Calcium channel blockers and cardiovascular protection

Cardiovascular disorders are expected to continue to increase with the general ageing of the world's population, and are already the leading cause of mortality worldwide. Optimal pharmacotherapy for cardiovascular disease is obviously required. Calcium channel blockers have been widely used in clinical practice due to their antihypertensive capacity.

Prevention of renal damage is a very important aim of antihypertensive therapy. This is particularly so taking into account the high prevalence of chronic kidney disease (CKD) in the general population. Aptitude of different antihypertensive drugs or their combinations to simultaneously control blood pressure while improving cardiovascular prognosis and avoiding the metabolic disturbances is warranted.

I - Combinations of dihydropyridine calcium channel antagonists and ace inhibitors are best for the management of cardiovascular diseases

Calcium channel blockers (CCBs) have a well-established role in the management of cardiovascular diseases. Their beneficial effects are related to systemic vasodilation caused by the inhibition of the inward-flow of calcium ions.

•  L-type calcium channels in vascular cells are a key therapeutic target in hypertension and are the preferred molecular target of the initial CCBs. More recently, 
•  T-type channels have been discovered, and there is emerging evidence of their significance in the regulation of arterial resistance.

The three major classes of CCBs have distinctive characteristics, and exhibit diverse functional effects depending on their interactions with the L-type calcium channel.

Dihydropyridines

Dihydropyridines (DHPs) are more potent vasodilators, and generally have less cardiodepressant action than other classes of CCBs such as diltiazem and verapamil. In addition, these drugs have several remarkable features that merit consideration in the management of hypertension (1).
Blood pressure (BP) response to this class of antihypertensive molecules is less dependent on patient factors such as age and race compared with other antihypertensive agents, as RAS inhibitors and contrasting ß-blockers and diuretics, DHPs have a neutral metabolic profile. CCBs have demonstrated an advantageous profile when administered as part of combination therapy.
Combinations of dihydropyridine calcium channel antagonists and ace inhibitors or angiotensin receptor antagonists exhibit additive effectiveness and a beneficial collateral-effect profile.  (2).

II - Searching for the optimal treatment to best curb the threat of diabetes in patients with renal dysfunction

There has been an increasing number of investigations regarding the renal function in big trials dealing with different aspects of cardiovascular disease in recent years. This growing interest has developed for various reasons, including :

1. high prevalence of nephrosclerosis as a cause of end-stage renal disease (ESRD) (3) and
2. capacity of minor alterations of renal function to predict a poor outcome for the patients (4).

Even a small increase in serum creatinine values, a diminished estimated glomerular filtration rate (GFR) (< 60 ml/min/1.73 m2), microalbuminuria, and/or proteinuria, heralds a significant elevation in cardiovascular events and death as well as in total mortality (4,5).
These variations are somewhat frequent in hypertensive patients and are related to an insufficient BP control as well as a clustering of other associated risk factors, mainly those seen in the metabolic syndrome (4-6).

The high prevalence of renal dysfunction in the general population and the frequent association of these alterations with high BP reinforces the need to know more about the long-term renal effects of the different antihypertensive agents or their combinations in this population, particularly in those patients presenting with high BP and metabolic syndrome.
Therefore, there is a need to choose the optimal antihypertensive agent with the best efficacy and most minor metabolic disturbances in order to avoid an increase in the development of diabetes mellitus during the chronic administration of certain antihypertensive agents, which can facilitate further renal damage and cardiovascular risk (7).

A) Overview of relevant trials regarding CCBs and renal protection in hypertensive patients

Previously published trials, in which different antihypertensive drugs were compared, showed that CCBs can be particularly positive for the long-term maintenance of GFR levels when compared to a diuretic and to an angiotensin-converting enzyme (ACE) inhibitor (8, 9).

• The INSIGHT study

The INSIGHT study randomized 6321 hypertensive subjects with one or more associated risk factors to the dihydropyridine CCB, nifedipine GITS or to the diuretic combination hydrochlorothiazide/amilozide for the treatment of hypertension. BP control throughout the study was similar in both groups, with no statistically significant difference in the primary combined endpoint of cardiovascular death, nonfatal myocardial infarction, stroke or heart failure. However, there was a small but significant decrease in estimated creatinine clearance during follow-up in the diuretic-treated subjects compared with the one observed in those receiving nifedipine GITS (8), suggesting that antihypertensive treatment based on a long-acting dihydropyridine may offer better renoprotection than therapy based on the diuretic combination co-amilozide.

• The ALLHAT study

The most significant results of the ALLHAT study also included the analysis of the changes observed in serum creatinine, slope of the reciprocal of serum creatinine, and also in
estimated creatinine clearance (9).
These results show that a total of 448, out of a total of 33357 patients, developed ESRD without significant differences between the three arms of the study. The slopes of the reciprocal of serum creatinine over time were virtually identical in the chlortalidone and lisinopril groups, whereas the decline in the amlodipine slope was significantly less than that of the chlortalidone arm.

Finally, the estimated creatinine clearance exhibited a significantly better preservation in the amlodipine arm that had a final mean value of 75.1 ml/min, which compared with 70.0 and 70.7 ml/min in the chlortalidone and lisinopril groups, respectively. However, the evidence regarding the efficacy and safety of CCBs from placebo-controlled studies was limited until the results of the ACTION (A Coronary disease Trial Investigating Outcome with Nifedipine GITS) study became available.

• ACTION trial

Relative to placebo, ACTION examined the effects on clinical outcomes of the dihydropyridine CCB nifedipine in a long-acting GITS (gastro-intestinal therapeutic system) formulation in 7665 patients with angina pectoris. The main conclusion was that the nifedipine GITS is safe in patients with stable symptomatic coronary disease - but with no effect on major cardiovascular end points - and reduces both the occurrence of new overt heart failure and the need for coronary interventions (10).
Assessment of the impact of nifedipine GITS on markers of renal dysfunction and on renal failure has confirmed that in patients with stable angina, creatinine and estimated creatinine clearance are potent independent predictors of total mortality, cardiovascular death or myocardial infarction, new overt congestive heart failure, and stroke or transient ischemic attack and nifedipine has little effect on renal function parameters and its effects on outcome do not depend on their presence. These properties may be clinically relevant (11).

Consequently, these results seem to differ from the available evidence indicating that the administration of an ACE inhibitor or an angiotensin receptor blocker (ARB) is required to protect renal function beyond the benefit obtained by BP control (12). The better evolution observed in both the slope of the reciprocal of serum creatinine and the estimated creatinine clearance with a CCB argue against recently published comparative studies in which an ACE inhibitor or an ARB have been shown to be better than a CCB in primary renal disease, type 2 diabetic nephropathy, and in African American patients with nephrosclerosis (13-15).

B) CCBs and cardiovascular outcomes. Focus on renal and coronary prevention

• Syst-Eur Study

The capacity of a CCB to protect the kidney in hypertensive patients seems to mainly depend on the capacity of these drugs to lower BP as shown by the analysis of renal data in the Syst-Eur (Systolic Hypertension in Europe) study (16) which demonstrated that lowering BP with nitrendipine caused a significant reduction in proteinuria and renal insufficiency events in those subjects actively treated with nitrendipine compared with those taking placebo (16).

The maintenance of a strict BP control represents the most relevant mean to maintain a preserved renal function in hypertensive patients. In fact, a recent publication indicated that a very strict BP control attained a similar degree of renal protection in type 2 diabetic patients, matching the control attained with enalapril or with the CCB nisoldipine (17). A good control of systemic BP counteracts the risk of afferent arteriolar vasodilation induced by the CCB by impeding the transmission of a still elevated systemic BP (18). CCBs can then be renoprotective in the presence of a preserved GFR provided that micro or macroalbuminuria are not present. If albumin excretion is elevated, then an ACE inhibitor or an ARB is required to obtain a full protection of the kidney (2,19).

• The Ascot Trial

The ASCOT trial was designed to provide further data on outcomes with newer agents as CCBs and ACE inhibitors over standard therapy with beta blockers and diuretics and begin to provide some information on combinations of agents.
The trial enrolled 19257 hypertensive patients with at least three other cardiovascular risk factors. Patients were randomized to one of two antihypertensive regimens: amlodipine (5/10mg) with or without perindopril (4/8 mg) or atenolol (50/100 mg) with or without the thiazide diuretic bendroflumethiazide (1.25-2.5 mg), as well as further treatment as required to reach a target BP of 140/90 mm Hg or less.

Of the overall population, 10305 patients with total cholesterol levels of 6.5 mmol/L or less were further randomized to receive atorvastatin 10 mg/d or placebo in a 2×2 factorial design-the lipid-lowering arm of the trial (ASCOT-LLA), which was stopped for noted efficacy of atorvastatin over placebo (20).
Final results of the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA) trial were presented in 2005. The primary outcome measure for the trial was nonfatal myocardial infarction and fatal coronary heart disease. There was a significant difference in all-cause mortality between groups-an 11% risk reduction in the amlodipine/perindopril group vs the atenolol/bendroflumethiazide group. A 10% reduction in the primary end point of nonfatal MI or fatal coronary heart disease (CHD) was found, but this did not reach statistical significance. Investigators pointed out that the power calculation for this end point had been based on 1150 events, and when the study was stopped, they had reached only 905 events.

The ASCOT-BPLA trial showed that an antihypertensive strategy based on amlodipine, with perindopril added as required, could significantly reduce all-cause mortality and other cardiovascular end points, including stroke, compared with an atenolol-based strategy, with the diuretic bendroflumethiazide added as required (21).

It will be interesting to see how many cases of crossover to an ACE inhibitor performed in patients receiving the diuretic or the CCB were due to the presence of a diminished renal function, and whether this could have contributed to create some biases in the final results. On the other hand, follow-up periods longer than 5 years are required to establish the most adequate antihypertensive therapy to uphold renal function.

C) Blood pressure control and nephroprotection in patients with established chronic kidney disease

Guidelines

According to recently published Guidelines (2, 19) the two main strategies to prevent progression of renal damage and to reduce cardiovascular risk in hypertensive patients with chronic kidney disease (CKD), are a strict BP control and the inhibition of the renin-angiotensin system. A strict BP control can be accompanied by reduction of proteinuria, but usually the fall in mean blood pressure required seeing a significant fall in proteinuria with practically any antihypertensive medication is above 20 mmHg (22).

• The AASK study

However, recent data from the AASK study have shown that, in African-American patients, attained mean blood pressure values of 128/78 mmHg did not differ from 141/85 mmHg in affording additional benefit of slowing the progressive fall in GFR values in hypertensive nephrosclerosis (15). This study suggests that in patients with non-diabetic renal disease, blockade of the renin-angiotensin system with either ACE inhibitor or ARB is superior to CCB in the progression of nephropathy in proteinuric patients. Amlodipine did appear to be equally effective as the ACE inhibitor when proteinuria was absent (15).

• Irbesartan Type 2 Diabetic Nephropathy Trial (IDNT) study

Data in proteinuric type 2 diabetic patients obtained in the IDNT study (14) also showed that at equal BP levels patients receiving irbesartan showed a 20% risk reduction when compared to those receiving placebo and a 23% when compared to those treated with amlodipine. There was no difference between the amlodipine and placebo groups (14).

• The Reduction of Endpoints in Non-insulin dependent diabetes mellitus with the Angiotensin II Antagonist Losartan (RENAAL) trial

The RENAAL trial included a patient population similar to that investigated in IDNT study who were randomised to receive losartan or placebo. Interestingly, more than 80% of patients in both groups were adjunctively treated with CCB to achieve the goal of BP control (23).

The positive effect of ARBs on slowing the progression of renal failure was not jeopardized by the simultaneous administration of a CCB. Furthermore, the antiproteinuric effect of losartan was not abrogated by the presence of a CCB. Non-dihydropyridine CCBs have been shown to lead to a reduction in albuminuria or proteinuria, in particular when associated to an ACE inhibitor (24, 25).
Data of the AASKD (12) point to a positive effect on renal function of amlodipine in patients with nephrosclerosis without proteinuria. Such an effect must be attributed to the existence of a good BP control. However, here again longer follow-ups are required to prove the capacities of an ACE inhibitor or an ARB to obtain a more complete renal protection in these patients (26).

D) Further evidences to resolve debate about CCBs and CV prognosis

• The ACTION study

The negative findings on cardiovascular outcomes with some short-acting formulations of calcium channel blockers, published in the 1990s, led to a reduction of CCBs therapeutic indication. As explained above, ACTION study showed that less new overt heart failure was reported in the nifedipine GITS group (117 of 3825 patients) than in the placebo group (158 of 3840), and coronary angiography and coronary bypass surgery were also lower in the nifedipine GITS than placebo group. Therefore, they conclude that the addition of this CCB to conventional treatment of angina pectoris has no effect on major cardiovascular event-free survival (27).

• The Camelot study

Likewise, the Antihypertensive therapy and regression of coronary artery disease: insights from the Comparison of Amlodipine versus Enalapril to Limit Occurrences of Thrombosis (CAMELOT) study enrolled 431 patients with coronary heart disease and randomised them to receive to amlodipine, enalapril, or placebo with a follow-up period of 24 months in order to observe coronary angiographic obstruction changes. The main results reported did not differ among groups and as compared to placebo, amlodipine treatment resulted in fewer ischemic events after 24 months of therapy, but the clinical benefit was not associated with a proportionate enhancement in arterial lumen magnitude (28).

• Jikei Heart Study

Finally, recent data has shed light to the controversy through the data showed on Jikei Heart Study (29), a large-scale clinical trial investigating the effect of a strict BP control (less than 130/80 mm Hg) with an added angiotensin receptor blocker, valsartan, compared with conventional treatment in a large Japanese population that was representative of the cardiovascular continuum of disease.

3081 patients, aged 20–79 years receiving to conventional treatment, were assigned either to valsartan (40–160 mg per day) or to other treatment without angiotensin receptor blockers. Primary endpoint was a composite of cardiovascular morbidity and mortality. The main conclusions reveal that the addition of valsartan to conventional treatment prevented more cardiovascular events than supplementary conventional treatment and those benefits are not completely explained by BP differences.

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.

Conclusion:

In hypertensive patients with or without CKD, CCBs are excellent antihypertensive drugs. The presence of microalbuminuria or proteinuria forces the need to use an ACE inhibitor or an ARB but does not impede the consideration of a CCB as a part of the combination of agents that will be required by most if not all patients. In the absence of albuminuria and with a preserved GFR (> 60 ml/min) a CCB can be contemplated as first step therapy and seems to preserve GFR in an adequate manner. In the presence of a diminished GFR without albuminuria a CCB can be used as first step therapy, but combination therapy and the addition of an ACE inhibitor or an ARB is adequate. Recent trials have facilitated data about more explicit coronary artery disease effects of CCBs, suggesting that these agents are safe and beneficial in the treatment of CHD.