In an editorial published recently in Hypertension, Dr. Daniel Jones, president-elect of the American Heart Association (AHA) and Dr. John Hall, editor, called for greater focus on hypertension saying that controlling high blood pressure more rigorously could save more lives. Jones and Hall noted that less than 30 percent of hypertensives worldwide are undergoing treatment while the remaining 70 percent needlessly suffer from uncontrolled high blood pressure even as safe, effective, and affordable drugs are widely available.

    Over the past four decades, medical researchers and the pharmaceutical industry have been devoting great attention to curbing hypertension, churning out various types and variants of drugs and treatment options. Antihypertensive drugs are classified into diuretics, beta-blockers, calcium-channel blockers (CCBs), angiotensin-converting-enzyme (ACE) inhibitors, and angiotensin-receptor blockers (ARBs).

    Many products have emerged from the laboratories but all these were mere reformulations and new combinations of existing types of antihypertensive drugs. According to Dr. Matthew Weir of the University of Maryland School of Medicine, while ACE inhibitors have been around for the past 25 years and ARBs have been in existence for more than 11 years, they are still trying to fully understand how these drugs really work.

New kid on the block

    Now comes aliskiren, the first drug in a new class of blood-pressure-lowering agents known as oral renin inhibitors. Results of new and long-term clinical studies presented during the 2006 World Congress of Cardiology (WCC) in Barcelona, Spain showed that this breakthrough medicine provides effective and well-tolerated treatment for hypertension, giving sustained 24-hour blood-pressure protection without the rebound surge even if patients stopped taking it for some time.

    Aliskiren, marketed under the global trade name Tekturna, got its first regulatory approval in March from the United States Food and Drug Administration (FDA) both as monotherapy and in combination with other drugs. Novartis, the Swiss pharmaceutical company behind aliskiren, had been developing the drug since 2002. It finally got the FDA's nod after submitting the results of six clinical trials conducted among patients with mild to moderate hypertension.

Aliskiren potency

    Researchers have been persistently trying to manipulate different points in the renin-angiotensin system (RAS) and for a good reason: the key to regulating the body's blood pressure lies in this little-known system. Renin is the enzyme that activates the system by releasing angiotensin II-a kind of protein that affects blood volume and blood-vessel constriction. While ACE inhibitors disable the central section of the renin- angiotensin cascade and ARBs block its lower rungs, aliskiren inhibits the system directly at the point that triggers its activation-at the renin itself.

    One study looked into the potency of aliskiren as a monotherapy and in combination with hydrochlorothiazide (HCTZ)-a commonly prescribed diuretic. Based on this study by Dr. Domenic Sica of the Medical College of Virginia Commonwealth University and his colleagues, once-daily aliskiren was able to control blood pressure round-the-clock for more than one year. This is a significant finding since most older drugs cannot provide 24-hour blood pressure protection whereas a lot of hypertensives typically experience a drastic increase in blood pressure in the wee hours of the morning. The study also found that even after the patients had stopped taking aliskiren during a one-month withdrawal period, they did not experience a potentially dangerous rebound rise in blood pressure, which was observed in patients taking placebo.

    "This study has opened up a whole series of scientific questions such as what it is … that allows this drug to continue to suppress PRA (plasma-renin activity) a month after it has been withdrawn," Dr. James Pool of the Baylor College of Medicine in Houston, Texas remarked after presenting data on the effects of aliskiren treatment and treatment withdrawal on plasma-renin concentrations and PRA.

    All throughout its clinical development program, aliskiren had consistently exhibited blood-pressure reductions by 10 mm Hg as monotherapy. Blood pressure further drops when given in combination with other antihypertensive drugs.

    Medical researchers who presented the results of clinical trials during the American Society of Hypertension meeting last year also hailed this new drug's ability to stabilize or even out blood pressure throughout the day, thus preventing fluctuations that may increase the patient's risk of end-organ damage.

    Before it got the FDA green light, aliskiren had to undergo evaluation to determine its safety. The evaluation involved over 6,460 patients, including 1,740 who underwent treatment for more than six months and 1,250 patients who were treated for more than one year. Just like any drug, this oral renin inhibitor has its share of side effects but these were usually mild and short-lived. The most common complaint of patients taking the drug was diarrhea but this occurred in only two percent of the patients studied. Allergic reactions characterized by swelling of the face, lips, or tongue and shortness of breath were rarely encountered.

Paradigm shift

    "The entry of this new class of antihypertensive drug may signal a paradigm shift in the way we treat hypertension," says Dr. Nathaniel Cortez, a cardiologist based in La Union. "Of course, medical practitioners like us are always on the look out for better treatment options for our patients especially those who cannot tolerate the side effects of existing medications," he said.

    Aliskiren's debut in the complex world of antihypertensive medicines is considered timely as issues of adverse effects against older drugs have been slowly coming out of the woodwork.

Downgrading beta blockers

    After conducting a new metaanalysis, Swedish researchers led by Dr. Lars Lindhock, have strongly suggested that beta-blockers, considered a first treatment option for primary hypertension, should be downgraded and should no longer be used as reference drugs in the future. This conclusion was arrived at after finding out that beta-blockers are not as effective as other antihypertensive drugs in preventing strokes.

    Another blow to beta blockers is the Atherosclerosis Risk in Communities Study, which reported a high 28-percent increase in new-onset type 2 diabetes among hypertensives taking beta-blockers. No significant increase, however, was reported among those taking diuretics, ACE inhibitors, and calcium-channel blockers.

Downplaying CCB's side effects

    Hypertensive patients taking high doses of calcium-channel blockers have also reported side effects, notably headache and edema or swelling due to fluid buildup in the legs. Additional data released at the WCC suggest that this problem may be solved by simply adding aliskiren to a low dose of Amlodipine -the most commonly prescribed calcium channel blocker. Studies show that the combined potency of aliskiren and low-dose amlodipine could significantly lower blood pressure just as well as higher doses of amlodipine alone without the side effect of edema that some people are unable to tolerate.

    In spite of the breakthrough scored by aliskiren, US doctors Franz Messerli and Richard Re remain skeptical. In an editorial published in the March 20 issue of the Journal of the American College of Cardiology, they raised the issue of whether there is really a need for another renin-system blocker. A new drug, they said, "has to be either more efficacious or safer (or both) than existing drugs" to deserve the adjective "better." While acknowledging that renin inhibitors may have fewer adverse effects than ACE inhibitors, they expressed doubt that aliskiren could outdo the ARBs in terms of efficacy and safety.

Renin inhibitors vs. ARBs and ACE inhibitors

    Results of another large-scale study presented during the 2007 meeting of the American College of Cardiology clearly showed that the combined blood pressure-lowering effect of aliskiren and valsartan (an ARB) was significantly greater than aliskiren or valsartan alone with additional blood pressure drop of up to 4.4/3.2 mm Hg over the monotherapy groups. The safety and tolerability profiles of aliskiren alone and in combination with valsartan were good enough with lower rates of adverse events for aliskiren all by itself compared with valsartan as a monotherapy

    Still another long-term study presented by Dr. Karl Andersen of Iceland during the same meeting compared the efficacy of aliskiren with the ACE inhibitor ramipril. According to Andersen, patients who were given aliskiren achieved significantly greater reductions in blood pressure than those on ramipril. Aliskiren's edge over ramipril was apparent on the 12th week before the option of adding HCTZ was done.

    Researcher Linda Brookes, in her disclosures of New Data on the Oral Renin Inhibitor in Patients with Hypertension, noted that although aliskiren's biological activity actually increases renin production, it nevertheless inhibits the activity of the renin produced and consequently its ability to form angiotensin II.

    "By contrast, ACE inhibitors, 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," Brookes wrote.

    Notwithstanding Aliskiren's good safety and tolerability profile, some quarters still remain skeptical when it comes to its possible long-term effects beyond the limits of completed clinical trials. Hypertension, being a chronic condition, requires a long-term treatment and patients may have to be on the drug for the rest of their lives. Messerli says this is to be expected whenever a new drug is introduced having as yet a narrow view of its efficacy and safety due to lack of data. To address these issues, many clinical trials are still being done and more in-depth and long-term studies are in the pipeline.

    Meanwhile, three other pharmaceutical giants (Speedel, Actelion, and Merck) are now in various stages of developing their own versions of renin inhibitors. Aliskiren, nonetheless, is perceived to be five years ahead of its clones or the next generation of renin inhibitors.

    For now, this new kid on the block is blazing a new trail in the treatment of hypertension. Given enough chances, it may prove to be the key to ensuring a more effective management of hypertension. M

 

 

References

1. www.diabetesincontrol.com: "FDA okays first direct renin inhibitor for hypertension"

2. www.pharma.us.novartis.com: "New long-term data show once-daily investigational compound aliskiren, a direct renin inhibitor, safely maintains 24-hour blood pressure reductions during one year"

3. www.theheart.org: "Beta blockers for hypertension" by Sue Hughes

4. www.medscape.com: "Aliskiren: A New Approach to Blocking the Renin Angiotensin System," by Linda Brookes, MSc

5. www.docguide.com: "Long-term Data Show Once-Daily Investigaqtional Compound...."

6. www.medscape.com: Hypertension Highlights, World Hypertension Day, ACC, 07 and RAAS Inhibition; "Looking Forward to Marking World Hypertension Day;" "Debate continues about Benefit Beyond Blood-Pressure Control"