Analysis of Recent Papers in Hypertension
 Jan Basile, MD, Senior Editor

Abstract

The cyclooxygenase-2 (COX2) inhibitors have been among the most widely prescribed pharmacologic agents in the world. They were developed to avoid the gastrointestinal complications that May occur with other nonsteroidal anti-inflammatory drugs (NSAIDs) and still control the pain of arthritis. After millions of Americans used the COX2 inhibitors, however, adverse cardiovascular (CV) events were reported for the three available members of this class—rofecoxib, celecoxib, and valdecoxib—questioning the wide use of these drugs. One member of the class, rofecoxib, was withdrawn voluntarily from the market last year by its manufacturer. To date, it is not clear under which circumstances, if any, patients with a history of heart disease should be allowed to take COX2 inhibitors. In addition, as all NSAIDs are known to cause sodium retention, their effects on blood pressure (BP) May be an additional concern in people with hypertension. Studies involving small numbers of subjects have suggested disparate effects of these agents on BP. In an effort to compare the effects of two COX2 inhibitors to a traditional NSAID on 24-hour BP control, the Celecoxib Rofecoxib Efficacy and Safety in Comorbidities Evaluation Trial (CRESCENT) was undertaken. CRESCENT was an international, double-blind randomized 12-week trial between May 2001 and April 2002 in which 404 patients with osteoarthritis of the knee or hip requiring daily NSAID therapy from 65 centers in seven countries were assigned to either 200 mg of celecoxib once daily (n=136), 25 mg of rofecoxib once daily (n=138), or 500 mg of naproxen twice daily (n=130). All individuals had hypertension and type 2 diabetes. On entry, they had similar baseline characteristics, including BP, serum creatinine, plasma glucose, and glycosylated hemoglobin levels, and were being treated with oral hypoglycemic agents and/or insulin. More than 98% were being treated with an angiotensin-converting enzyme inhibitor (84%) or an angiotensin-II receptor blocker (18%); more than 60% were receiving multiple antihypertensive agents. Twenty-four hour ambulatory BP monitoring and arthritis efficacy assessments were conducted at randomization and at 6 and 12 weeks of treatment. The primary end point of the study was the mean change from baseline in average 24-hour ambulatory systolic BP at Week 6. Secondary end points for BP included mean change from baseline at Week 12 for average 24-hour ambulatory BP and pulse pressure, changes from baseline in daytime (6 a.m.–10 p.m.) and nighttime (10 p.m.–6 a.m.) BPs, and the number of patients who were dropped from the study because of a change in medication for loss of BP control. Additionally, the three osteoarthritis efficacy assessments were evaluated. All three treatments reduced arthritis symptoms including pain, mobility, and stiffness at both 6 and 12 weeks of treatment. For the primary end point at Week 6, rofecoxib increased systolic BP 4.2 mm Hg with no increase seen with celecoxib (−0.1 mm Hg) or with naproxen (−0.8 mm Hg). The BP difference between rofecoxib and celecoxib was 3.78 mm Hg and between rofecoxib and naproxen it was 3.85 mm Hg. There was no difference between celecoxib and naproxen. The secondary end point results for clinic BP reflected the changes in ambulatory BP results. In addition, the percentage of subjects with baseline normotension (24-hour systolic BP <135 mm Hg) who developed ambulatory hypertension at Week 6 was greater with rofecoxib (30%) compared with celecoxib (16%), which was not different from naproxen (19%). The hourly ambulatory systolic BP curves over 24 hours from baseline to 6 weeks revealed an increase from baseline only in the rofecoxib group. This was the first clinical trial in patients with type 2 diabetes and hypertension to compare COX2-specific inhibitors and a nonspecific NSAID at equally effective doses for osteoarthritis management. Treatment with rofecoxib but not celecoxib or naproxen induced a significant increase in 24-hour ambulatory systolic BP. There was also a tendency for previously normotensive individuals to become hypertensive on follow-up. Careful monitoring of BP when NSAIDs or COX2 inhibitors are chosen for patients with osteoarthritis, diabetes, and hypertension appears to be warranted. —Sowers JR, White WB, Pitt B, et al. The effects of cyclooxygenase-2 inhibitors and nonsteroidal anti-inflammatory therapy on 24-hour blood pressure in patients with hypertension, osteoarthritis, and type 2 diabetes mellitus. Arch Intern Med. 2005;165:161–168. Millions of Americans have used COX2 inhibitors, which were intended to avoid the gastrointestinal complications that May occur with other NSAIDs. All of the current publicity about the COX2 inhibitors has physicians wondering if these drugs should be used at all in patients who remain at risk for CV disease. A recent editorial in The Journal of Clinical Hypertension1 addressed this problem in some detail. While trials with the three structurally distinct COX2 inhibitors have documented some increase in risk of myocardial infarction and/or stroke, most experts believe that the short-term, low-dose use of these medications remains safe. For example, myocardial infarction and stroke risk increase with celecoxib (Celebrex; Pfizer Inc., New York, NY) was seen in only one long-term colon cancer prevention study using doses at or above 400 mg/d. In all studies at 200 mg/d, the dose used for the treatment of arthritis, no risk was seen. With valdecoxib (Bextra; Pfizer Inc., New York, NY), although there is a higher risk of serious skin reactions, the only increase in cardiac risk was seen in a high-dose, post-cardiac bypass study, a clinical setting in which the use of this drug is now contra-indicated. Rofecoxib (Vioxx; Merck & Co., Inc., Whitehouse Station, NJ), which was voluntarily withdrawn from the marketplace by its manufacturer in September 2004, has been shown to increase CV risk when used at a dose of 50 mg/d, even over the short-term. Only one study has suggested a CV risk at 25 mg daily, and then only after continuous use for 18 months. The consensus now is that all COX2 inhibitors May increase the risk of CV events, but the risk varies by specific drug, its dose, and duration of therapy. The current short-term study found that at equivalent doses for osteoarthritis management, treatment with rofecoxib but not celecoxib or naproxen induced a significant increase in 24-hour systolic BP at 6 weeks of therapy. This is in keeping with a recent meta-analysis2 that included 45,451 patients from 19 randomized controlled trials for whom BP data were available. This reported that COX2 inhibitors raised BP to a greater degree than either placebo or nonselective NSAIDs. As in the present study, rofecoxib accounted for the majority of BP elevation. While the mechanism(s) for these differences between agents remains unknown, differences in intrarenal prostaglandin production, endothelial prostacyclin, and platelet-inhibitory prostaglandins May all contribute. While all COX2 inhibitors May be associated with some changes in BP, the merits of each individual agent and their disparate effects on BP should be considered when these are used in people who remain at risk for the development of or who already have established hypertension, even for short-term use. This present information assumes even greater importance since an advisory panel of the Food and Drug Administration recently voted to keep the currently approved selective COX2 inhibitors on the US market. Inhibition of the renin-angiotensin system (RAS) with either angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blocker (ARB) therapy has been associated with an improvement in cardiovascular (CV) morbidity and mortality as well as renal preservation in people at high risk for chronic kidney disease. Since renin catalyzes the first and rate-limiting step of this system, there has been enthusiasm for developing direct renin inhibitors. Although IV administration of early renin inhibitors reduces angiotensin levels and lowers blood pressure (BP) without significant adverse effects, oral agents in this class have been associated with poor bioavailability, low potency, short duration of action, and high cost, making oral renin inhibitors as a treatment for hypertension and CV disease impractical. The present placebo-controlled study compared the antihypertensive efficacy and safety of various doses of aliskiren, the first in a new class of orally effective, nonpeptide, low-molecular-weight renin inhibitors, with the ARB irbesartan. In this multi-center, randomized, double-blind, parallel-group study, eligible patients included men and women 18 years of age or older with mild-to-moderate essential hypertension (mean sitting diastolic BP of 95-110 mm Hg after placebo washout). Exclusion criteria included severe hypertension (systolic BP >180 mm Hg or diastolic BP >110 mm Hg, type 1 diabetes mellitus, poorly controlled type 2 diabetes mellitus, and history of established CV disease (including myocardial infarction, stroke, or heart failure). After withdrawal of previous antihypertensive medication during a 2-week washout period, subjects entered a 2- to 4-week single-blind placebo run-in period. Subjects were then randomized to treatment with aliskiren 150 mg, 300 mg, or 600 mg; placebo; or irbesartan 150 mg once daily for 8 weeks. The primary end point analyzed was change in mean trough seated diastolic BP. Mean trough seated systolic BP, safety and tolerability measures, and trough-to-peak ratio were secondary end points. Of the 793 recruited subjects, 652 satisfied inclusion criteria at the end of the placebo run-in phase and were randomized to active treatment. Daily treatment with each dose of aliskiren reduced trough seated diastolic BP significantly more than placebo (change in diastolic BP from baseline with aliskiren 150 mg, 300 mg, and 600 mg was 9.28, 11.77, and 11.5 mm Hg respectively; change with irbesartan 150 mg was 8.88 mm Hg compared to 6.34 mm Hg with placebo). For trough systolic BP, all doses of aliskiren also showed significantly greater change from baseline than placebo (reduction in systolic BP from baseline with aliskiren 150 mg, 300 mg, and 600 mg was 11.36, 15.76, and 15.73 mm Hg, respectively; reduction with irbesartan 150 mg was 12.50 mm Hg compared to a decrease with placebo of 5.28 mm Hg). The effects of aliskiren on systolic and diastolic BP showed significant dose dependence, but only up to 300 mg. The antihypertensive effect of aliskiren 150 mg was similar to irbesartan 150 mg, but aliskiren 300 mg lowered diastolic BP to a significantly greater degree than irbesartan 150 mg. The peak for BP reduction for both aliskiren and irbesartan appeared to be at least 6 hours after dosing. The trough-to-peak ratios determined 6 hours after dosing for aliskiren 150 mg was similar to irbesartan 150, with a significantly greater ratio for aliskiren 300 mg. The incidence of adverse events and the number of study discontinuations were low at all doses of aliskiren and similar to the results with placebo or irbesartan. No subjects in the aliskiren groups reported a serious adverse event during the treatment period. It has been over 10 years since the last new antihypertensive class was introduced for clinical use. Aliskiren, an oral renin inhibitor at 150 mg, appears to offer significant BP-lowering efficacy and tolerability comparable to placebo and irbesartan 150 mg in subjects with mild-to-moderate essential hypertension.—Gradman AH, Schmieder RE, Lins RL, et al. Aliskiren, a novel orally effective renin inhibitor, provides dose-dependent antihypertensive efficacy and placebo-like tolerability in hypertensive patients. Circulation. 2005;lll:1012-1018. Multiple clinical outcomes trials confirm the benefits of RAS blockade with ACE-inhibitor or ARB therapy in patients with hypertension, chronic kidney disease, and established CV disease. Oral renin inhibitors offer the potential advantage of blocking the activation of the RAS at its most proximate step, the cleavage of angiotensinogen to angio-tensin I. As there are alternate ACE-independent pathways whereby angiotensin I can be converted into angiotensin II, renin inhibitors theoretically offer more complete interruption of angiotensin II formation than ACE-inhibitor therapy. In addition, the use of renin inhibitors is not associated with increased circulating bradykinin and the untoward cough and angioedema often associated with ACE-inhibitor therapy. While ARB therapy also provides RAS blockade with a lessened risk of side effects than ACE-inhibitor therapy, the use of ARBs is associated with an increase in angiotensin II, which May still interact with other unblocked angiotensin receptors (AT2, AT3, and AT4). In comparison, renin inhibitors that decrease the amount of circulating angiotensin II result in a decrease in activation of all angiotensin receptors; the clinical significance of which remains unknown. Aliskiren, developed using molecular modeling and crystallographic structural analysis, lacks the extended peptide-like backbone of previous oral renin inhibitors and appears to have good bioavailability and an extended duration of action, allowing it to be administered once daily. In preclinical studies, aliskiren was shown to lower BP significantly in animal models, including sodium-depleted marmosets and spontaneously hypertensive rats. Studies in humans with aliskiren have shown dose-dependent decreases in plasma renin activity and angiotensin II formation in doses up to 300 mg daily; in another report, doses of 300 mg daily were found to lower daytime ambulatory systolic BP to a similar extent as 100 mg of the ARB losartan. While the current study is the first to report that the 600-mg dose of aliskiren has no greater BP-lowering capability than when administered at 300 mg, it remains unclear if higher doses May still lead to greater blockade of the RAS system and possibly provide additional non-BP associated benefit. The present study, along with other available evidence, confirms that aliskiren, a novel nonpeptide, orally active renin inhibitor, provides substantial BP reduction when given once daily, with a side-effect profile similar to an ARB irbesartan. Whether aliskiren results in protection from heart attack, stroke, and nephropathy similar to ACE inhibitor or ARB therapy needs to be evaluated in future clinical trials.