use of nifedipine in the treatment of hypertension

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Drug Profile 10.1586/14779072.3.1.43 © 2005 Future Drugs Ltd ISSN 1477-9072 43 CONTENTS Overview of the market Introduction to the compound Chemistry Pharmacodynamics Pharmacokinetics & metabolism Clinical efficacy Postmarketing surveillance Safety & tolerability Expert opinion Five-year view Key issues References Affiliations www.future-drugs.com Use of nifedipine in the treatment of hypertension Roberto Pontremoli , Giovanna Leoncini and Angelica Parodi Author for correspondence University of Genoa, Department of Internal Medicine, Viale Benedetto XV, 6-16132 Genoa, Italy Tel.: +39 103 538 932 Fax: +39 103 538 932 [email protected] KEYWORDS calcium channel blockers, cardiovascular mortality, hypertension, nifedipine Hypertension is an important modifiable risk factor for cardiovascular disease; its prevention and treatment currently represent major health concerns around the world, especially in western countries. Effective, well-tolerated drugs such as dihydropyridine calcium channel blockers, to be used either alone or in combination treatments, play a key role in reducing cardiovascular morbidity and mortality. The extended-release formulation of nifedipine given once daily provides a relatively constant concentration profile and has proved to be effective in reducing blood pressure values. In the International Nifedipine gastrointestinal therapeutic system Study: Intervention as a Goal in Hypertension Treatment (INSIGHT) study, it was demonstrated that nifedipine confers cardiovascular protection as effectively as diuretics in high-risk patients, with a smaller incidence of adverse metabolic consequences. Furthermore, two INSIGHT substudies demonstrated that nifedipine prevents the progression of carotid atherosclerosis and reduces the worsening of coronary calcifications, supporting the use of calcium channel blockers in hypertensive patients – especially those at high cardiovascular risk. This review discusses the existing clinical evidence supporting the use of nifedipine in the treatment of hypertension. Expert Rev. Cardiovasc. Ther. 3(1), 43–50 (2005) Hypertension is the most important modifiable risk factor for cardiovascular disease, the lead- ing cause of death in both men and women. Prevention and treatment of cardiovascular disease currently represent important public health challenges in western countries. The prevalence of hypertension has increased over the past 10 years, reaching an alarming level of 25% among the general population in the USA and an even higher percentage in Europe [1]. Most importantly, as the preva- lence of hypertension rises with age, and the number of older adults continues to grow, there will be an increasingly large number of elderly subjects with hypertension requiring treatment. Despite extensive proof of the benefits that result from lowering blood pressure, and the availability of several effec- tive antihypertensive drugs, recent surveys indicate that a disappointingly low percent- age of patients (i.e., <30%) reach adequate blood pressure control. While this is probably due to a variety of concomitant causes, it has been suggested that a more aggressive approach to pharmacologic treatment is desirable in order to further reduce cardio- vascular mortality among the general popu- lation. In clinical practice, most hyperten- sive patients can achieve recommended blood pressure targets only when combina- tion therapy is used. To reach this goal, recent international guidelines suggest that treatment should be started with a combina- tion of two drugs in a significant percentage of patients [2,3]. Overview of the market Six major classes of antihypertensive drugs are currently used in clinical practice, includ- ing β-blockers, α-adrenoceptor blockers, cal- cium channel blockers, diuretics, angi- otensin-converting enzyme inhibitors and angiotensin-II-receptor antagonists. These drugs have proved to be equally effective in For reprint orders, please contact [email protected]

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Page 1: Use of nifedipine in the treatment of hypertension

Drug Profile

10.1586/14779072.3.1.43 © 2005 Future Drugs Ltd ISSN 1477-9072 43

CONTENTS

Overview of the market

Introduction tothe compound

Chemistry

Pharmacodynamics

Pharmacokinetics & metabolism

Clinical efficacy

Postmarketing surveillance

Safety & tolerability

Expert opinion

Five-year view

Key issues

References

Affiliations

www.future-drugs.com

Use of nifedipine in the treatment of hypertensionRoberto Pontremoli†, Giovanna Leoncini and Angelica Parodi

†Author for correspondenceUniversity of Genoa, Department of Internal Medicine, Viale Benedetto XV, 6-16132 Genoa, ItalyTel.: +39 103 538 932Fax: +39 103 538 [email protected]

KEYWORDScalcium channel blockers, cardiovascular mortality, hypertension, nifedipine

Hypertension is an important modifiable risk factor for cardiovascular disease; its prevention and treatment currently represent major health concerns around the world, especially in western countries. Effective, well-tolerated drugs such as dihydropyridine calcium channel blockers, to be used either alone or in combination treatments, play a key role in reducing cardiovascular morbidity and mortality. The extended-release formulation of nifedipine given once daily provides a relatively constant concentration profile and has proved to be effective in reducing blood pressure values. In the International Nifedipine gastrointestinal therapeutic system Study: Intervention as a Goal in Hypertension Treatment (INSIGHT) study, it was demonstrated that nifedipine confers cardiovascular protection as effectively as diuretics in high-risk patients, with a smaller incidence of adverse metabolic consequences. Furthermore, two INSIGHT substudies demonstrated that nifedipine prevents the progression of carotid atherosclerosis and reduces the worsening of coronary calcifications, supporting the use of calcium channel blockers in hypertensive patients – especially those at high cardiovascular risk. This review discusses the existing clinical evidence supporting the use of nifedipine in the treatmentof hypertension.

Expert Rev. Cardiovasc. Ther. 3(1), 43–50 (2005)

Hypertension is the most important modifiablerisk factor for cardiovascular disease, the lead-ing cause of death in both men and women.Prevention and treatment of cardiovasculardisease currently represent important publichealth challenges in western countries. Theprevalence of hypertension has increased overthe past 10 years, reaching an alarming level of25% among the general population in theUSA and an even higher percentage inEurope [1]. Most importantly, as the preva-lence of hypertension rises with age, and thenumber of older adults continues to grow,there will be an increasingly large number ofelderly subjects with hypertension requiringtreatment. Despite extensive proof of thebenefits that result from lowering bloodpressure, and the availability of several effec-tive antihypertensive drugs, recent surveysindicate that a disappointingly low percent-age of patients (i.e., <30%) reach adequateblood pressure control. While this is probably

due to a variety of concomitant causes, it hasbeen suggested that a more aggressiveapproach to pharmacologic treatment isdesirable in order to further reduce cardio-vascular mortality among the general popu-lation. In clinical practice, most hyperten-sive patients can achieve recommendedblood pressure targets only when combina-tion therapy is used. To reach this goal,recent international guidelines suggest thattreatment should be started with a combina-tion of two drugs in a significant percentageof patients [2,3].

Overview of the marketSix major classes of antihypertensive drugsare currently used in clinical practice, includ-ing β-blockers, α-adrenoceptor blockers, cal-cium channel blockers, diuretics, angi-otensin-converting enzyme inhibitors andangiotensin-II-receptor antagonists. Thesedrugs have proved to be equally effective in

For reprint orders, please contact [email protected]

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Pontremoli, Leoncini & Parodi

44 Expert Rev. Cardiovasc. Ther. 3(1), (2005)

reducing high blood pressure and, except for α-blockers, areall currently recommended for beginning treatment. Meta-analyses of available randomized clinical trials have clearly dem-onstrated that blood pressure reduction in itself accounts formost of the protective effects of treatment [4,5]. However, smalldifferences between drug classes may exist with regards to theirefficacy at preventing specific cardiovascular diseases beyondblood pressure control, especially in some subgroups ofpatients, such as the elderly or those with diabetes or a previoushistory of cardiovascular events. Calcium channel blockers, forinstance, have proved to be especially effective in the treatmentof the elderly and those with isolated systolic hypertension.Interestingly, in the last few years, meta-analyses suggest thatcalcium channel blockers reduce the risk of stroke more effec-tively than other types of treatment in hypertensive patientsand, at least in part, independently of the degree of blood-pres-sure-lowering effect [5,6]. Furthermore, calcium channel block-ers are devoid of the unfavorable metabolic side effects thatcharacterize other compounds, such as diuretics and β-blockers.Since their introduction nearly 30 years ago, it has been proventhat these drugs are safe and effective, both when used alone orin combination therapy, even in patients with comorbid condi-tions such as diabetes and dyslipidemia. Calcium channelblockers are a heterogeneous group of drugs with differentchemical structures but with a common mechanism of action.Five major classes are currently known:

• Benzothiazepines (diltiazem)

• Dihydropyridine (i.e., nifedipine)

• Diphenylalkylamines (verapamil)

• Diarylaminopropylamine (bepridil)

• Benzimidazole-substituted tetralines (mibefradil, currentlywithdrawn from the market)

The most frequent side effects of calcium channel blockers areflushing, headache and peripheral edema, which occur in lessthan 10% of cases. Given the above, it is not surprising that cal-cium channel blockers are among the most successful drugs forhypertension treatment currently on the market.

Introduction to the compoundNifedipine is the forerunner of dihydropyridine calciumchannel blockers. It was originally developed by Bayer andplaced on the market in the 1960s. The drug is available in thefollowing doses and forms of delivery:

• Immediate-release capsules: 10 and 20 mg

• Extended-release tablets: 30, 60 and 90 mg

ChemistryNifedipine is a 3,5-pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-4-(2-nitrophentyl)-dimethyl ester, with an empiricalformula of C17H18N2O6 [101]. Its structure is illustrated inFIGURE 1. Nifedipine is a yellow crystalline substance, which ispractically insoluble in water but soluble in ethanol. It has amolecular weight of 346.3.

PharmacodynamicsNifedipine selectively inhibits the transmembrane influx ofcalcium ions into cardiac and vascular smooth muscle cells,which interfers with the contractility process, while produc-ing no effect on serum calcium concentrations. At cardiaclevel, nifedipine dilates the main coronary arteries both innormal and ischemic regions. Furthermore, nifedipine is apowerful inhibitor of coronary artery spasm. Thus, adminis-tration of nifedipine increases poststenostic coronary bloodflow, as well as myocardial oxygen delivery, while reducingtotal peripheral resistance and the requirement for oxygen.These properties account for the efficacy of nifedipine forchronic stable and vasospastic angina. The reduction of cal-cium influx in vascular smooth muscle cells causes arterialvasodilation and decreases peripheral vascular resistance.Nifedipine acts on both small and large arteries by increas-ing arterial compliance, resulting in a reduction of bloodpressure. At the beginning of treatment, there is usually asmall increase in heart rate, which is a reflex sympatheticresponse to vasodilatation.

Pharmacokinetics & metabolismNifedipine is rapidly and almost completely absorbed by thegastrointestinal tract after sublingual, oral or rectal adminis-tration [7]. Bioavailibity is proportional to the dose: followingoral administration, nifedipine is detectable in serum within10 min, and reaches mean plasma concentration after 30 to60 min. Nifedipine is extensively converted into inactivemetabolites, and approximately 80% is eliminated throughthe kidneys. The half-life in plasma is approximately 2 h anddoes not change significantly, even at the various doses.Hepatic biotransformation is the predominant route for thedisposal of nifedipine [8].

Owing to the relatively short half-life of nifedipine, severaldelivery systems have been developed to provide longer drugdelivery. Two extended-release formulations have been proposedon the market:

NH

COCH3

H3COC

H

NO2

CH3

H3C

OO

Figure 1. Nifedipine.

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• Nifedipine gastrointestinal therapeutic system (GITS)

• Nifedipine coat–core (CC)

Nifedipine GITS is a twice-coated bilayer tablet: an active layercontaining the drug and an osmotic layer that is pharmaco-logically inert but osmotically active. A semipermeable mem-brane with an orifice surrounds this core and forms a light pro-tective coating, allowing constant drug release. As water fromthe gastrointestinal tract enters the tablet, pressure in theosmotic layer increases and pushes against the drug layer, forc-ing a suspension of the drug through the orifice in the activelayer. Nifedipine GITS provides a constant release rate forapproximately 20 to 22 h, and a relatively constant concentra-tion–time profile throughout the 24-h dosing interval. Thepharmacokinetics of nifedipine GITS are linear over the doserange of 30 to 180 mg, and absorption and elimination are notsubject to saturation. The GITS formulation is capable ofreducing both systolic and diastolic blood pressure for up to30 to 36 h following administration of the dose [9]. Administra-tion of the GITS formulation in the presence of food slightlyincreases the initial rate of drug absorption, but does not influ-ence the extent of drug bioavailability [10]. There is no need toadjust the dosage in chronic renal insufficiency, since no sub-stantial changes in plasma concentration or bioavailability havebeen detected in patients with impaired renal function [11].

Nifedipine CC is an extended-release formulation that consistsof an external coat containing a slow-release formulation and aninternal core containing a fast-release formulation. After inges-tion under fasting conditions, peak plasma concentration occursat approximately 2.5 to 5 h, with a second small peak 6 to 12 hpost dose. The elimination half-life of nifedipine CC is approxi-mately 7 h, compared with 2 h when nifedipine is administeredas an immediate-release capsule. Once-daily dosing ofnifedipine CC under fasting conditions results in decreased fluc-tuation of nifedipine in the plasma concentration comparedwith the immediate-release formulation.

The US Food and Drug Administration (FDA) does notacknowledge the two extended-release formulations as beingtherapeutically equivalent. However, due to its lower market cost,the CC formulation is widely prescribed in several countries.

Clinical efficacyBlood-pressure-lowering effectNifedipine GITS reduced blood pressure in placebo-controlledtrials as well as in comparative clinical trials [12,13]. The GITSformulation has shown equal or better antihypertensive efficacythan atenolol, with a more favorable effect on lipid profile inpatients with mild-to-moderate hypertension [14]. Moreover,extended-release nifedipine is as effective as enalapril in decreas-ing blood pressure [15]. In the International Nifedipine GITSStudy: Intervention as a Goal in Hypertension Treatment(INSIGHT) study [16], slow-release nifedipine and co-amiloz-ide equally reduced both office and 24-h ambulatory bloodpressure in hypertensive patients with additional cardiovascularrisk factors. Interestingly, the step-by-step treatment strategy

used in this study (i.e., dose-titration of the randomized drug,addition of the second drug, dose doubling of the additionaldrug and, finally, addition of any other antihypertensive drugexcept for calcium channel blockers or diuretics) effectivelylowered mean blood pressure (58% of the subjects in the nifed-ipine group and 57% in the co-amilozide group reached blood-pressure values lower than 140/90 mmHg). This is at variancewith other large interventional trials in which a disappointinglylow percentage of patients reached target blood pressure.

Trials on cardiovascular mortalityThe Shanghai Trial Of Nifedipine in the Elderly (STONE)was the first study to show beneficial effects on cardiovascularmorbidity with the use of long-acting nifedipine in patientswith hypertension [17]. It was designed as a single-blind, con-trolled trial of nifedipine versus placebo in a large cohort ofelderly patients (1632 subjects aged between 60 and79 years). Patients were alternatively assigned to receive eitherlong-acting nifedipine (a formulation produced in China), orplacebo after a 4-week run-in period. After a mean follow-upof 30 months there was a significantly greater decrease (-59%)in the probability of events in the nifedipine group. The trialconfirmed that nifedipine is able to significantly decrease therisk of stroke (by 2.3-fold) and severe arrhythmia in elderlyhypertensives. Although providing important, useful informa-tion for clinical practice, the STONE study has been criti-cized for some major weaknesses, especially for the lack of adouble-blind design. More recently, other prospective, rand-omized, placebo-controlled interventional trials confirmedthat lowering systolic blood pressure by using calcium chan-nel blocker-based treatment is associated with a significantreduction in stroke in elderly patients with isolated systolichypertension [18,19].

INSIGHT was a prospective, randomized, double-blindtrial to compare the efficacy of a long-acting calcium-channelantagonist, nifedipine GITS, versus co-amilozide (a combina-tion of the diuretics hydrochlorotiazide and amiloride) onmortality and morbidity in high-risk hypertensive patients[16]. Inclusion criteria were defined as:

• Age between 55 and 80 years

• Blood pressure at least 150/95 mmHg or 160 mmHgsystolic

• At least one additional cardiovascular risk factor: hyper-cholesterolemia, smoking, family history of myocardial inf-arction, left ventricular hypertrophy, coronary artery dis-ease, left ventricular strain, peripheral vascular disease,proteinuria or diabetes

All patients received nifedipine GITS 30 mg, once daily orhydrochlorotiazide 25 mg/amiloride 5 mg once daily. Ofthose whose blood pressure remained higher than 140/90,four additional dose-titration steps were performed. The pri-mary outcome was a composite end point of stroke, intra-cerebral or subarachnoid hemorrhage, myocardial infarction,heart failure and death by cerebral or cardiovascular causes,

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46 Expert Rev. Cardiovasc. Ther. 3(1), (2005)

including sudden cardiac death. Nifedipine and co-amilozidewere equally effective at reducing blood pressure. There wasno significant difference in the total number of primary out-comes between the two groups and, similarly, there were nodifferences in secondary outcomes, combined primary andsecondary outcomes, all-cause mortality and cardiovascularmortality, or nonfatal cardiovascular events (FIGURE 2). How-ever, subgroup analysis revealed that fatal myocardial infarc-tion and nonfatal heart failure occurred more frequently inthe nifedipine group. Although these results should be inter-preted with caution, these drugs should not be considered as afirst-choice treatment in patients with chronic heart failure.The incidence of diabetes was greater in the co-amilozidegroup (p = 0.02). Furthermore, even among patients withdiabetes at baseline, nifedipine GITS proved to be as effec-tive as diuretics at reducing cardiovascular complications,and even more effective than diuretics at reducing all-causemortality (p = 0.03) [20].

Trials on intermediate end pointLong-term treatment with nifedipine GITS has been dem-onstrated to improve left ventricular diastolic performancein patients with essential hypertension [21]. Furthermore,nifedipine GITS at a dose of 30 to 150 mg for 12 to19 months produces significant regression of the left ven-tricular mass when used as monotherapy in patients withadvanced hypertension [22,23].

Two studies, designed as side branches of INSIGHT,looked for differences between nifedipine and diuretic ther-apy on the progression of atherosclerosis in high-risk hyper-tensive patients. One of these substudies was carried out bydouble-helix computerized tomography to evaluate whether

administering nifedipine rather than diuretics slows downthe progression of calcifications in the coronary arteries.This study demonstrated a significantly greater reduction incoronary calcification over a 3-year period in the nifedipinegroup [24].

The other study used ultrasonography of the carotid arteries tocompare the effect of nifedipine with that of co-amilozide on theworsening of carotid-wall thickening in hypertensive patients [25].Among all the published studies regarding the antiatheroscleroticproperties of calcium channel blockers in hypertensivepatients [26–28] nifedipine was the only drug to provide a signifi-cant decrease in the progression of intima-media thickness over a4-year follow-up (FIGURE 3).

Previously, the International Nifedipine Trial on Antiatheros-Clerotic Therapy (INTACT) study showed that nifedipinereduced the incidence of new angiographic lesions by 28%(p = 0.03) in 348 patients with mild coronary artery diseasecompared with placebo [29]. Interestingly, these changesoccurred despite a slight increase in blood-pressure values inboth groups over 3 years. Therefore, these findings takentogether indicate that nifedipine exerts an antiatheroscleroticeffect at the carotid and coronary level. These properties ofnifedipine may be due, at least in part, to the favorable effecton endothelial dysfunction [30]. In fact, recently, in the Eval-uation of Nifedipine and Cerivastatin On the Recovery ofEndothelial dysfunction (ENCORE) study, coronaryendothelial function improved by 88% after 6 months inpatients with coronary artery disease who received nifedipineGITS compared with placebo [31]. Nifedipine had no signifi-cant effect on blood pressure, further supporting the conceptthat its antiatherosclerotic effect is independent of bloodpressure changes.

Postmarketing surveillanceOver the past few years, the safety ofnifedipine and, in general, of dihydropyri-dine calcium channel blockers has some-times been questioned, owing to a possibleassociation with an increased risk ofcardiovascular events. In fact, a number ofstudies have demonstrated that the short-acting formulation may cause unpredicta-ble blood pressure reduction in the clinicalsetting [32–34]. The 1997 Joint NationalCommittee VI report advised that usingimmediate-acting nifedipine to treathypertensive emergencies is unacceptablebecause of the inability to control the rateor degree of the drop in blood pressure.However, this effect was not observed withlong-acting formulations [35,36] due to dif-ferences in pharmacokinetics andpharmacodynamics. The hemodynamicresponse to nifedipine is, in fact, influencedby the rate of increase of its concentration

Stroke

Heart failure

Myocardial infarction

Nonfatal 0.5255 (1.7%) 63 (2%)

Fatal 0.8412 (0.3%) 11 (0.3%)

Othercardiovascular death

0.8513 (0.4%) 12 (0.4%)

Fatal 0.632 (0.1%) 1 (<0.1%)

Nonfatal 0.02824 (0.8%) 11 (0.3%)

Sudden death 0.4317 (0.5%) 23 (0.7%)

Fatal 0.01716 (0.5%) 5 (0.2%)

Nonfatal 0.5361 (1.9%) 56 (1.8%)

Composite end point 0.34200 (6.3%) 182 (5.8%)

p-valueCo-amilozideNifedipine Relative risk

Nifedipinebetter

Co-amilozidebetter

0.4 0.6 0.8 1.0 1.5 2.0 2.5 3.0 3.5

Figure 2. Primary end point in the Intervention as a Goal in Hypertension Treatment (INSIGHT) study [18].

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in plasma [37]. The heart rate increases when nifedipine isadministered rapidly (within 3 min), but remains unchanged if thesame plasma concentration is reached gradually (within 5 to 7 h).Short-acting calcium channel blockers lead to major fluctuationsin blood pressure and heart rate, whereas the slow-releaseformulation produces a sustained, 24-h therapeutic effect.

There have also been suggestions that dihydropiridineagents may increase the risk of coronary events, cancer,bleeding, depression and other severe adverse events, mainlyin elderly patients. However, recent large clinical trials haveconvincingly demonstrated that long-acting calcium channelblockers are not associated with any of the above mentionedevents [38–40].

Safety & tolerabilitySeveral large trials have proved the safety and tolerability ofnifedipine GITS. In a multicenter trial that compared nifed-ipine GITS with felodipine extended release in 277 mild-to-moderate hypertensive patients, nifedipine showed an ade-quate blood pressure response in 80% of patients (77% inthe felodipine group) [41]. The most frequent adverse effectswere headache and edema, with the same incidence in thetwo groups of patients. This study demonstrated that once-daily nifedipine GITS is highly effective and generally well-tolerated in patients with essential hypertension. A largetrial that assessed the difference in the quality of life of394 hypertensive male patients taking atenolol or nifedipineGITS, demonstrated that patients receiving nifedipine had amore favorable quality-of-life profile, psychosocial well-being, sexual satisfaction and vitality [42]. Differences relatedto type of treatment are especially pronounced in patientsover 50 years of age [43].

Severe, adverse drug reactions to nifedipine (short release)were studied in a large trial on 2371 hospitalized, elderlyhypertensive patients [44]. The most frequent adverse effectswere hypotension and tachycardia. After adjusting for poten-tial confounders, it was found that age was significantly and

independently associated with the severe adverse reactionscaused by nifedipine. Since the late 1980s, a few trialsinvolving administration of calcium channel blockers topatients with coronary heart disease provided evidenceregarding an increase in mortality with the use of dihydro-pyridine agents (mainly with short acting nifedipine). How-ever, data are too scarce to provide reliable proof concerningany overall effect that calcium channel blockers may have.More recently, A Coronary disease Trial Investigating Out-come with Nifedipine GITS (ACTION) has evaluated thesafety of nifedipine on long-term outcome in more than7000 patients with stable angina pectoris [45]. The additionof nifedipine GITS to conventional treatment has noadverse effect on the incidence of cardiovascular events,while reducing the rate of new overt heart failure

Table 1. Summary of the clinical efficacy of nifedipine gastrointestinal therapeutic system in hypertension.

Efficacy Comments

Antihypertensive efficacy Effective and well tolerated in lowering blood pressure in a wide range of hypertensive patients

Efficacy versus other drugs Higher efficacy in the elderly population

Patient subgroups No difference with regard to gender and ethnic background

Cardiovascular protection The INSIGHT trial showed effectiveness in preventing cardiovascular complicationsLower incidence of diabetes in the nifedipine group as compared to the co-amilozide group

Metabolic effects Less hyperglycemia and hyperuricemia is observed with nifedipine than co-amilozide

Quality of life Maintained in mild-to-moderate hypertension

INSIGHT: International Nifedipine gastrointestinal therapeutic Study: Intervention as a Goal in Hypertension Treatment.

-0.01

0.00

0.01

0.02

0.03

0.04

0.05

INSIGHT

Car

otid

IMT

yea

rlypr

ogre

ssio

n (m

m/y

ear)

MIDAS VHAS ELSA

NS

p < 0.002p = 0.007

Calcium channel blockerDiuretic or β-blocker

NS

Figure 3. Calcium channel blockers and the progression of carotid intima-media thickness.ELSA: European Lacidipine Study on Atherosclerosis; IMT: Intima-media thickness; INSIGHT: International Nifedipine GITS Study: Intervention as a Goal in Hypertension Treatment; NS: Not significant; MIDAS: Multicenter Isradipine Diuretic Atherosclerosis Study; VHAS: Verapamil in Hypertension and Atherosclerosis Study [24–27].

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48 Expert Rev. Cardiovasc. Ther. 3(1), (2005)

(p = 0.015), as well as the need for coronary angiography(p < 0.0001) and bypass surgery (p = 0.002). Finally, meta-analyses of the available randomized trials in hypertensivepatients provide evidence in favor of calcium channel blockersat preventing stroke, even beyond blood pressure control [4–6].

Expert opinionWhether administered alone or with other agents, nifedipineis an effective antihypertensive drug for treating mild-to-severe hypertension. Its extended-release formulation pro-vides prolonged duration of action, thus making it suitablefor once-daily administration. Its good tolerability profileand the lack of adverse metabolic effects makes it suitablefor first-line treatment and/or combination therapy.

The results of INSIGHT demonstrated that nifedipine providescardiovascular protection that is equivalent to what can beobtained by diuretics in high-risk patients, albeit with a smaller

incidence of adverse metabolic consequences such as gout andnew-onset diabetes. Furthermore, the favorable effect that wasobserved on carotid intima-media thickness and coronary calci-fication support the use of dihydropyridine calcium channelblockers in high-risk hypertensive patients (TABLE 1).

Five-year viewTo date, the treatment of hypertension remains a major healthproblem around the world, especially in western countries. Amore aggressive therapeutic attitude is certainly desirable inclinical practice in order to increase the number of hyperten-sive patients whose blood pressure is adequately controlled,and to obtain a further reduction in cardiovascular morbidityand mortality. In an attempt to achieve this aim, a key role isplayed by effective, well-tolerated drugs such as dihydropyrid-ine calcium channel blockers, to be used either alone or incombination treatment.

Key issues

• Blood pressure control is currently unsatisfactory in the population at large. A more aggressive approach to pharmacologic treatment is desirable in order to reduce cardiovascular mortality. In clinical practice, most hypertensive patients only achieve recommended blood-pressure targets when combination therapy is used.

• The use of safe, well-tolerated drugs, devoid of long-term, adverse metabolic consequences, such as dihydropyridine calcium channel blockers, is important in order to obtain adequate blood pressure values and reduce cardiovascular mortality.

• Nifedipine slow-release formulation, given alone or in combination therapy, is highly effective and well tolerated in a wide variety of patients. Its metabolic profile makes it ideal for long-term treatment in an attempt to achieve target organ damage protection and reduction of cardiovascular mortality.

ReferencesPapers of special note have been highlighted as:• of interest•• of considerable interest

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2 Chobanian AV, Bakris GL, Black HR et al. National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National High Blood Pressure Education Program Coordinating Committee. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure: the JNC 7 report. J. Am. Med. Assoc. 289, 2560–2572 (2003).

3 European Society of Hypertension – European Society of Cardiology Guidelines Committee. 2003 European Society of Hypertension – European Society of Cardiology guidelines for the management of arterial hypertension. J. Hypertens. 21, 1011–1053 (2003).

4 Neal B, MacMahon S, Chapman N; Blood-Pressure-Lowering Treatment Trialists' Collaboration. Effects of ACE inhibitors, calcium antagonists, and other blood-pressure-lowering drugs: results of prospectively designed overviews of randomized trials. Blood-Pressure-Lowering Treatment Trialists' Collaboration. Lancet 356, 1955–1964 (2000).

5 Turnbull F; Blood-Pressure-Lowering Treatment Trialists' Collaboration. Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively designed overviews of randomized trials. Lancet 362, 1527–1535 (2003).

6 Angeli F, Verdecchia P, Reboldi GP et al. Calcium-channel blockade to prevent stroke in hypertension: a meta-analysis of 13 studies with 103,793 subjects. Am. J. Hypertens. 17, 817–822 (2004).

7 Raemsch KD, Sommer J. Pharmacokinetics and metabolism of nifedipine. Hypertension 5, 18–24 (1983).

8 Guengerich FP, Martin MV, Beaune PH et al. Characterization of rat and human liver microsomal cytochrome P-450

forms involved in nifedipine oxidation, a prototype for genetic polymorphism in oxidative drug metabolism. J. Biol. Chem. 15, 5051–5060 (1986).

9 Zanchetti A. Trough and peak effects of a single daily dose of nifedipine gastrointestinal therapeutic system (GITS) as assessed by ambulatory blood pressure monitoring. Italian Nifedipine GITS Study Group. J. Hypertens. 2(5) S23–S27 (1994).

10 Chung M, Reitberg DP, Gaffney M, Singleton W. Clinical pharmacokinetics of nifedipine GITS. A controlled-release formulation of nifedipine. Am. J. Med. 83, 10–14 (1987).

11 Schneider R, Stolero D, Griffel L et al. Pharmacokinetic profile of nifedipine GITS in hypertensive patients with chronic renal impairment. Drugs 48(Suppl.), 116–121 (1984).

12 Krakoff LR. Effectiveness of nifedipine gastrointestinal therapeutic system for treatment of hypertension: results of the MATH trial. J. Cardiovasc. Pharmacol. 21, 14–17 (1993).

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Website

101 Physician’s Desk Referencephysician.pdr.net(Accessed December 2004)

Affiliations• Roberto Pontremoli, MD, PhD

University of Genoa, Department of Internal Medicine, Viale Benedetto XV, 6-16132 Genoa, ItalyTel.: +39 103 538 932Fax: +39 103 538 [email protected]

• Giovanna LeonciniUniversity of Genoa, Department of Internal Medicine, Viale Benedetto XV, 6-16132 Genoa, Italy

• Angelica ParodiUniversity of Genoa, Department of Internal Medicine, Viale Benedetto XV, 6-16132 Genoa, Italy