination with ramipril in patients with diabetes. Eur Heart J. 2006;25(suppl):118.  P789.
7. Weir M, Bush C, Zhang J, et al. Antihypertensive efficacy and safety of the oral renin inhibitor aliskiren in patients with hypertension: a pooled analysis. Eur Heart J. 2006;27(suppl):299.  1796.

Given the medical need for maintenance of anticoagulation in so many medical situations, particularly in cardiovascular patients, and given the many challenges posed for patients and healthcare givers alike by the present options, the search for safe and effective alternatives to warfarin can be seen as urgent. The most recent candidates are the direct thrombin inhibitors, which have failed so far to offer a definitive alternative, and direct inhibitors of activated factor X (factor Xa). Several presentations at the recent World Congress of Cardiology (WCC) in Barcelona, Spain, revealed data from early clinical studies with factor Xa inhibitors that represented crucial steps in the development of these new anticoagulants and their progression to next-phase clinical trials.

Phase 2 Studies With Rivaroxaban (BAY 59-7939)

Two dose-finding studies from the phase 2 program investigating rivaroxaban for the initial treatment and secondary prophylaxis of symptomatic, proximal deep vein thrombosis (DVT) were presented at the WCC.

• The ODIXa-DVT (Oral DIrect factor Xa inhibitor - Bay 59-7939 in patients with acute symptomatic Deep Vein Thrombosis) trial investigated rivaroxaban given at dosages of 10, 20, and 30 mg twice daily and 40 mg once daily.^[1]
  
  
• The EINSTEIN-DVT study used once-daily rivaroxaban doses of 20, 30 and 40 mg.^[2]

Together, ODIXa-DVT and EINSTEIN-DVT enrolled 1156 patients with acute, symptomatic DVT. Both studies assessed rivaroxaban against the active control, standard therapy of parenterally administered heparin, such as a low-molecular-weight heparin (LMWH, eg, enoxaparin) or unfractionated heparin, followed by a vitamin K antagonist (eg, warfarin) for up to 12 weeks. In ODIXa-DVT, rivaroxaban reduced clot size after 21 days and at 3 months with low rates of venous thromboembolism (VTE) recurrence. Similar results were seen in the EINSTEIN-DVT study. Overall, the rate of recurrent DVT was low across all groups and similar across all rivaroxaban doses, and there was similar efficacy between standard therapy and all of the rivaroxaban doses tested.

Background

Rivaroxaban is a new, novel, oral, direct factor Xa inhibitor in clinical development for the prevention and treatment of thromboembolic disorders The drug is being developed jointly by Bayer (Leverkusen, Germany) and Scios (Freemont, California), a Johnson & Johnson company. Rivaroxaban is > 10,000-fold more selective for factor Xa than related serine proteases and does not require a cofactor (eg, antithrombin). It inhibits prothrombinase and clot-bound factor Xa activity in addition to free factor Xa activity, and regulates thrombin generation. In animal models, rivaroxaban effectively prevented venous and arterial thrombosis when given prophylactically, and was effective at treating VTE and preventing thromboembolic death. Bleeding times were not significantly prolonged at antithrombotic rivaroxaban doses.

The pharmacokinetics of rivaroxaban in healthy subjects were predictable and dose proportional at steady state, and inhibition of factor Xa activity and prolongation of prothrombin time associated with rivaroxaban correlated closely with its plasma concentrations. Studies in healthy subjects showed that rivaroxaban does not prolong the QTc interval, and has no clinically relevant interaction with aspirin or digoxin. Its predictable pharmacology and low propensity for food and drug interactions suggest that rivaroxaban is unlikely to require routine coagulation monitoring. Phase 2 studies of rivaroxaban for the prevention of VTE after major orthopaedic surgery demonstrated that rivaroxaban was effective and well tolerated, with a wide therapeutic window.

According to Prof. Harry B?ler, MD, PhD (Academic Medical Center, Amsterdam, The Netherlands), principal investigator of EINSTEIN-DVT, "All the doses of rivaroxaban studied provided effective anticoagulation, with a low incidence of recurrent VTE in both studies in patients with symptomatic deep vein thrombosis. Moreover, the efficacy and safety of all doses of rivaroxaban were similar to the standard therapy -- typically a heparin followed by warfarin."

Commenting on the safety in both of the studies, Prof. Giancarlo Agnelli, MD (University of Perugia, Italy), lead investigator of ODIXa-DVT, said, "Importantly, rivaroxaban showed a favorable safety profile with low rates of any bleeding or adverse events, and no signal for liver toxicity. No study arm was stopped and all the doses tested, irrespective of the dosing regimen, were considered safe and effective in this setting."

The results of these studies supported the decision to proceed with phase 3 clinical trials. These will be carried out for 2 chronic indications: stroke prevention in atrial fibrillation and treatment of venous thromboembolism. The first regulatory filing in a chronic indication is expected in 2009. Rivaroxaban is already in phase 3 clinical development for VTE prevention after major elective orthopaedic surgery. The RECORD (REgulation of Coagulation in major Orthopaedic surgery reducing the Risk of DVT and PE) study program began in December 2005. A filing for this indication is anticipated for late 2007.

ODIXa-DVT

ODIXa-DVT enrolled 613 patients aged > 18 years with acute, symptomatic, objectively confirmed, proximal DVT, without symptomatic pulmonary embolism (PE). Patients were randomized to 3 months' double-blind rivaroxaban 10, 20, or 30 mg twice daily, 40 mg once daily, or open-label, oral vitamin K antagonist (eg, warfarin) with initial subcutaneous enoxaparin (1 mg/kg twice daily, until a stable INR of 2.0-3.0 was maintained for 2 consecutive days).

All endpoints were centrally adjudicated without knowledge of treatment allocation. The primary efficacy endpoint was reduced thrombus burden (≥ 4-point improvement in thrombus score based on complete compression ultrasound) without recurrent VTE (recurrence or extension of DVT, PE, or VTE-related death) at Day 21. Thrombus regression after 21 days of treatment was achieved in 43.8%-59.2% of the rivaroxaban-treated patients and in 45.9% of patients treated with active comparator (Table 1). There was no significant dose-response relationship with rivaroxaban given twice daily for the primary efficacy endpoint (P = .67). Thrombus regression at Day 84, the secondary efficacy endpoint, was achieved in 76.2%-92.5% of the rivaroxaban-treated patients and in 81.3% of patients treated with active comparator.

Table 1. ODIXa-DVT: Primary and Secondary Efficacy Endpoints

	Rivaroxaban				Enoxaparin/ VKA (n = 109)
	10 mg BID (n = 100)	20 mg BID (n = 98)	30 mg BID (n = 109)	40 mg OD (n = 112)
Primary efficacy endpoint (95% CI)	53.0% (42.8, 63.1)	59.2% (48.8, 69.0)	56.9% (47.0, 66.3)	43.8% (34.4, 53.4)	45.9% (36.3, 55.7)
Secondary efficacy endpoint (95% CI)	78.0% (68.1, 86.0)	79.5% (69.6, 87.4)	82.5% (73.4, 89.4)	76.2% (66.7, 84.1)	81.3% (72.0, 88.5)

BID = twice daily; CI = confidence interval; OD = once daily; VKA = vitamin K antagonist;% CI = 95% confidence interval

The incidence of nonfatal PE and recurrent DVT within 3 months of study treatment was low (Table 2). There were 2 VTE-related deaths (fatal PE) on rivaroxaban.

Table 2. ODIXa-DVT: Secondary Efficacy Endpoints: Symptomatic Recurrent VTE at 3 Mos

	Rivaroxaban				Enoxaparin/ VKA (n = 112)
	10 mg BID (n = 106)	20 mg BID (n = 100)	30 mg BID (n = 111)	40 mg OD (n = 114)
Nonfatal PE	0 (0.0%)	1 (1.0%)	1 (0.9%)	1 (0.9%)	0 (0.0%)
Recurrent DVT	1 (0.9%)	1 (1.0%)	1 (0.9%	1 (0.9%)	1 (0.9%)
VTE related death(fatal PE)	1 (0.9%)	0 (0.0%)	0 (0.0)%	1 (0.9%)	0 (0.0%)

BID = twice daily; DVT = deep vein thrombosis; PE = pulmonary embolism; OD = once daily; VKA = vitamin K antagonist; VTE = venous thromboembolism

The incidence of major bleeding, the primary safety endpoint, was low in all the rivaroxaban groups (Table 3). There was no significant dose-response relationship between the twice-daily dosing schedule of rivaroxaban and major bleeding (P = .39).

Table 3. ODIXa-DVT: Safety Results

	Rivaroxaban				Enoxaparin/ VKA (n = 126)
	10 mg BID (n = 119)	20 mg BID (n = 117)	30 mg BID (n = 121)	40 mg OD (n = 121)
Major bleeding (95% CI)	2 (1.7%) (0.2, 5.9)	2 (1.7%) (0.2, 6.0)	4 (3.3%) (0.9, 8.2)	2 (1.7%) (0.2, 5.8)	0 (0.0%) (0.0, 2.9)

BID = twice daily; CI = confidence interval; OD = once daily; VKA = vitamin K antagonist

There was no signal for liver toxicity associated with 3 months' treatment with rivaroxaban. The incidence of treatment-emergent alanine aminotransferase (ALT) elevations > 3x the upper limit of normal (ULN) was lower in the rivaroxaban groups than in the comparator group within the first 21 days, and there were no significant differences after 21 days.

EINSTEIN-DVT

The aim of this randomized, multinational, double-blind (for rivaroxaban), open-label, active-comparator-controlled study was to determine the optimum once-daily dose of rivaroxaban for the treatment of DVT, relative to standard therapy (LMWH/heparin plus a vitamin K antagonist).

A total of 543 patients with confirmed, acute, symptomatic DVT, but not concomitant PE, were randomized to oral rivaroxaban 20, 30, or 40 mg once daily, or vitamin K antagonist (warfarin, acenocoumarol, phenprocoumon, or fluindione) with LMWH/heparin (tinzaparin, enoxaparin, or unfractionated heparin was administered until the vitamin K antagonist induced a stable INR > 2). Treatment continued for 12 weeks. Assessments of bleeding times were performed within 36 hours of randomization and at the end of treatment.

The primary efficacy endpoint was a composite of symptomatic, recurrent DVT or symptomatic PE (fatal or nonfatal), and deterioration of the thrombotic burden, assessed by compression ultrasound and a perfusion lung scan at Week 12. This occurred in 6.0% of the combined groups of patients receiving rivaroxaban compared with 9.9% of patients receiving standard therapy (Table 4). There was no significant dose-response relationship with rivaroxaban for the primary efficacy endpoint (P = .8615). Symptomatic VTE events were reported in 1.7%-3.6% of patients on rivaroxaban compared with 6.9% of patients on standard therapy.

Table 4. EINSTEIN-DVT: Efficacy Results

	Rivaroxaban			Standard Therapy (n = 101)
	20 mg OD (n = 115)	30 mg OD (n = 112)	40 mg OD (n = 121)
Primary efficacy endpoint (95% CI)	7 (6.1%) (2.5, 12.1)	6 (5.4%) (2.0, 11.3)	8 (6.6%) (2.9, 12.6)	10 (9.9%) (4.9, 17.5)
Secondary efficacy endpoints:
Nonfatal PE	1 (0.9%)	1 (0.9%)	0 (0.0%)	1 (1.0%)
Recurrent DVT	2 (1.7%)	1 (0.9%)	1 (0.8%)	7 (6.9%)
VTE-related death	0 (0.0%)	2 (1.8%)	1 (0.8%)	0 (0.0%)

CI = confidence interval; DVT = deep vein thrombosis; OD = once daily; PE = pulmonary embolism; VTE = venous thromboembolism

Clinically relevant bleeding, the primary safety endpoint, occurred in 4.7% of the combined groups of patients receiving rivaroxaban compared with 8.8% of those on standard therapy (Table 5). A dose-dependent decrease in clinically relevant bleeding was suggested, but not confirmed (P = .1445). The incidence of major bleeding was low and there was no apparent dose dependency with rivaroxaban for major bleeding (P = .4707).

Table 5. EINSTEIN-DVT: Safety Results

	Rivaroxaban			Standard Therapy (n = 137)
	20 mg OD (n = 135)	30 mg OD (n = 134)	40 mg OD (n = 136)
Clinically relevant bleeding (95% CI [%])	8 (5.9%) (2.6, 11.3)	8 (6.0%) (2.6, 11.4)	3 (2.2%) (0.5, 6.3)	12 (8.8%) (4.6, 14.8)
Major bleeding	1 (0.7%)	2 (1.5%)	0 (0.0%)	2 (1.5%)

CI = confidence interval; OD = once daily

There appeared to be no substance-specific effects on laboratory parameters, including liver enzymes, during the 12 weeks of treatment.

Animal Model

The results of a study that compared the antithrombotic effects of rivaroxaban with enoxaparin in various rodent arterial and venous thrombosis models were also presented by researchers from Bayer Health Care (Wuppertal, Germany).^[3] Pretreatment with rivaroxaban or enoxaparin dose-dependently inhibited both venous and arterial thrombosis. The effective doses of rivaroxaban were similar in all the arterial models, and rivaroxaban was more potent than enoxaparin. In the venous model, lower doses of both rivaroxaban and enoxaparin were required to inhibit thrombosis, and enoxaparin was more potent than rivaroxaban. The effective doses of enoxaparin differed between the arterial and venous models to a much greater extent than for rivaroxaban.

The researchers believe that their findings suggest that direct inhibition of factor Xa may be a preferable strategy to antithrombin-dependent inhibition for the prevention of arterial thrombotic diseases.

Otamixaban (XRP0673) -- SEPIA-PCI

Otamixaban, a novel, parenteral, synthetic small molecule, is currently being studied for possible use in patients with acute coronary syndrome (ACS) and/or those undergoing percutaneous coronary intervention (PCI). Potential advantages of this agent, in addition to direct inhibition of factor Xa, include proximal inhibition of the coagulation cascade, reversible and short initial half-life (20-30 min), elimination via feces/bile, and no significant renal elimination. The compound is being developed by sanofi-aventis (Basel, Switzerland).

The latest results came from the Study to Evaluate Pharmacodynamics, Safety and Tolerability, and Pharmacokinetics of Several Intravenous Regimens of Factor Xa Inhibitor Otamixaban (XRP0673), in Comparison to Intravenous Unfractionated Heparin, in Subjects Undergoing Non-Urgent Percutaneous Coronary Intervention (SEPIA-PCI).^[4] SEPIA-PCI was a phase 2, randomized, double-blind, double-dummy, parallel-group, dose-ranging study carried out in 10 countries in North America, Europe, and South Africa. The results were presented by lead investigator Marc Cohen, MD (Newark Beth Israel Medical Center, New Jersey).

Patients undergoing nonurgent PCI were randomized to receive 1 of 5 otamixaban regimens (an intravenous bolus followed by a 3-hour intravenous infusion or unfractionated heparin (weight-adjusted intravenous bolus[es] to achieve target activated clotting time as per current guidelines), prior to PCI. Other treatments included aspirin, clopidogrel, and optional glycoprotein IIb/IIIa inhibitors. A total of 947 patients (median age, 63 years; 77% male) participated in the study.

The highest dose of otamixaban (Dose 5, 0.14 mg/kg/0.2 mg/kg/hour) reduced F1+F2 significantly more than unfractionated heparin did (Table 6). There was no dose response for the Day 30 composite efficacy endpoint (death, myocardial infarction, and target vessel revascularization). There was a dose response for TIMI bleeding at Day 3; fewer bleeds occurred than with unfractionated heparin among lower otamixaban doses and more bleeds occurred than with unfractionated heparin across higher otamixaban doses. Most bleeds were minimal. These data will aid in the design of clinical investigations of otamixaban for the treatment of ACS.

Table 6. SEPIA-PCI: Results

(mg/kg / mg/kg/hr)	Dose 1 (.025/.035)	Dose 2 (.045/.065)	Dose 3 (.080/.120)	Dose 4 (.120/.160)	Dose 5 (.140/.200)	UFH
Prothrombin fragment F1+F2 (nmol/L) change from baseline (median)	-0.2	-0.3	-0.2	-0.2	-0.3	-0.2
Comparison vs UFH	ND	ND	ND	P = .1191	P = .008
Anti-Xa (ng/mL) at end of infusion (median)	64.51	154.59	393.31	571.32	691.04
Comparison with dose 1		P<.0001	P<.0001	P<.0001	P < .0001
TIMI major/minor/ minimal bleeding at Day 3 or hospital discharge	37 (24.8%) (N = 149)	65 (42.2%) (N = 154)	66 (41.8%) (N = 158)	77 (49.7%) (N = 155)	86 (55.1%) (N = 156)	59 (37.3%) (N = 158)
Comparison vs UFH	P = .018	P = .402	P = .410	P = .03	P = .002
Triple composite endpoint (death, MI, or TVR)	9 (5.8%) (N = 155)	11 (7.1%) (N = 155)	6 (3.8%) (N = 159)	4 (2.5%) (N = 159)	8 (5.1%) (N = 157)	9 (5.6%) (N = 160)
Comparison vs UFH	P = .948	P = .601	P = .431	P = .150	P = .834
Median aPTT at end infusion	42.0	46.0	61.0	68.0	81.0

aPTT = activated partial thromboplastin time. MI = myocardial infarction. TVR = target vessel revascularization. UFH = unfractionated heparin

A similar dose-ranging, randomized, double-blind, phase 2 trial is ongoing to compare the efficacy and safety of 5 intravenous regimens of otamixaban with an active control of unfractionated heparin and eptifibatide in patients with mild to moderate non-ST elevation ACS scheduled to undergo an early catheterization and PCI. The SEPIA-TIMI 42 trial aims to enroll around 2700 patients. The study began in June 2006, and key results are expected to be available in the beginning of 2008.

DU-176b

The orally active direct factor-Xa inhibitor, DU-176b, is in phase 2 clinical trials in the United States, Europe, and Japan with Daiichi Sankyo (Tokyo, Japan). The first clinical data on DH-176b, also presented earlier this year at the 55th Annual Scientific Session of the American College of Cardiology (ACC'06), held March 11-14 in Atlanta, Georgia,^[5] suggest that DU-176b may be useful for preventing arterial as well as venous thrombosis, with a significantly wide therapeutic window.^[6]

Mohammad Urooj Zafar, MD, and other researchers from Mount Sinai School of Medicine, New York, NY, carried out a phase 1 study using a single 60-mg dose of DU-176b in 12 healthy adults in an ex vivo model of thrombosis. Venous thrombosis was reduced by 28% at 1.5 hours and by 21% at 5 hours, and arterial thrombosis fell by 26% and 17%, respectively, over the same period (Table 7). The anti-factor Xa activity peaked at 1.5 hours, returning to normal by 12 hours post dose. The antithrombotic effect mirrored changes in the clotting parameters, which could be used for monitoring in a clinical setting. The implications of tissue factor pathway inhibition by DU-176b as a new therapeutic tool require further study in larger clinical trials, Dr. Zafar said.

Table 7. Effects of DU-176b on Thrombus Formation and Clotting Parameters

	Pretreatment	Post Dose (hrs)
		1.5	5	12
Venous thrombosis (reduction)	-	28%*	21%*	3%
Arterial thrombosis (reduction)	-	26%*	17%*	3%
Thrombin generation ETP (reduction)	-	27%*	10%*	-3%
Anti-Xa activity (IU/mL)	-	3.6 ? 1.6)	1.6 ? 0.3	0.3 ? 0.2
Drug level (mg/mL)	-	240 ? 5.4	127 ? 22	37 ? 10
PT (sec)	13.4 ? 0.7	20.3 ? 1.9*	17.5 ? 1.5)*	14.7 ? 0.7*
aPTT (sec)	32.3 ? 3.2	41.1 ? 5.4*	37.8 ? 3.9*	33.6 ? 3.1*
INR	1.1 ? 0.1	2.2 ? 0.4*	1.7 ? 0.3*	1.3 ? 0.1*

*P<.05 vs pretreatment.
aPTT = activated partial thromboplastin time; ETP = endogenous thrombin potential. INR = international normalized ratio; PT = prothrombin time

TGN 255

TGN 255 is an intravenous anticoagulant, initially being developed for anticoagulation in hemodialysis by Trigen (London, UK). TGN 255 is intended to overcome many of the issues associated with heparin use. Subsequent indications for TGN 255 will be for anticoagulation during cardiovascular procedures including PCI, peripheral arterial revascularization, and coronary artery bypass graft (CABG) surgery. Previous studies, including a phase 2 trial in patients undergoing chronic hemodialysis, suggested that it has the appropriate pharmacokinetic and pharmacodynamic properties of selectivity, highly predictable dose-response relationships with clinically relevant markers of coagulation, and rapid onset and appropriate offset of effect. The new results of a phase 1 interaction study between TGN 255 and aspirin plus clopidogrel showed that the combination did not affect the pharmacokinetic or pharmacodynamic parameters of TGN 255 in healthy males.^[7]

Twelve subjects (aged 18-55 years) received TGN 255 alone, aspirin plus clopidogrel alone, or TGN 255 plus aspirin plus clopidogrel. A dose of 80 mg/hour of TGN 255 was administered as an intravenous infusion over 6 hours on Day 1. Two single doses of aspirin and clopidogrel were given, 300 mg and 150 mg, respectively, on the day before and then 300 mg plus 75 mg just before administration of TGN 255 on Day 1. The plasma concentration of TGN 255 during the infusion was maintained above 2 mcg/mL, and the aspirin plus clopidogrel combination did not influence the pharmacokinetic parameters of TGN 255. The observed increases of thrombin time, activated partial thromboplastin time, and prothrombin time were similar whether TGN 255 was administered alone or on top of aspirin plus clopidogrel. The data support further clinical evaluation of TGN 255 in combination with aspirin plus clopidogrel in relevant patient populations, Trigen researchers concluded.

References

1. Agnelli G, Gallus A, Goldhaber S, et al. Treatment of acute, symptomatic, proximal deep vein thrombosis with the oral, direct factor Xa inhibitor rivaroxaban (BAY 59-7939) - the ODIXa-DVT dose-ranging study. Eur Heart J. 2006;27(suppl):761.  P4569.
2. B?ler HR, on behalf of the EINSTEIN-DVT study group. Once-daily treatment with an oral, direct factor Xa inhibitor - rivaroxaban (BAY 59-7939) - in patients with acute, symptomatic deep vein thrombosis. The EINSTEIN-DVT dose-finding study. Eur Heart J. 2006;27(suppl):761.  P4568.
3. Perzborn E, Arndt H, Fischer E, et al. Antithrombotic effects of rivaroxaban - an oral direct factor Xa inhibitor - in models of arterial and venous thrombosis: comparison with enoxaparin, an antithrombin-dependent anticoagulant. Eur Heart J. 2006;27(suppl):762.  P4571.
4. Cohen M, Bhatt DL, Alexander JH, et al. SEPIA-PCI: a randomized, double-blind, d