Calcium Channel Blockers and Renal Protection: Insights from the Latest Clinical Trials
Julián Segura,
José A. García-Donaire and
Luis M. Ruilope
Hypertension Unit, Hospital 12 de Octubre, Madrid, Spain
Address correspondence to: Dr. Luis M Ruilope, Hypertension Unit, Hospital 12 de Octubre, Avenue Córdoba s/n, 28041 Madrid, Spain. Phone: 34-91-3908198; Fax: 34-91-3908035; E-mail: ruilope{at}ad-hocbox.com
Calcium channel blockers have been widely used in clinical practicebecause of their antihypertensive capacity. Prevention of renaldamage is a very important aim of antihypertensive therapy.This is particularly so taking into account the high prevalenceof chronic kidney disease (CKD) in the general population. Recentdata have shown that CKD is related to the absence of adequateBP control and also to the clustering of other cardiovascularrisk factors seen in the metabolic syndrome. The knowledge ofthe capacities of the different antihypertensive drugs or theircombinations to simultaneously control BP while protecting thekidney and avoiding the facilitation of metabolic alterationsis warranted. Recent data from the Intervention as a Goal inHypertension Treatment trial, Antihypertensive and Lipid-LoweringTreatment to Prevent Heart Attack Trial, and African AmericanStudy of Kidney Disease and Hypertension (AASK) allow the conclusionthat in hypertensive patients with preserved renal functionor with CKD, calcium channel blockers are effective antihypertensivedrugs to be considered alone or in combination with an angiotensin-convertingenzyme inhibitor or an angiotensin receptor blocker.
Calcium channel blockers (CCB) are widely used for the treatmentof cardiovascular disease, particularly angina pectoris, arrhythmias,and arterial hypertension. Their beneficial effects are relatedto systemic vasodilation caused by the inhibition of the inwardflow of calcium ions through the L-type calcium channels inthe cell membrane. Three main classes of CCB are in currentuse: The benzothiazepines (diltiazem), phenylalkylamines (verapamil),and dihydropiridines (nifedipine, amlodipine, and others).
A growing interest in the investigation of renal function inbig trials that deal with different aspects of cardiovasculardisease has developed in recent years. This is justified bydifferent reasons, including the high prevalence of nephrosclerosisas a cause of ESRD (1) and the capacity of minor alterationsof renal function to predict a poor outcome for the patients(2). The finding of a small increase in serum creatinine values,a diminished estimated GFR (<60 ml/min per 1.73 m2), microalbuminuria,and/or proteinuria heralds a significant elevation in cardiovascularevents and death as well as in total mortality (2,3). Thesealterations are frequent in the hypertensive population andare related to an inadequate BP control and also to the clusteringof other associated risk factors, particularly those seen inthe metabolic syndrome (2–4).
The elevated prevalence of albuminuria and/or a diminished renalfunction in the general population in United States (5) andthe frequent association of these alterations with high BP reinforcesthe need to know more about the long-term renal effects of thedifferent antihypertensive agents or their combinations in thehypertensive population, in particular in patients who presentwith high BP and metabolic syndrome. This necessity is relatedto the potential capacity of these drugs to worsen the metabolicprofile of the hypertensive patient, leading to an increasein the development of diabetes during the chronic administrationof certain antihypertensive agents, thus facilitating furtherrenal damage and cardiovascular risk (6).
CCB and Renal Protection in Recent Trials in Hypertensive Patients
Two recently published trials in which different antihypertensiveagents were compared have shown that CCB could be particularlypositive for the long-term maintenance of GFR levels when comparedwith a diuretic and with an angiotensin-converting enzyme (ACE)inhibitor. These were the Intervention as a Goal in HypertensionTreatment trial (INSIGHT) and the Antihypertensive and Lipid-LoweringTreatment to Prevent Heart Attack Trial (ALLHAT) (7,8).
The INSIGHT study randomized 6321 hypertensive patients whohad one or more associated risk factors to the dihydropyridineCCB, nifedipine gastrointestinal therapeutic system (GITS),or the diuretic combination hydrochlorothiazide/amilozide forthe treatment of hypertension. BP control throughout the studywas similar in both groups, with no statistically significantdifference in the primary combined end point of cardiovasculardeath, nonfatal myocardial infarction, stroke, or heart failure.However, there was a small but significant decrease in estimatedcreatinine clearance during follow-up in the diuretic-treatedpatients compared with the one observed in those who receivednifedipine GITS (7), suggesting that antihypertensive treatmentthat is based on a long-acting dihydropyridine may offer betterrenoprotection than therapy that is based on the diuretic combinationco-amilozide.
The recent publication of the main results of the ALLHAT studyalso included the analysis of the changes observed in serumcreatinine, slope of the reciprocal of serum creatinine, andalso estimated creatinine clearance (8). The results show thata 448 of 33,357 patients developed ESRD without significantdifferences among the three arms of the study. The slopes ofthe reciprocal of serum creatinine over time were virtuallyidentical in the chlorthalidone and lisinopril groups, whereasthe decline in the amlodipine slope was significantly less thanthat of the chlorthalidone arm. Finally, the estimated creatinineclearance exhibited a significantly better preservation in theamlodipine arm that had a final mean value of 75.1 ml/min, thancompared with 70.0 and 70.7 ml/min in the chlorthalidone andlisinopril groups, respectively.
These results seem to differ from the available evidence indicatingthat the administration of an ACE inhibitor or an angiotensinreceptor blocker (ARB) is required to protect renal functionbeyond the benefit obtained by BP control (9). The better evolutionobserved in both the slope of the reciprocal of serum creatinineand the estimated creatinine clearance with a CCB argues againstrecently published comparative studies in which an ACE inhibitoror an ARB were shown to be better than a CCB in primary renaldisease, in type 2 diabetic nephropathy, and in black patientswith nephrosclerosis (10–12).
CCB, BP Control, and Renal Protection in the Presence of Preserved Renal Function
The capacity of a CCB to protect the kidney in hypertensivepatients seems to depend mainly on the capacity of these drugsto lower BP as shown by the analysis of renal data in the SystolicHypertension in Europe study (13), which demonstrated that loweringBP with nitrendipine caused a significant reduction in proteinuriaand renal insufficiency events in patients who were activelytreated with nitrendipine compared with those who took placebo(13).
The maintenance of a strict BP control represents the most relevantmeans to maintain a preserved renal function in hypertensivepatients. In fact, a recent publication indicated that a verystrict BP control attained a similar degree of renal protectionin patients with type 2 diabetes, matching the control attainedwith enalapril or with the CCB nisoldipine (14). A good controlof systemic BP counteracts the risk for afferent arteriolarvasodilation induced by the CCB by impeding the transmissionof a still elevated systemic BP (15). A CCB then can be renoprotectivein the presence of a preserved GFR provided that micro- or macroalbuminuriais not present. If albumin excretion is elevated, then an ACEinhibitor or an ARB is required to obtain full protection ofthe kidney (16,17).
The ALLHAT study demonstrated a very good control of BP withfinal mean values for systolic/diastolic BP of 133.9/75.4, 134.7/74.6,and 135.9/75.4 mmHg for chlorthalidone, amlodipine, and lisinopril,respectively, and with 66% of patients achieving BP values <140/90mmHg (8). Small but significant differences in the control ofsystolic BP were seen in favor of the chlorthalidone arm, whichfurther favor the concept of a protective effect of amlodipine.It will be interesting to see how many cases of crossover toan ACE inhibitor performed in patients who received the diureticor the CCB were due to the presence of a diminished renal functionand whether this could have contributed to create some biasesin the final results. However, follow-ups longer than 5 yr arerequired to prove which is the most adequate antihypertensivetherapy to maintain a preserved renal function.
CCB, BP Control, and Nephroprotection in Patients with Established Chronic Kidney Disease
According to recently published guidelines (16,17), the twomain strategies to prevent progression of renal damage and toreduce cardiovascular risk in hypertensive patients with chronickidney disease (CKD) are a strict BP control and the inhibitionof the renin-angiotensin system. A strict BP control can beaccompanied by reduction of proteinuria, but usually the fallin mean BP required to see a significant fall in proteinuriawith practically any antihypertensive medication is >20 mmHg(18). However, recent data from the African American Study ofKidney Disease and Hypertension (AASK) study have shown that,in black patients, attained mean BP values of 128/78 mmHg didnot differ from 141/85 mmHg in affording additional benefitof slowing the progressive fall in GFR values in hypertensivenephrosclerosis (12). This study suggests that in patients withnondiabetic renal disease, blockade of the renin-angiotensinsystem with either ACE inhibitor or ARB is superior to CCB inthe progression of nephropathy in proteinuric patients. Amlodipinedid seem to be equally effective as the ACE inhibitor when proteinuriawas absent (12).
Data in proteinuric patients with type 2 diabetes obtained inthe Irbesartan Diabetic Nephropathy Trial study (11) also showedthat at equal BP levels, patients who received irbesartan showeda 20% risk reduction when compared with those who received placeboand a 23% risk reduction when compared with those who were treatedwith amlodipine. There was no difference between the amlodipineand placebo groups (11). The Reduction of Endpoints in Noninsulindependent diabetes mellitus with the Angiotensin II AntagonistLosartan trial included a patient population similar to thatinvestigated in Irbesartan Diabetic Nephropathy Trial, who wererandomized to receive losartan or placebo. It is interestingthat >80% of patients in both groups were treated adjunctivelywith CCB to achieve the goal of BP control (19). The positiveeffect of the ARB to halt the progression of renal failure wasnot jeopardized by the simultaneous administration of a CCB.Furthermore, the antiproteinuric effect of losartan was notabrogated by the presence of a CCB. Nondihydropiridine CCB havebeen shown to lead to a reduction in albuminuria or proteinuria,in particular when associated to an ACE inhibitor (20,21).
The data of the AASK (12) point to a positive effect on renalfunction of amlodipine in patients with nephrosclerosis withoutproteinuria. Such an effect must be attributed to the existenceof a good BP control. However, here again, longer follow-upsare required to prove the capacities of an ACE inhibitor oran ARB to obtain more complete renal protection in these patients(22).
In hypertensive patients with or without CKD, CCB are excellentantihypertensive drugs. The presence of microalbuminuria orproteinuria forces the need to use an ACE inhibitor or an ARBbut does not impede the consideration of a CCB as a part ofthe combination of agents that will be required by most, ifnot all, patients. In the absence of albuminuria and with apreserved GFR (>60 ml/min), a CCB can be contemplated asfirst-step therapy and seems to preserve GFR in an adequatemanner. In the presence of a diminished GFR without albuminuria,a CCB can be used as first-step therapy. However, a high percentageof patients will require combination therapy, and the additionof an ACE inhibitor or an ARB will be adequate.
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Abstract
Introduction
