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American Society of Hypertension and European Congress of Rheumatology/European League Against Rheumatism
American Society of Hypertension
Research on fixed-dose combination therapy for hypertension, as it has in recent years, took center stage at the American Society of Hypertension (ASH) Annual Meeting and Exposition from May 21 to 24, 2011, in New York City. Approximately 2,500 hypertension specialists and other health professionals attended the sessions. Four fixed-dose clinical trials and a review of the effects of coffee/caffeine intake are presented.
A Focus on Fixed-Dose Combinations
Azilsartan (Edarbi) Plus Chlorthalidone May Be Superior to Olmesartan Plus Hydrochlorothiazide (Benicar HCT) in Stage 2 Systolic Hypertension
- William C. Cushman, MD, University of Tennessee College of Medicine, Memphis, Tenn.
- Robert A. Phillips, MD, PhD, University of Massachusetts Medical School, Worcester, Mass.
Azilsartan medoxomil (Edarbi, Takeda), an angiotensin II receptor blocker (ARB) approved by the FDA in February 2011, has demonstrated superior blood pressure (BP)-lowering effects in clinical trials. Similarly, chlorthalidone (CLD), a potent, long-acting thiazide-like diuretic, has been shown to be more effective than hydrochlorothiazide (HCTZ) and very well tolerated in clinical trials, Dr. Cushman said at an ASH late-breaking clinical trial press conference.
In the first, large forced-titration study of a fixed-dose combination of an ARB with CLD, fixed-dose combinations of azilsartan/CLD 20 mg/12.5 mg once daily, force-titrated to 40/25 mg or 40/12.5 mg once daily, then force-titrated to 80/25 mg, was compared with a fixed-dose combination of olmesartan (Benicar HCT, Daiichi Sankyo) plus HCTZ 20 mg/12.5 mg once daily, force-titrated to 40/25 mg (the highest approved dose). The 12-week phase 3, multicenter, double-blind, randomized study included 1,071 patients (mean age, 57 years) with a mean body mass index (BMI) of 31.6 kg/m2.
Mean systolic BP in these patients was between 160 and 190 mm Hg; diastolic BP was 119 mm Hg or below. The primary endpoint was the change from baseline to week 12 in trough sitting systolic BP. Mean baseline systolic BP was approximately 165 mm Hg. (Stage 2 hypertension is normally defined as a reading above 160/100 mm Hg.)
At 12 weeks, clinical systolic BP was reduced by 42.5 and 44 mm Hg in the azilsartan/CLD 40/25-mg and 80/25-mg groups, respectively, compared with 37.1 mm Hg in the olmesartan/HCTZ 40/25-mg group (P < 0.001 for both azilsartan combinations vs. olmesartan/HCTZ). The azilsartan/CLD patients also experienced significantly greater changes in 24-hour mean systolic BP, assessed via ambulatory monitoring (−33.9 mm Hg for 40/25 mg and −36.3 for 80/25 mm Hg, compared with −27.5 mm Hg for olmesartan/HCTZ; P < 0.001 for both azilsartan groups).
Overall, tolerability was relatively similar for the lower dose of azilsartan/CLD and the maximum approved dose of olmesartan/HCTZ. Permanent drug discontinuations, however, were more frequent in patients receiving azilsartan/CLD 80/25 mg (14.8% vs. 8.7% for azilsartan/CLD 40/25 mg, respectively, and 7.1% for olmesartan/HCTZ 40/25 mg, respectively).
Acknowledging the effects of the greater BP-lowering capacity of CLD compared with HCTZ on the trial results, Dr. Phillips, the ASH press conference moderator, commented:
“If olmesartan had been combined with 25 mg of CLD, the blood pressure reductions would likely have been more similar between the azilsartan and olmesartan groups.”
He pointed out that olmesartan and CLD are not available as a fixed-dose combination tablet.
Olmesartan (Benicar) May Be More Effective Than Losartan (Cozaar)
- Henry A. Punzi, MD, Clinical Assistant Professor, University of Texas Southwestern Medical School, Dallas, and Punzi Medical Center and Trinity Hypertension Research Institute, Carrollton, Tex.
Angiotensin receptor blockers (ARBs) have shown efficacy in lowering hypertension with 24-hour coverage, safety, and adverse-event (AE) profiles similar to those of placebo. However, important pharmacological differences among ARBs may affect their efficacy, as witnessed by monotherapy studies showing that olmesartan medoxomil (Benicar) 20 to 40 mg once daily lowered BP more effectively than losartan potassium (Cozaar, Merck) 50 to 100 mg once daily.
Dr. Punzi and colleagues conducted a phase 4 prospective, forced-titration trial evaluating the comparative efficacy of olmesartan and losartan after six weeks at once-daily maximum doses of olmesartan 40 mg and losartan 100 mg following a run-in period. The main efficacy endpoint was the change from baseline in sitting diastolic BP at week 8.
For enrollment into the study, patients’ mean sitting systolic BP had to be 180 mm Hg or below, and diastolic BP had to be between 95 and 115 mm Hg at two consecutive visits. The study included 941 subjects.
Among treatment-naive subjects, baseline BP measurements were 157.4 ± 10.9/101.8 ± 4.3 mm Hg in the olmesartan group and 156.3 ± 10.8/101.1 ± 3.9 mm Hg in the losartan group. Among treatment-experienced subjects, baseline BP values were 158.4 ± 10.2/100.9 ± 4.0 mm Hg with olmesartan and 158.8 ± 10.1/101.3 ± 4.2 mm Hg with losartan.
The analysis showed that olmesartan lowered diastolic BP significantly more than losartan at week 8 in the treatment-naive population (−9.7 mm Hg vs. −6.6 mm Hg, respectively; P = 0.0232) and in the non–treatment-naive population (−9.6 mm Hg vs. −7.3 mm Hg, respectively; P = 0.0013).
More subjects receiving olmesartan therapy achieved their target goals (BP below 140/90 mm Hg at any time during randomized treatment) whether or not they had previously received antihypertensive medications (42.6% receiving olmesartan vs. 27% receiving losartan; P < 0.05). Ambulatory BP measurements showed that both treatments enabled BP reductions throughout the 24-hour dosing interval. Both drugs were also well tolerated with a low overall incidence of AEs in both treatment-naive and treatment-experienced patients.
“If someone with hypertension shows up who is not taking any medication or has been off medication for a while, you will have a much better reduction with this monotherapy and get about a 42% chance of going below 140/90 mm Hg with one pill,” Dr. Punzi said.
He also noted that a systolic BP reduction of 5 mm Hg could reduce heart attacks by about 24% and strokes by almost 30%. Finally, he commented that although there is a strong dose response with olmesartan, there is none with losartan.
Olmesartan/Amlodipine (Azor) Plus HCTZ (Tribenzor) Is Well Tolerated in Older Patients: The TRINITY Study
- Stephen Chrysant, Professor of Medicine, University of Oklahoma College of Medicine, Oklahoma City, Okla.
- Suzanne Oparil, MD, Professor of Medicine, University of Alabama School of Medicine, Birmingham, Ala.
“Older people tend to have more hypertension, and it’s more difficult to control—partly because they have stiff blood vessels and more adverse reactions to drugs—because they are taking more of them,” Dr. Oparil said in an interview. Commenting further on the triple therapy tested in Dr. Chrysant’s clinical trial, she said that all three components have positive effects on vascular stiffness, whereas the diuretic also reduces volume and olmesartan decreases oxidative potential.
The study was a subgroup analysis of TRINITY (Triple Therapy with Olmesartan Medoxomil, Amlodipine, and HCTZ in Hypertensive Patients), which evaluated subjects with moderate-to-severe hypertension. The primary endpoint of the prespecified subgroup analysis was the long-term efficacy and safety of a three-drug combination: olmesartan 40 mg/amlodipine 5 or 10 mg (Azor) plus HCTZ 12.5 or 25 mg (Tribenzor, Daiichi Sankyo). During a 40-week, open-label extension period, an algorithm was used to model real-world clinical practice in patients both younger and older than 65 years of age. Titration to a higher dose was allowed if the BP goal of 140/90 mm Hg was not maintained or reached after week 16.
Among patients younger than 65 years of age (N = 1,698), mean sitting baseline BP (N = 1698) was 162.7/100.5 mm Hg in the olmesartan 40-mg/amlodipine 5-mg plus HCTZ 12.5-mg group and 172.9/103.2 mm Hg in the olmesartan 40-mg/amlodipine 10-mg plus HCTZ 25-mg group. Among those 65 years of age and older (N = 414), baseline BP was 168.9/96.4 mm Hg in the lower-dose combination group (olmesartan 40 mg/amlodipine 5 mg plus HCTZ 12.5 mg) and 179.3/96.8 in the higher-dose combination group (olmesartan 40 mg/amlodipine 10 mg plus HCTZ 25 mg).
At week 52 or early termination, mean diastolic BP ranged from 78.5 to 83.8 mm Hg in participants younger than age 65 and from 74 to 77.5 mm Hg in participants older than 65. In addition, the percentage of participants reaching BP goals ranged from 45% to 79.8% in those younger than age 65 and from 42.3% to 79.9% in those older than 65. The proportion of patients reaching lower targets of below 120/80 mm Hg ranged from 22.5% to 35.3% in those under 65 years of age and from 21.6% to 26.6% in those 65 years of age and older.
Most adverse events (AEs), predominantly dizziness, peripheral edema, nasopharyngitis, and upper respiratory tract infection, were mild or moderate and were similar in both age groups. Drug-related AE rates were 9.9% to 19.4% in patients younger than 65 years of age and 13.3% to 21.1% for those 65 years of age and older.
Long-term treatment with olmesartan/amlodipine/HCTZ in study participants, both younger and older than age 65, was well tolerated and effective, Dr. Chrysant concluded. BP goals were reached similarly regardless of age category.
She recommended: “Start with an ARB with amlodipine first and see what happens. If needed, add a diuretic in a fixed-dose triple combination.”
Initial Aliskiren Plus HCTZ (Tekturna HCT) Benefits Hypertensive Obese and Diabetic Patients
- Raymond R. Townsend, MD, Professor of Medicine and Hypertension Program Director, University of Pennsylvania, Philadelphia, Pa.
“The population with obesity, hypertension, and diabetes is hard to treat and has the most risk in terms of target organ damage—and therefore the greatest opportunity for target organ preservation,” Dr. Townsend said.
He presented a post hoc subgroup analysis of patients with a BMI exceeding 30 kg/m2 from an eight-week study of stage 2 hypertension (a mean systolic BP of between 160 and 200 mm Hg) and diabetes mellitus. Among 860 randomized patients, 607 were obese (mean age, 58 years, 70% Caucasian); the mean BMI was 38.8 kg/m2. The mean BMI in non-obese patients was 26.9 kg/m2.
Subjects received 150/12.5 mg of aliskiren/HCTZ (Tekturna, Novartis), a renin inhibitor, in a single-tablet combination or 5 mg of amlodipine (e.g., Norvasc) alone. Doses were doubled after one week, and treatment continued for another seven weeks. Mean systolic BP and diastolic BP at baseline was 167.5/92.2 mm Hg, respectively, in obese patients and 168.2/89.3 mm Hg, respectively, in non-obese patients.
Reporting the primary endpoint, Dr. Townsend said that after eight weeks of treatment in obese patients, aliskiren/HCTZ provided significantly larger mean reductions (−28.9 vs. −26.3 mm Hg) in systolic BP (the primary endpoint) than amlodipine (additional least-squares mean reduction of 2.6 mm Hg; P < 0.05). Among non-obese patients, the aliskiren/HCTZ additional reduction was nonsignificant (−28.6 vs. −26, respectively), which was a larger absolute reduction of 2.7 mm Hg but in a smaller group.
Also at eight weeks, rates of BP control (below 130/80 mm Hg) were significantly higher in the aliskiren/HCTZ group in both obese patients (22.9% vs. 14%; P < 0.01) and non-obese patients (24.6% vs. 13.1%; P < 0.01).
Although both treatments were well tolerated, peripheral edema was observed more frequently with amlodipine (15.2% for non-obese patients, 16.7% for obese patients vs. 0.8% and 2.6%, respectively, for aliskiren/HCTZ). Angiotensin-converting enzyme (ACE) inhibitors or ARB/HCTZ combinations, Dr. Townsend emphasized, can reduce peripheral edema rates by about half.
He concluded: “Aliskiren/HCTZ 300/25 mg provided significantly larger mean sitting systolic blood pressure reductions and greater blood pressure control rates than amlodipine 10 mg after eight weeks.”
Moderate Caffeine Intake Might Not Affect Hypertension: A Meta-Analysis
- Esther Lopez-Garcia, PhD, Department of Preventive Medicine and Public Health, School of Medicine, Autonoma University of Madrid, Madrid, Spain
Associations between coffee and caffeine and blood pressure (BP) among normotensive individuals have been widely studied and have consistently shown acute BP increases after caffeine intake. Cohort studies, however, have suggested that hypertension risk and cardiovascular risk (myocardial infarction and stroke) are not increased by habitual consumption.
“The effects of coffee and caffeine on already hypertensive patients, in whom even slight blood pressure increases may [cause] harm, however, have not been studied sufficiently to guide medical advice,” Dr. Lopez-Garcia pointed out.
To ascertain acute BP effects, longer-term associations between habitual coffee consumption and cardiovascular disease (CVD) and mortality risks among hypertensive individuals, Dr. Lopez-Garcia and colleagues conducted a survey of existing controlled trials to determine the effects of coffee and caffeine intake on BP.
The team identified five trials assessing acute effects (of less than one week) of caffeine on BP, five trials of longer-term effects of one week or more, and five cohort studies on associations between habitual coffee consumption and cardiovascular events. A meta-analysis of the acute studies (N = 500) showed an overall increase of 8.10 mm Hg (95% confidence interval [CI], 6.2–10) for systolic BP and 5.6 mm Hg (95% CI, 4.2–6.9) for diastolic BP. Acute BP increases lasted up to three hours.
In the four evaluable studies of longer-term effects of either a coffee-free or a caffeine-free diet or a diet including coffee or decaffeinated coffee, systolic BP changes varied (−0.9 mm Hg, −0.5 mm Hg, 1.5 mm Hg, and 5.2 mm Hg).
In the five studies of longer-term BP effects across varieties of subgroups, the net change ranged in a generally even distribution, from −7.1 to 5.2 mm Hg.
In five studies of habitual coffee consumption and cardiovascular risk in hypertensive individuals (N = 25,000), four studies found no associations, and one study noted a doubling of stroke risk.
Overall, the effects of coffee among hypertensive patients were similar to those in normotensive subjects. While still recommending moderation among individuals with uncontrolled hypertension, Dr. Lopez-Garcia said, “In those patients with well-controlled blood pressure, it may be safe to consume coffee.”
Dr. Lopez-Garcia’s research was supported by Ram n y Cajal Hospital of Madrid.
European Congress of Rheumatology/European League Against Rheumatism (EULAR)
More than 7,000 medical professionals attended the EULAR international conference in London from May 25 to 28, 2011. Three trials of substantial potential clinical significance stood out from the rest. They were an extension of a phase 3 study of pegloticase (Krystexxa) for gout, a phase 3 study of the investigational oral biologic tofacitinib for rheumatoid arthritis refractory to disease modifying anti-rheumatic drugs, and a large, long-term registry study of cancer incidence in arthritis patients receiving anti–tumor necrosis factor therapy.
Gout and Arthritis Therapies
Long-Term Gout Therapy With Pegloticase (Krystexxa) Therapy Is Safe and Effective
- Lee Simon, MD, Head Regulatory Consultant, Leerink Swann/MEDACorp, Boston, Mass.
- Maxime Dougados, MD, EULAR President and Professor of Rheumatology, René Descartes University, Paris, France
Data from an extension study of a 24-week phase 3 trial showed that gout patients who responded well to pegloticase (Krystexxa, Savient) also achieved prolonged improvement of symptoms. The drug was safe for up to 2.5 years.
“The findings are fantastic,” said commentator Dr. Dougados at a press briefing. He said that the results could contribute significantly to a re-examination of regulatory guidelines in Europe for gout treatment.
The goal of the 126-week extension trial was to determine the risks and benefits of the long-term use of pegloticase, with a focus on outcomes in patients treated every two weeks, the recommended regimen. In the previous 24-week study, researchers had enrolled 212 patients with gout that was refractory to conventional therapy. Of these patients, 84 (80% men) received 8 mg of pegloticase every four weeks; 85 patients (mean age, 56.3 years), with a mean disease duration of 15.4 years, received 8 mg pegloticase every two weeks; and 43 patients received placebo.
Analysis of the 24-week trial revealed that pegloticase 8 mg every two weeks normalized serum uric acid levels within 24 hours, and 36 of 85 subjects (42%) who were treated every two weeks became “persistent responders,” with uric acid levels below 6 mg/dL at six months. This group also achieved significant reductions of gout flares at 24 weeks (a mean of 6.6 painful flares per year at baseline). Most patients achieved no-flare status by the end of 24 weeks. Subjects who completed the 24-week trial entered the multiyear and open-label extension.
Among the 35 persistent responders entering the open-label extension, 19 chose to receive pegloticase therapy 8 mg every two weeks. Among these patients, 84% continued to have normalized uric acid levels for more than two years. Among subjects who chose pegloticase 8 mg every two weeks in the extension study, most were flare-free by its end.
In the 24-week trial, of the 58 subjects who at baseline and in the extension trial received pegloticase 8 mg every two weeks, 41 (71%) had tophi (chalky deposits of a uric acid compound) at baseline. By week 13 of the 24-week trial, 45% had achieved partial or complete tophus resolution. By week 50, or 26 weeks into the extension trial, 90% of the subjects had achieved complete or partial tophus resolution; 78% of all tophi had resolved completely (P < 0.006 from baseline). Outcomes were similar at weeks 78 and 102.
The investigators reported three infusion reactions after 609 infusions in the 24-week trial and three infusion reactions after 810 infusions in the extension trial (24 to 120 weeks).
Investigator and presenter Lee Simon, MD, concluded: “Prolonged administration for up to 2.5 years of pegloticase 8 mg every two weeks is safe and effective in subjects with persistent normalization of uric acid.”
Pegloticase is approved in the U.S. for the treatment of chronic gout refractory to conventional urate-lowering therapy. On May 26, 2011, Savient Pharmaceuticals announced that its Marketing Authorization Application had been accepted for review by the European Medicines Agency.
Savient supported this study.
Oral Tofacitinib Shows Efficacy and Safety In Refractory Rheumatoid Arthritis
- Joel Kremer, MD, Chief of Medicine, Albany Medical College, Albany, N.Y.
Patients with rheumatoid arthritis (RA) that has been refractory to one or more standard disease-modifying anti-rheumatic drugs (DMARDs) achieved reduced signs and symptoms of disease after receiving Pfizer’s investigational oral Janus kinase (JAK) inhibitor tofacitinib (formerly, tasocitinib, CP-690550).
In the first results from a 12-month phase 3 trial, both doses of the drug, 5 mg twice daily and 10 mg twice daily, were superior to placebo for all primary endpoints. Investigators enrolled 792 patients with RA who had not responded to DMARDs; 81.4% were women ranging from 50.8 to 53.3 years of age. Among these patients, 315 received tofacitinib 5 mg twice daily, 318 received 10 mg twice daily, and 159 received placebo. At month 3, all placebo subjects were randomly and blindly assigned to receive tofacitinib 5 mg twice daily (n = 79) or 10 mg twice daily (n = 80). At the sixth month, all patients were similarly advanced to the final six-month phase of the study without a change in the study medication.
Subjects received concurrent non-biologic background therapy with DMARDs. After six months of treatment, 52.7% of the 315 patients receiving tofacitinib 5 mg twice daily achieved at least a 20% clinical improvement in symptoms (ACR 20 criteria on the American College of Rheumatology scale), the first primary endpoint of the trial. Among the 318 patients receiving tofacitinib 10 mg, 58.3% achieved ACR 20. Among the 159 patients who began placebo therapy, 31.2% achieved ACR 20.
At the sixth month, more patients receiving tofacitinib achieved the second primary endpoint of clinical remission of disease, defined as a disease activity score based on a 28-joint count and the erythrocyte sedimentation rate (DAS28-4 ESR) response below 2.6. Only 2.8% of the placebo subjects achieved remission, compared with 11% of those receiving tofacitinib 5 mg twice daily (P = 0.001) and 14.8% of patients receiving 10 mg twice daily (P < 0.0001).
For the third primary endpoint, the investigators also evaluated changes from baseline to month 3 in the Health Assessment Questionnaire Disability Index (HAQ–DI). Those subjects receiving tofacitinib 5 mg twice daily achieved a 0.46 decline in scores, subjects receiving 10 mg twice daily achieved a 0.56 decline, and placebo patients achieved a 0.21 decline.
Reporting the 12-month safety analysis, Dr. Kremer said that four patients died during the trial. One cardiovascular death was considered by the adjudication committee to be unrelated to treatment. Another death might have been related to infections triggered by treatment, but the patient’s family’s refusal to allow an autopsy precluded verification. Four patients with drug-related opportunistic infections (two with tuberculosis, one with pneumonia, one with herpes) responded well to treatment.
Dr. Kremer concluded, “We hope that after careful consideration of benefit–risk equations, this compound will provide an additional valuable treatment option for patients who have experienced inadequate response to prior treatments.”
Anti–Tumor Necrosis Factor Agents for Arthritis Do Not Appear to Raise Cancer Risk: The DANBIO Registry
- Lene Dreyer, MD, PhD, Department of Rheumatology, Gentofte Hospital (Copenhagen University Hospital), Copenhagen, Denmark
An analysis of data from a Danish national registry study suggests that newer biologics used to treat arthritis, including infliximab (Remicade, Centocor), adalimumab (Humira, Abbott), certolizumab pegol (Cimzia, UCB), golimumab (Simponi, Merck), and etanercept (Enbrel, Pfizer), do not increase the risk of cancer overall.
Dr. Dreyer said: “Some studies have suggested that treatment with anti-TNF drugs may increase an individual’s risk of cancer, so our aim was to look at data on long-term use in a large population using a variety of anti-TNFs to see whether such treatment in Danish arthritis patients is associated with an increased cancer risk.”
Evaluating long-term data from patients in the Danish Biologics (DANBIO) national registry, researchers found that only 3% of subjects receiving anti-TNF therapy for arthritis were subsequently found to have a first cancer within nine years of initiating treatment. Overall risk did not change with the type of arthritis being treated.
Of the 13,699 patients with arthritis in the registry, 8,101 had not received anti–TNF agents previously; 5,598 had received anti-TNF treatment for RA (n = 3,496), psoriatic arthritis (n = 670), ankylosing spondylitis (n = 858), or another form of arthritis (n = 499). The investigators compared cancer incidence among patients who had received anti-TNF agents and anti–TNF-naive subjects for up to nine years after individual enrollment in the registry.
During a period of 23,965 person-years, a total of 313 cancers appeared in both groups; within nine years, cancer developed in 181 patients (3%) who received anti-TNF treatment. The incidence of cancer in patients receiving anti–TNF agents was the same as that in the anti–TNF-naive subjects, with a relative risk of 1.03 (95% CI, 0.82–1.30). No increased overall cancer risk was noted among men or women or in specific age groups.
The study was supported by grants from the Danish Rheumatism Association and the Danish Cancer Society.