Translating Worldwide CCB Experience into Clinical Practice: Emerging Data on the Next Generation of CCBs

At a symposium held May 15, 2002, during the Annual Meeting of the American Society of Hypertension, experts discussed the role of calcium channel blockers in hypertension treatment, as evidenced by trials from around the world. They also presented data on the next generation of membrane-bound calcium channel blockers, such as lercanidipine, available globally for the last six years and soon to be available in the United States.

This program was supported by an educational grant from Forest Laboratories, Inc.

Getting to Goal in Complex Patients

“Many hypertensive patients have complex hypertension,” said C. Venkata S. Ram, MD, Clinical Professor of Internal Medicine, The University of Texas Southwestern Medical Center at Dallas, and Director, Texas Blood Pressure Institute. “Pure, simple, straightforward hypertension is uncommon because many patients harbor coexisting risk factors or comorbid medical conditions, making their hypertension ‘complex,’ irrespective of the level of blood pressure,” he said.

In patients with metabolic disorders (such as diabetes and hyperlipidemia) or cardiovascular, renal, or neurological disease, even a modest increase in systemic blood pressure levels can be detrimental. These conditions may be undiagnosed and not yet clinically manifested at the time of evaluation for hypertension. However, target organ damage may have already begun.

Patients with both diabetes and hypertension are at the greatest risk for developing renal failure, but before this happens many of them have some degree of chronic renal insufficiency. “There is an opportunity to intervene there,” said Dr. Ram.

Patients with concomitant cardiovascular diseases, such as coronary artery disease and congestive heart failure, are at high risk of morbidity and mortality. In the general population, systolic blood pressure increases with older age in both men and women, putting them at greater risk for cardiovascular disease.

Certain ethnic populations, such as African Americans, tend to have complex hypertension because they are more likely to have significant target organ damage even at only slightly elevated blood pressure levels.

“Patients with complex hypertension require aggressive and optimal blood pressure control to abort further progression of clinical manifestations of the disease,” said Dr. Ram. Unfortunately, “blood pressure control in many patients is not optimal.” (See Table 1)

Pharmacologic Approaches
To achieve the target blood pressure goal in complex patients it is often necessary to use a combination of drugs. “Most antihypertensive drugs reduce blood pressure by reducing peripheral vascular resistance,” said Dr. Ram. However, it’s important to accomplish this without activating the renin angiotensin system or the sympathetic nervous system because this may contribute to target organ damage. He suggested combining a calcium channel blocker with a drug that blocks the renin-angiotensin system.

Dr. Ram cited the Hypertension Optimal Treatment (HOT) Trial, which included 21,000 patients and found that aggressive blood pressure control can only be achieved with combination therapy (Lancet 1998;351:1755-62). “Monotherapy can be used initially; but ultimately multiple medications have to be used,” said Dr. Ram, adding that “where ambitious blood pressure goals are required, patients need two or three drugs.” He pointed to several studies which found that combining a calcium channel blocker with an ACE inhibitor provides an additive effect on both systolic and diastolic blood pressure in patients with complex hypertension (Hypertension 1987; 9:629-633; CPT 1986:39:43).

In one of the studies, by Sareli et al., South African patients were treated with placebo, monotherapy, or combination therapy (Arch Int Med 2001;161:965-971). “A surprising finding of this study was that calcium channel blockers were more effective than diuretics as initial treatment in this population of black patients,” said Dr. Ram.

In the European Cooperative Study of Lisinopril in Diabetes (EUCLID), aggressive blood pressure control halted progression of diabetic retinopathy (Lancet 1999;353:617-22). “This suggests that in addition to renal protection, aggressive blood pressure control may also have an impact on other diabetic complications,” said Dr. Ram.

In the RENAAL study, by Brenner et al., patients were given an ARB, and other antihypertensive drugs were added if necessary (N Engl J Med 2001;345: 861-869). In patients receiving more than one drug, the combination of an ARB and a calcium channel blocker provided the greatest reduction in arterial blood pressure.

In a multicenter European study, which enrolled 150 patients with nondiabetic renal disease, patients received an ACE inhibitor, a calcium channel blocker, or a combination of these (Nephrol Dial Transplant2001; 16: 2158-65). The combination provided a greater reduction in arterial blood pressure than either drug alone. And the rate of decline in renal function was lower in the patients taking the combination compared to either monotherapy.
<br>A study by Shigihara of 33 diabetic patients with hypertension compared an ACE inhibitor alone to a combination of an ACE inhibitor plus a calcium channel blocker (Hypertens Res 2000;23:219-26). “The reduction in proteinuria was much greater in the patients taking the combination,” said Dr. Ram.

Dr. Ram concluded that for patients with complex hypertension, combination therapy is required to achieve target blood pressure levels in order to prevent the progression of the disease and perhaps even cause regression or reversal of target organ damage.

For the majority of patients with hypertension, combination therapy is required to achieve blood pressure goals.
 • For complex patients, lower, more intensive treatment yields better outcomes.
 • Calcium channel blockers are an important and often necessary component

“Calcium channel blockers are highly effective antihypertensive agents, both alone and in combination with other therapeutic agents, including thiazide diuretics, beta-adrenergic blockers, and drugs that block the renin-angiotensin system,” said William B. White, MD, Professor of Medicine, University of Connecticut School of Medicine, Farmington.

However, about seven years ago, calcium channel blockers were thought to be unsafe because it was proposed that they may induce myocardial infarctions. In response to safety concerns, several clinical trials were conducted around the world. Dr. White discussed these studies, which refute the claims and provide evidence that calcium channel blockers are effective in improving cardiovascular outcomes.

In the Syst-Eur trial patients were randomized to nitrendipine (with the possible addition of enalapril or hydrochlorothiazide) or placebo (Lancet 1997;350:757-64). Among nondiabetic patients in the treatment group, there was a 26% reduction in all fatal and nonfatal cardiac endpoints. “All endpoints were significantly better for diabetic hypertensive patients,” said Dr. White.

He noted that when results of the Systolic Hypertension in the Elderly Program (SHEP), which used a diuretic, are compared to results of the Syst-Eur trial, which used a calcium channel blocker, there is a similar reduction in mortality, cardiovacular endpoints, stroke, and coronary events for nondiabetics (see Figure 1). Additionally, in the Syst-Eur trial, active treatment reduced the incidence of new-onset dementia compared to placebo, which was not found in SHEP.

The Syst-China study was modeled after Syst-Eur; it included elderly Chinese patients with isolated systolic hypertension, and nitrendipine was compared to placebo (J Hypertens 1998;16:1823-29). Unlike Syst-Eur, Syst-China was an open label study. Like Syst-Eur, this study demonstrated that stepwise antihypertensive drug treatment starting with a dihydropyridine calcium channel blocker improved prognosis in terms of fatal and nonfatal strokes. And the benefit of active therapy was markedly enhanced in diabetic patients.

The Intervention as a Goal in Hypertension Treatment (INSIGHT) trial directly compared the calcium channel blocker nifedipine in a long-acting gastrointestinal transport system (GITS) with the diuretic combination hydrochlorothizide plus amiloride (Lancet 2000;356:366-72). About 75% of the patients were over 60 years old with comorbid risk factors, such as hyperlipidemia, smoking, and diabetes. At the end of 4 years, 70% of patients were still on monotherapy. Blood pressure control was nearly identical between the two groups, as were the primary endpoints of MI, stroke, and cardiovascular death (see Figure 2).

The next study Dr. White discussed was the Nordic Diltiazem Study (NORDIL), which was an open label trial that compared diltiazem to “conventional therapy,” consisting of a diuretic, a beta blocker, or a combination of the two (Lancet 2000;356:359-65). In this study of almost 10,000 patients, diltiazem was not as effective in reducing systolic blood pressure as conventional therapy (by about 3 mmHg). Reduction in diastolic blood pressure was similar for the two treatment groups. “Despite this small difference, there was no disadvantage to diltiazem,” said Dr. White. There were fewer strokes in the diltiazem group and fewer MIs in the conventional therapy arm. However, neither of these differences reached statistical significance.

He described several meta-analyses. The Blood Pressure Trialists Group, by MacMahon et al. (Lancet 2000;356: 1955-1964), assessed placebo-controlled trials of calcium channel blockers involving 5,520 patients, and determined that this class of drug reduced stroke by 39% and major cardiovascular events by 28%. In a recent meta-analysis, Opie et al. concluded that calcium channel blockers are similar to diuretics or beta-blockers with respect to total and cardiovascular mortality as well as other major cardiovascular events (JACC 2002;39:315-322).

Dr. White concluded that “numerous clinical trials since 1996 have demonstrated that calcium antagonists are safe and effective for preventing cardiovascular disease in patients with hypertension.”

The Evolution of CCBs: Past, Present, and Future

Franz H. Messerli, MD, Clinical Professor of Medicine, Department of Medicine, Tulane University School of Medicine, New Orleans, discussed the efficacy of calcium channel blockers, after noting the change in thinking about antihypertensive therapy over the last few decades.

In 1974, it was reported in Lancet that “antihypertensive agents produce no obvious benefits in patients over 65.” Modern Geriatrics reported that therapy was not indicated for symptomless elderly patients with a diastolic blood pressure reading of up to 120 mmHg. The Standard Textbook of Cardiology claimed that mild benign hypertension, defined as 220/100 mmHg, did not require treatment with drugs.

“By today’s standards this is absolutely terrible,” said Dr. Messerli, adding that “results from the Syst-Eur do away with this thinking.” Based on the results of Syst-Eur, the Joint National Committee has labeled long-acting dihydropyridine calcium antagonists as appropriate agents in older patients.

Dr. Messerli continued by discussing treatment for diabetics. “Patients with diabetes should be on a statin, aspirin, and an ACE inhibitor or an ARB,” he said. And if combination therapy is needed to achieve aggressive blood pressure goals, a calcium channel blocker is a good choice. He noted that having diabetes in addition to hypertension virtually doubles a person’s total mortality and almost triples cardiovascular mortality. He also explained that “the benefits of blood pressure reduction in these diabetic hypertensives exceed the benefits of blood sugar reduction.”

Dr. Messerli reviewed a series of studies which suggested that for diabetic hypertensive patients, calcium antagonists were better at reducing left ventricular hypertrophy than drugs that block the renin angiotensin system.

“A common side effect of calcium antagonists is pedal edema, which is dose-dependent,” Dr. Messerli continued. However, the newer calcium antagonist lercanidipine appears to be less likely to cause this side effect. In a double-blind study by Fogari (Curr Ther Res Clin Exp 2000; 61: 850-862) nifedipine GITS was much more likely to cause

pedal edema than lercanidipine, objectively measured by ankle-foot volume. Lercanidipine not only has a better side effect profile than nifedipine, it is
equivalent in its ability to lower blood pressure.

Dr. Messerli concluded the following about calcium antagonists: “Blood pressure can be lowered in all patients for whom they are indicated, they are useful in combination with all other drug classes, and there are no harmful adverse effects.” In the past, pedal edema associated with calcium antagonists contributed to patients not complying with their treatment and hence a diminished ability to reach target blood pressure goals.

A Comparison of Older CCBs to the Next Generation

Alberto Zanchetti, MD, Professor of Medicine, University of Milan, Ospedale Maggiore, Italy, presented findings from the COHORT Trial, a multicenter study that compared the tolerability of three calcium channel blockers: lercanidipine, lacidipine, and amlodipine.

He began by citing the 1999 WHO/ISH Guidelines, which state the following: “All subgroups of calcium antagonists are effective and well tolerated in lowering blood pressure. They are of demonstrated benefit for the prevention of stroke in elderly patients with systolic hypertension...Long-acting calcium antagonists are preferred and rapid-onset, short-acting calcium antagonists should be avoided. Calcium antagonists are particularly recommended for elderly patients with systolic hypertension and for black patients. Adverse effects include tachycardia, flushing, ankle edema, and (with verapamil) constipation.”

There are three groups of long-acting dihydropyridines. The first are naturally short-acting compounds in special galenic preparations that make them long acting (e.g., nifedipine GITS); second are compounds with a long plasma half-life (e.g., amlodipine); and third are compounds with strong membrane binding and slow release to calcium channels (e.g., lacidipine and lercanidipine).

“While it’s well documented that antihypertensive therapy is beneficial,” said Dr. Zanchetti, “it can’t have any success without patient compliance, which partly depends on the tolerability of the agents.

COHORT Trial
The COHORT Trial was a double-blind, randomized trial comparing the tolerability of lercanidipine to amlodipine and lacidipine in 828 hypertensive patients 60 years and older in Italy who were followed for 6 months to 2 years.

After a 2-week wash-out period, patients were randomized to the starting dose of lercanidipine (10 mg), amlodipine (5 mg), or lacidipine (2 mg). For those not reaching a blood pressure goal of 140/90 mmHg after 4 weeks, the doses could be doubled. At week 8, those not reaching goal were given enalapril or atenolol, and, if still not controlled, hydrochlorothiazide was added.

Patients were included who had a systolic blood pressure greater than 160 mmHg and/or a diastolic blood pressure greater than 95 mmHg at the end of the wash-out period. The primary endpoint was percent of patients with ankle edema.

“There was a considerable reduction in blood pressure that was identical in the three groups,” said Dr. Zanchetti. Systolic blood pressure was reduced by about 30 mmHg and diastolic by 15 mmHg. About 50% of patients in all groups achieved normal blood pressure.

Adverse effects that were spontaneously reported or detected by investigators were the usual ones associated with dihydropyridines, including edema, dizziness, vertigo, flushing, headache, palpitations, tachycardia, and asthenia. Of these, edema was the most frequent.

“For edema, there was a statistically significant difference between amlodipine and the membrane-bound compounds,” said Dr. Zanchetti. After the first 6 months of treatment, about 19% of amlodipine patients had edema, with an odds ratio of 2.5 compared to lercanidipine. The differences between amlodipine and the other two drugs were statistically significant. For all the other side effects, the incidence was very low and there was no statistical difference between the groups. In addition, at study end, the patients receiving amlodipine had the highest rate of study discontinuation due to edema (9%) compared to those taking lercanidipine (2%) and lacidipine (1%).

A symptom checklist given to patients showed that more patients receiving amlodipine reported limb swelling and limb heaviness than patients in
either of the other groups.

Dr. Zanchetti concluded: “The newest generation dihydropyridines, lercanidipine and lacidipine, were significantly better tolerated than amlodipine when used as a single agent or as starting therapy in combination with other antihypertensive drugs. For an equivalent therapeutic response, treatments based on these agents were associated with significantly lower rate of leg edema or symptoms association with leg swelling, dropouts due to leg edema, and dropouts due to any adverse event.”

Hypertension Is Not All Alike, Nor Is its Treatment

John H. Laragh, MD, Director, Cardiovascular Center, and Professor of Med-icine, Weill Medical College, Cornell University, New York City, offered some concluding remarks about calcium channel blockers and how they fit in treatment.

“The dihydropyridine calcium channel blockers are a seductive class of antihypertensive drug because of their great vasodilator potency, which promptly induces the largest decreases in blood pressure,” he said. For many years, this drug class had the highest annual sales of any antihypertensive, led by nifedipine.

“This broad usage gradually revealed a serious side effect profile limiting their rational use,” said Dr. Laragh. The adverse effects largely result from arteriolar overdilation, which causes dose-related peripheral and cerebral edema formation and sympathetic nervous activation in response to hypotension. The resulting lower pressures are accompanied by increases in venous return (preload), leading to higher heart rates and cardiac outputs, and thence to overperfusion with headache and a bleeding tendency from capillary dilation. This means the dihydropyridines can often worsen heart failure and they are not usually indicated during an acute MI or stroke or even during nosebleeds.

To address this side effect problem, a new dihydropyridine molecule, lercanidipine, was developed, which has a more attractive side effect profile. This natriuretic CCB can be used alone or in combination with an antirenin drug, such as an ACE inhibitor, ARB, or beta blocker, all three of which act to correct CCB-induced edema formation and to quiet its sympathetic nervous overactivity. In this way, lercanidipine might possibly replace diuretic therapy as the second drug, added to an antirenin system agent, whenever necessary.

When antihypertensive drug therapy was introduced, most people believed that blood pressure reduction by whatever means was the only goal of drug treatment. However, this strategy over the last 10 years or more, even when using more potent new drugs, has continued to produce dismal treatment success worldwide, with correction rates of only 9% to 25%.

“The present treatment strategy is flawed and we need to reexamine the belief that all hypertension is alike,” said Dr. Laragh. It’s known that mechanistically there are two different types of hypertension: salt-mediated low renin hypertension, involving 30% to 35% or patients, and plasma renin-mediated, occurring in the other 65% to 70%. Moreover, there are basically two types of antihypertensive drugs: the natriuretic sodium-volume anti-V drugs and the antirenin system R drugs.

Accordingly, the soul of all antihypertensive treatment is to get each patient on the correct primary drug and, when necessary, follow-up drug types. Ambulatory plasma renin testing has now become widely available, using a new robotic chemiluminesence Direct Renin test that, for the first time, matches the accuracy of the labor intensive Sealey-Laragh method. Thus, following an ambulatory plasma renin test, the sodium-volume mediated V patients (PRA < 0.65) should be treated first with a V drug (diuretic, spironolactone, or a natriuretic CCB), while R patients (PRA > 0.65) are first treated with an antirenin R drug (CEI, ARB, or beta blocker), which will also protect them from a later renin-angiotensin mediated fatal heart attack, heart failure, stroke, or kidney failure.

Within the framework of this more rational mechanistically targeted Laragh method, it is possible that a new generation of improved CCB-natriuretic
vasodilators, as exemplified by lercanidipine, could have significant roles for implementing the renin test guided treatment. In this context, the future for clinical science, and possibly for lercandipine too, for achieving better patient care to prolong useful life is quite promising.

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