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Despite JNC-7, Old Prescribing Practices Persist, While New First-Line Antihypertensive Drug Combinations Are Approved
Linda Brookes, MSc Published: 06/17/2009

The National Heart, Lung, and Blood Institute (NHLBI) initially thought the results of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) it supported should and would change the antihypertensive prescribing practices (and largely based their new Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure [JNC-7] guidelines on those results) -- but a new review of the evidence finds otherwise. Yet another substudy of the famous Losartan Intervention For Endpoint reduction in hypertension (LIFE) trial has teased out the protective value of increased high-density lipoprotein (HDL) cholesterol levels again, but it is the corresponding editorial commentary that draws the important treatment implications for practitioners. Finally this month, a flurry of approvals for new fixeddose combination treatments, plus 2 new antihypertensive drug classes underscore the continuing progress in treatment approaches for hypertension and resistant hypertension.

Effect of ALLHAT and JNC 7 on Initial Antihypertensive Drug Therapy Less Than Expected
The effect of the results of the ALLHAT, published in 2002 [1] and the release of the JNC 7 report[2] may not have had as great an effect as the authors hoped, according to the results of a new study. Lead author Paul Muntner, PhD (Mount Sinai School of Medicine, New York), and other US investigators report in Hypertension [3] that the initial effect of ALLHAT and JNC 7 was to reverse the previous decline in diuretic use as initial antihypertensive drug therapy. [4] Over the longer term, however, diuretic use has plateaued, and most patients are still not initiating treatment with a thiazide-type diuretic as part of their regimen. Based largely on the results of ALLHAT, along with other outcome trials in hypertension, JNC 7 recommended thiazide-type diuretics as initial pharmacologic treatment, alone or in combination with another drug, for most patients with hypertension. At that time the NHLBI, sponsor of ALLHAT and JNC 7, launched a physician and public education program aimed at incorporating this recommendation, among others, into clinical practice. To determine whether it has affected physician practice and prescribing patterns, Dr. Muntner and his colleagues compared antihypertensive medication prescriptions filled by patients who initiated pharmacologic antihypertensive treatment in a large managed care organization during 3 periods: (1) July 1, 2001, to June 30, 2002, before release of these publications (n = 1354); (2) July 1, 2003, to June 30, 2004, to assess short-term changes (n = 1542); and (3) July 1, 2004, to June 30, 2005, to assess extended changes (n = 1865). They found that the proportion of patients initiating antihypertensive treatment with a thiazide-type diuretic increased in 2001 to 2002 and 2003 to 2004 (from 30.6% to 39.4%; P < .001), but did not increase further in 2004 to 2005 (36.5%). This result is "impressive," but "highlights a substantial disconnect between the JNC 7 clinical guidelines and clinical practice," the researchers note. Overall, inclusion of -blockers as part of initial antihypertensive medication did not change (20.1% in 2001-2002 vs 19.0% in 2004-2005). Use of calcium-channel blockers (CCBs) as initial therapy

decreased in the short term (16.7% to 13.8%), but returned to pre-publication levels later (16.9% in 2004-2005). ALLHAT and JNC 7 appeared to have resulted in a reduction in the use of angiotensinconverting enzyme inhibitors as initial therapy, from 32.8% to 28.9% in 2001 to 2001 and 2004 to 2005. However, prescriptions of angiotensin receptor blockers (ARBs), a drug class that was not included as a treatment arm in ALLHAT, increased over the same period, from 8.6% to 15.9%. By 2004 to 2005, renin-angiotensin blocking agents were the class of antihypertensive drugs most often prescribed as initial treatment, alone or with other drugs.
Comment

In an editorial accompanying this analysis,[4] Canadian authors Ross D. Feldman, MD (University of Western Ontario, London), and Finlay A. McAlister, MD (University of Alberta, Edmonton), attribute the study's findings to "the fact that the ALLHAT message was not universally accepted by many key opinion leaders in the United States," which "undoubtedly negatively impacted its ability to influence practice." In addition, "divergent goals of the pharmaceutical companies representing non-ALLHAT recommended drugs" could have significantly lessened the impact of the study, they suggest. They point out that "a single study, no matter how large and how well done, may not be seen as the 'last word' in any field." Incorporating clinical trials' findings into clinical practice requires "a concerted effort," making use of strategies such as "pathways, real-time clinical reminders, disease management strategies, local opinion leaders, academic detailing, and audit and feedback," they say. Guideline developers should "foster active implementation processes that incorporate such proven strategies to ensure that the outstanding contribution of trialists such as the ALLHAT team move beyond the printed page and into clinical practice." Elsewhere, the ALLHAT findings have been revisited, to address some of the controversies and questions that arose from its initial publication, and the results reported in the Archives of Internal Medicine.[5] Jackson T. Wright Jr, MD, PhD (Case Western Reserve University Cleveland, Ohio), and other members of the ALLHAT Collaborative Research Group conclude, perhaps not surprisingly, that further analyses of ALLHAT data and the results of other trials and meta-analyses continue to support ALLHAT's original findings. Dr Wright and co-authors reiterate the original conclusions from ALLHAT that "neither the -blocker, angiotensin-converting enzyme inhibitor, nor the CCB surpasses the thiazide-type diuretics as initial therapy for control of blood pressure or reduction of cardiovascular or renal clinical outcomes (when compared at appropriate dosage)." They look forward to additional insights from continuing "passive follow-up of ALLHAT participants for morbidity and mortality using administrative databases."

LIFE Substudy Shows Smaller Decrease in High-Density Lipoprotein Cholesterol With Losartan, Associated With Greater Cardiovascular Benefit
Further evidence that stabilizing or increasing levels of HDL-C during treatment of hypertension is independently associated with a better outcome has emerged from the LIFE trial. In the Journal of Hypertension,[6] Michael Hecht Olsen, MD, PhD (University of Copenhagen, Glostrup, Denmark), and other LIFE trial investigators report the results of a substudy, previously reported in part at the 2005 annual meeting of the American College of Cardiology, [7] showing that a losartan-based regimen was associated with a lesser decrease in HDL-C compared with an atenolol-based regimen. They suggest that this smaller decrease in HDL-C could explain about one third of the beneficial effect of the

losartan-based regimen on cardiovascular morbidity and mortality compared with atenolol-based treatment seen in the LIFE trial.[8] The LIFE trial (supported by Merck) compared the effects of an ARB (losartan)-based regimen vs a blocker (atenolol)-based regimen on a composite primary endpoint of cardiovascular death, nonfatal stroke, and myocardial infarction in patients with hypertension (sitting blood pressure 160-200/95-115 mm Hg) and left ventricular hypertrophy. Dr. Olsen and colleagues analyzed data from 8611 patients with HDL-C measurements taken at baseline and annually during a mean of 4.8 years on losartanbased or atenolol-based treatment. HDL-C levels at baseline were similar in the 2 treatment groups. HDL-C decreased during the first 2 years of treatment and then increased steadily in both groups. The HDL-C decrease was smaller in the patients randomized to losartan compared with those randomized to atenolol (1.376 vs 1.20 mmol/L, respectively, at 2 years). HDL-C levels remained higher on losartan during the remainder of the study (1.42 vs 1.36 mmol/L, 1.47 vs 1.40 mmol/L, and 1.48 vs 1.42 mmol/L at 3, 4, and 5 years; all P < .001). The treatment difference was independent of baseline exercise, prior antihypertensive treatment, statin, or hydrochlorothiazide treatment, and could not be explained by changes in alanine aminotransferase. Although the decrease in HDL-C was less pronounced in patients with diabetes mellitus or the metabolic syndrome, treatment differences persisted. Baseline HDL-C 1.43 mmol/L was associated with a 50% reduction, and a median decrease from baseline to median in-treatment HDL-C of > 0.098 mmol/L was associated with a 70% increase in the composite primary endpoint.
Important Implications

Like the LIFE investigators, an editorial in the same issue of the Journal of Hypertension [9] points out that the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure-Lowering Arm (ASCOT-BPLA) was the first study to demonstrate that HDL-C levels could explain an outcome difference between 2 treatment regimens (amlodipine perindopril vs atenolol bendrofluazide) [10] and that the LIFE data are consistent with these findings. Editorialist Fabio Angeli, MD (Hospital Santa Maria della Misericordia, Perugia, Italy), and co-authors suggest that antihypertensive drugs might be divided into 2 broad categories: "lipid-hostile" and "lipid-beneficial/neutral." Another important message of the LIFE substudy, they say, is that the favorable prognostic effect of blood pressure reduction with any drug could be outweighed by an adverse effect on lipids. "The strong prognostic impact of HDL-C and its modifications of treatment on the risk of coronary events in hypertensive patients justifies any effort directed at raising HDL-C through lifestyle measures, statins, and antihypertensive drugs possibly devoid of adverse impact on lipid metabolism," they state.

First Fixed-Dose Triple Antihypertensive Combination Approved in the United States


The first fixed-dose combination pill containing 3 drugs has been approved for use in the United States by the US Food and Drug Administration (FDA). Exforge HCT, which is marketed by Novartis, combines the CCB amlodipine, the ARB valsartan, and the diuretic hydrochlorothiazide (HCTZ). [11] Exforge HCT is indicated for the treatment of hypertension, but not as an initial therapy. Tablets are available in fixed dosages of amlodipine/valsartan/hydrochlorothiazide of 5/160/12.5 mg, 10/160/12.5 mg, 5/160/25 mg, 10/160/25 mg, and 10/320/25 mg. Dosing is once daily. A patient may be switched to Exforge HCT or Exforge HCT may be added if blood pressure is not adequately controlled with any 2 antihypertensive drugs from the classes of CCBs, ARBs, and diuretics.

The FDA approval was based on the results of a double-blind, active-control study of Exforge HCT carried out in 2271 patients with moderate-to-severe hypertension (mean baseline systolic blood pressure/diastolic blood pressure [SBP/DBP] 170/107 mmHg).[12] Patients received treatments of amlodipine/valsartan/HTCZ 10/320/25 mg, valsartan/HCTZ 320/25 mg, amlodipine/valsartan 10/320 mg, or HCTZ/amlodipine 25/10 mg. At study initiation patients assigned to the 2-component arms received lower doses of their treatment combination while patients assigned to the Exforge HCT arm received 160/12.5 mg valsartan/HCTZ titrated to 5/160/12.5 mg after 1 week, while all other patients continued on their initial doses. After 2 weeks, all patients were titrated to their full treatment dose. At week 8, the triple combination therapy produced greater reductions in blood pressure than each of the 3 dual combination treatments (P < .0001 for DBP and SBP reductions). The reductions in SBP/DBP with Exforge HCT were 7.6/5.0 mm Hg greater than those with valsartan/HCTZ, 6.2/3.3 mm Hg greater than those with amlodipine/valsartan, and 8.2/5.3 mm Hg greater than those with amlodipine/HCTZ. The full blood pressure-lowering effect was achieved 2 weeks after being on the maximal dose of Exforge HCT. In a press release issued by Novartis,[13] David A. Calhoun, MD (University of Alabama at Birmingham), commented that "The majority of people with hypertension will require more than 1 medication to control their blood pressure and it is not uncommon for patients with severe hypertension and/or patients requiring stricter blood pressure control to need 3 or more medications. With a triple combination option, appropriate patients may experience a simpler routine of a convenient, once-daily pill to help them control their high blood pressure." In the United States, Exforge and Exforge HCT will be offered at the same price on a dose equivalent basis, so that the diuretic in Exforge HCT is essentially added at no additional cost. Exforge HCT is currently under review in the European Union. According to the JNC 7 report[3] most hypertensive patients will require 2 or more antihypertensive drugs for effective blood pressure control; and in hypertensive patients with lower blood pressure goals or with substantially elevated blood pressure, 3 or more antihypertensive drugs may be required.

Second Fixed-Dose Combination CCB/ARB Receives US Approval as FirstLine Antihypertensive Therapy


In May, the FDA approved the fixed-dose combination of a CCB and an ARB -- amlodipine plus olmesartan medoxomil -- as a first-line therapy for patients likely to need multiple antihypertensive agents to achieve their blood pressure goals.[15] Azor, marketed by Daiichi Sankyo, is the second CCB/ARB fixed dose combination to be approved in the United States as first-line therapy, following approval of Exforge. This indication for Azor is in addition to FDA marketing approval for treatment of hypertension other than as first line, granted in September 2007. Azor tablets are marketed in doses (amlodipine/olmesartan medoxomil content) of 5/20 mg, 10/20 mg, 5/40 mg, and 10/40 mg. Azor may now be used as initial therapy in patients who are likely to need multiple antihypertensive agents to achieve their blood pressure goals. Initial therapy with Azor is not recommended in patients 75 years of age or older or in hepatically impaired patients. Azor may be substituted for its individually titrated components. Azor may also be used to provide additional blood pressure lowering for patients in whom blood pressure is not adequately controlled with amlodipine (or another dihydropyridine CCB) alone, or with olmesartan medoxomil (or another ARB) alone.

The Azor first-line approval was based on data from a pivotal registrational trial that provided estimates of the probability of patients attaining blood pressure goals with Azor compared with amlodipine or olmesartan alone. The 8-week multicenter, randomized, double-blind, placebocontrolled, parallel group factorial study randomized 1940 patients with mild-to-severe hypertension to 1 of the following 12 treatment arms: placebo; monotherapy treatment with amlodipine 5 mg or 10 mg; monotherapy treatment with olmesartan medoxomil 10 mg, 20 mg, or 40 mg; or combination therapy with amlodipine/ olmesartan medoxomil at doses of 5/10 mg, 5/20 mg, 5/40 mg, 10/10 mg, 10/20 mg, and 10/40 mg. Patients discontinued their prior antihypertensive treatment. The mean baseline blood pressure of the study population was 164/102 mm Hg. Treatment with Azor resulted in statistically significant greater reductions in DBP and SBP compared with the respective monotherapy components, with similar effects in men and women, black and white patients, patients with and without diabetes, and patients 65 years of age and older and in those younger than 65 years of age. A total of 1684 patients entered a 44-week open-label extension and received combination therapy with amlodipine 5 mg plus olmesartan 40 mg. During the open-label extension, patients who did not achieve a blood pressure goal of < 140/90 mm Hg (< 130/80 mm Hg in patients with diabetes) were titrated to amlodipine/olmesartan 10/40 mg. Patients whose blood pressure was still not adequately controlled were offered additional HCT 12.5 mg and subsequently 25 mg as required to achieve adequate blood pressure goal. In a press release issued by Daiichi Sankyo,[16] Keith C. Ferdinand, MD (Emory School of Medicine, Atlanta, Georgia), said. "The approval of Azor as a first-line therapy gives doctors an important treatment option that may help the many patients who require multiple medications avoid several treatment steps to achieve their blood pressure goals. Fixed-dose combinations like Azor provide patients with a more convenient option than separate monotherapies, which may help simplify the treatment regimen and decrease overall pill burden." The JNC 7 report recommends that consideration should be given to initiating antihypertensive therapy with 2 drugs, either as separate prescriptions or in fixed-dose combinations, when blood pressure is more than 20 mm Hg above SBP goal or 10 mm Hg above DBP goal. [3] The initiation of therapy with more than 1 drug increases the likelihood of achieving blood pressure goal in a more timely fashion, the report says.

Initial Phase 3 Results With Endothelin Receptor Antagonist Darusentan Show Significant Blood Pressure Reductions in Resistant Hypertension
Darusentan, an oral, once-daily endothelin receptor antagonist, has been shown in a phase 3 clinical trial to reduce blood pressure significantly compared with placebo after 14 weeks in patients with resistant hypertension, defined as failure to achieve goal blood pressure while adhering to full doses of an appropriate 3-drug regimen that includes a diuretic. In the trial, half the patients on darusentan achieved their goal blood pressure compared with one fourth on placebo. The most frequently reported adverse events were related to fluid retention and/or edema; 5 patients taking darusentan reported cardiovascular events. Data from the trial (DAR-311) were presented at the 24th annual scientific meeting of the American Society of Hypertension held May 6-9, 2009 in San Francisco. [16] The trial is part of a clinical program known as DORADO (Fixed Doses of Darusentan as Compared to Placebo in Resistant Hypertension) being carried out by Gilead Sciences (Foster City, California), the company developing darusentan. Darusentan selectively blocks the endothelin type-A receptor, which if activated by endothelin-1 (ET-1), leads to vasoconstriction and cell proliferation. Elevated ET-1 blood

concentrations have been reported in some patients with hypertension, including several subgroups of hypertensive patients that have been historically difficult to treat. In an international phase 3 trial, 379 patients were randomized 7:7:7:11 to 1 of 3 doses of darusentan (50, 100, or 300 mg/day) or placebo for up to 14 weeks as an add-on to existing antihypertensive regimens. The mean patient age was 62 years old (39% older than 65). Mean body mass index was 32 kg/m2, 40% of patients were diabetic, and 25% had chronic kidney disease. At 14 weeks, mean reductions in trough sitting SBP of 16.5, 18.1, 18.1, and 8.6 mm Hg and in trough sitting DBP of 10.1, 9.9 , 10.7, and 5.3 mm Hg were seen for darusentan 50 mg, 100 mg, 300 mg, and placebo, respectively. All comparisons for darusentan were statistically significant ( P < .001), achieving the coprimary endpoints of the study. Ambulatory blood pressure monitoring performed at week 14 showed significant (P < .001) reductions from baseline in 24-hour SBP and DBP in patients treated with darusentan. Reductions in ambulatory SBP were maintained throughout the 24-hour monitoring period with no significant changes in heart rate. SBP goal of < 140 mm Hg (or < 130 mm Hg in patients with diabetes and chronic kidney disease) 53.1%, 53.1%, 48.2%, and 27.3% in the 50-mg, 100-mg, 300mg, and placebo groups, respectively (P < .001 for all darusentan vs placebo). The most common adverse events associated with darusentan were peripheral edema/edema, fluid retention, dizziness, headache, and fatigue. Most cases were mild to moderate in severity. Liver function test results were comparable between treatment groups, with liver enzyme (aminotransferase) concentrations > 3 times the upper limit of normal range being reported in 3 patients: 1 each in the placebo, 100-mg, and 300-mg darusentan groups. There were small mean decreases in hemoglobin and total protein concentrations in all groups. No changes in white blood cell or platelet counts were observed. One cardiac-related death occurred in a patient receiving placebo. Five patients had cardiovascular events on darusentan: 2 had myocardial infarction (both with prior history of coronary artery disease), 1 had recurrence of heart failure that was present at baseline, and 2 had heart failure with preserved ejection fraction that responded rapidly to diuretic therapy. "Because of the increased risk of a number of life-threatening cardiovascular conditions associated with failure to control blood pressure, including stroke and heart attack, it is essential that new therapeutic approaches be evaluated for treatment of resistant hypertension," said lead investigator Michael A. Weber, MD (SUNY Downstate Medical College of Medicine, Brooklyn, New York). [17] "These data are important because they showed meaningful reductions in blood pressure when darusentan was added to existing antihypertensive regimens in a very difficult-to-treat patient population." In addition to DAR-311, a second phase 3 clinical trial, DAR-312 (DORADO-AC) is evaluating the safety, efficacy, and tolerability of darusentan as an add-on treatment for resistant hypertension. DAR312 is expected to be completed with data available by the end of 2009. DAR-312 is an international phase 3 double-blind, placebo- and active-controlled, parallel group trial, in which approximately 770 patients were randomized to receive darusentan (titrated to the optimal dose of 50, 100, or 300 mg once daily), an active comparator (guanfacine 1 mg once daily), or placebo. The co-primary endpoints of the trial are the changes from baseline to week 14 in trough sitting SBP and trough sitting DBP, as measured by sphygmomanometry. Patients who complete the 14-week assessment period are eligible to enroll in the respective long-term safety extension studies, DORADO-EX and DORADO-AC-EX. [17]

Nicotinic Channel Blocker in Exploratory Study for Treatment of Resistant Hypertension

A nicotinic channel blocker, TC-5214, is being investigated as potential augmentation therapy for resistant hypertension in a phase 2 exploratory study, according to an announcement by Targacept (Winston-Salem, North Carolina), a company spun off from R.J. Reynolds Tobacco Co. in 2000 to develop drugs based on its understanding of neuronal nicotinic receptors (NNRs). [18] TC-5214 is the S(+) enantiomer of mecamylamine hydrochloride, a drug initially developed for its ganglion-blocking activity and introduced in the United States in the mid-1950s for the treatment of severe hypertension. [19] The S-(+)- and R-(-)-enantiomers of mecamylamine have been shown to exhibit different profiles with respect to inhibition of the 42 NNR subtype, activation of which has been shown to cause renal sympathoexcitation and an increase in blood pressure. [20] Targacept researchers identified the S-(+) enantiomer (TC-5214) as more effective than R-(-)-mecamylamine (TC-5213) at low concentrations (micromolar range) in inhibiting the low-sensitivity isoforms of human 42 NNRs. [21] They also found that TC-5214 potentiated and TC-5213 inhibited agonist-induced activation of high-sensitivity 42 NNRs. The double-blind, placebo-controlled phase 2 exploratory study of TC-5214 will involve approximately 12 subjects with resistant hypertension who will receive either a single escalating dose of TC-5214 or placebo once per week for 4 weeks and then a fixed daily dose of TC-5214 or placebo over the next 2 weeks. The single site study is expected to be completed in the second half of 2009. In a press release issued by Targacept,[18] Carlos M. Ferrario, MD (Wake Forest University School of Medicine, Winston-Salem, North Carolina), said that the mechanistic rationale for TC-5214 is compelling for the treatment of resistant hypertension. "I am excited to see it investigated in the clinic", he commented. TC-5214 is also in clinical development as an augmentation therapy for major depressive disorder in patients who are inadequate responders to first-line antidepressant treatments. Targacept acquired the commercial rights to mecamylamine hydrochloride in 2002 and it is currently available as a 2.5-mg tablet (Inversine) for the management of moderately severe to severe essential hypertension and uncomplicated malignant hypertension.
References

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Authors and Disclosures


Author(s)
Linda Brookes, MSc

freelance medical writer based in London and New York Disclosure: Linda Brookes, MSc, has disclosed no relevant financial relationships.
Medscape Cardiology 2009 Medscape, LLC