Long-acting dihydropyridine calcium channel blockers (CCBs) are safe and effective agents for reducing blood pressure and reducing the risk of cardiovascular (CV) outcomes, stated Prof. Giuseppe Mancia of Milan, Italy, based on evidence accumulated over the past decade.

The controversy surrounding CCBs which began in the mid-1990s about the possible increased risk of myocardial infarction (MI), coronary heart disease (CHD), and cardiovascular disease (CVD), cancer, and bleeding, has been clearly settled. Mancia reviewed data from clinical trials that support the safety and efficacy of this class of anti-hypertensive agent.

Cardioprotection with long-acting CCBs

Significantly less cardiovascular (CV) disease and less cardio-specific events occurred in patients with hypertension treated with a CCB compared to placebo, in the Blood Pressure Lowering Treatment Trialists Collaboration (BPLTTC) meta-analysis of clinical trials with nearly 3000 people in each arm.

The STONE and Syst-China studies, conducted in Chinese hypertensive patients and compared a dihydropyridine CCB to either placebo or untreated control group showed clear reductions with the CCB. CV events were reduced by 60% with the CCB compared to 37% with placebo or untreated control, stroke by 57% and 38% respectively, and 26% and 39% respectively. The more recent FEVER study with felodipine, also conducted in China, CV events were reduced by 20-3% in association with a small blood pressure reduction (achieved BP 138/82 with felodipine, 142/83 with placebo).

Long-acting CCBs are also cardioprotective when compared to other treatments. The INSIGHT study showed no difference in outcomes between the nifedipine GITS and hydrochlorothiazide/amiloride groups, “suggesting that nay protection provided by traditional treatment is replicated by treatment based on a CCB,” stated Mancia.

No difference in cardioprotection between long-acting CCBs and other treatment regimens was also shown in a 2000 meta-analysis comparing ACE inhibitors versus beta blockers versus CCBs.

CCBs do not increase non-CV risk

Several studies have confirmed there is no increased risk of cancer with CCBs. The ALLHAT study clearly showed that the 6-year rate of non-CV events was not increased with the CCB amlodipine.

Non-cardiovascular events in the ALLHAT study

Chlorthalidone Amlodipine Lisinopril
Cancer 9.7 10.0 9.9
Gastrointestinal bleeding leading to hospitalization 8.8 8.0 9.6
Non-CV death 8.9* 7.8* 8.3

* p=0.02

Stroke and all-cause mortality were less and overall cardioprotection was similar with amlodipine compared to lisinopril in the ALLHAT study in patients with coronary artery disease according to a recent subanalysis. Stroke incidence was 4.8% in the amlodipine group and 6.1% in the lisinopril group (p=0.050) and all-cause mortality was 16.3% and 18.4% respectively (p=0.06). For the primary endpoint in ALLHAT, fatal CHD and nonfatal MI, the curves for the cumulate event rates were superimposable with no difference between treatment regimens.

Notably, results from some recent trials suggest a greater degree of cardioprotection with a long-acting CCB. In the VALUE trial, MI was significantly less with amlodipine compared to valsartan.

Do CCBs protect against HF?

In the ALLHAT study, the incidence of heart failure was 40% greater with amlodipine compared to chlorthalidone in all of the subgroups analyzed. However, Mancia said the diagnosis of heart failure “was problematic” in ALLHAT, and that the softer criteria for heart failure diagnosis in the trial likely, which included peripheral edema, resulted in “excessive diagnosis of heart failure.” The incidence of heart failure was 10-times higher in ALLHAT compared to the INSIGHT study, in which the patients had a similar patient profile and similar agents, and the diagnostic criteria for heart failure was much stricter.

Heart failure was prevented in the ACTION trial with nifedipine GITS compared to placebo in nearly 4000 patients with hypertension and established angina pectoris (47% versus 76% incidence, respectively).

CCBs and diabetes

Long-acting CCBs reduced CV events in patients with diabetes compared to non-diabetics in the Syst-Eur trial compared to placebo, dismissing the incorrect message that CCBs are not effective in this population. With nifedipine compared to placebo, all-cause mortality was reduced by 41% and 8% respectively, CV mortality by 70% and 18%, stroke by 69% and 35%, and CV events by 62% and 25%. The BPLTTC meta-analysis showed that CV morbidity was the same for each of the different treatment regimens examined.

Renal disease and CCBs

Mancia stated some caveats must be considered when reviewing the evidence for the use of CCBs for renal protection. There are inconsistencies in the comparative data against renin-angiotensin system inhibitors (ACE inhibitors/angiotensin receptor blockers), and that in some studies, such as the AASK study, the conclusions against CCBs are inconsistent with other data. He also stated that preservation of glomerular filtration rate (GFR), “considered a risk marker for CV disease,” was better with a CCB.

Blood pressure control is renal protective, regardless of the treatment regimen, and combination therapy with a CCB is frequently needed to achieve BP control. In the RENAAL study, 4 of 5 patients treated with losartan also required a CCB to achieve goal BP control. The ASCOT study demonstrated the efficacy of combination therapy with contemporary agents and the combination of the CCB amlodipine and the ACE inhibitor perindopril lowered blood pressure more than did the beta blocker/thiazide combination.

Earlier prevention of CV disease and events

Prevention of organ damage and future CV events at a much earlier phase in the process is the future of cardiovascular prevention, stated Mancia. The HDFP study showed that the residual risk remains high even in the patients in whom blood pressure was lowered. CCBs are better at some types of organ protection than some other antihypertensive agents and have favorable effects on endothelial dysfunction and progression of large artery thickening and arteriosclerosis.

CHD, CHF and stroke

Evidence from the Blood Pressure Lowering Treatment Trialists Collaboration (BPLTTC) meta-analysis related to comparisons to long-acting CCBs was reviewed by Prof. Stephen MacMahon from Sydney, Australia. This meta-analysis was from the second cycle produced by the group and included 29 randomized trials, 162,431 patients, and more than 700,000 patient years (Lancet 2003;362:1527-1535; Arch Intern Med 2005;27:1410-1419). Data from the trials completed since this meta-analysis were also reviewed.

CCBs compared to placebo

This analysis included 4 trials, 7482 patients, and 617 major cardiovascular (CV) events). The data “clearly refuted” the concern that CCBs increase coronary heart disease (CHD). Stroke was reduced by 40% with an 8 mmHg reduction in systolic blood pressure, CHD by 20%, and for heart failure there was “no clear benefit or adverse effect”, and total CV disease was reduced by 20% with a long-acting CCB. Heart failure was defined as death or hospitalization for heart failure.

CCBs vs diuretics

This analysis included 10 trials, 68,449 patients, and 6873 major CV events. CCBs were slightly better than diuretics for reducing stroke (RR 0.93), equivalent for CHD (RR 1.01), less effective for heart failure (RR 1.31), and there “no net difference” for total CV disease (RR 1.02).

CCBs versus ACE inhibitors

In this analysis there were 6 trials, 25,758 patients, and 3964 major CV events. CCBs were more effective for stroke (RR 0.89), less effective for heart failure (RR 1.22), and there was no difference for CHD (RR 1.04) and total CV disease (RR 1.03).

CCBs compared to other drugs

No difference in the prevention of total CV disease events in the comparison of CCBs and ACE inhibitors (RR 1.09 vs 1.01 respectively) and of CCBs and beta blockers/diuretics (RR 1.02 vs 1.04 respectively).

Newer trials with CCBs

The results for the efficacy of CCBs from four new trials were reviewed by MacMahon. The VALUE trial compared amlodipine-based treatment and valsartan-based treatment in 15,000 high-risk patients with hypertension. INVEST compared verapamil-based and atenolol-based treatments in 22,500 patients with hypertension and CHD. ACTION compared in 7500 patients with established coronary artery disease treatment with nifedipine GITS and placebo. The ASCOT trial compared amlodipine-based and atenolol-based treatment in 19,000 patients with hypertension.

For stroke, the CCB produced a significantly greater reduction in ASCOT, a trend towards a greater reduction in VALUE and ACTION, and in INVEST no clear difference was seen between the treatments.

For MI, the CCB produced a “nominally significant” reduction in VALUE, a trend towards a better outcome in ASCOT, and no clear difference was seen in ACTION and INVEST.

For heart failure, the CCB produced a reduction in ACTION (RR 0.7), a trend towards a greater reduction in ASCOT, and no clear difference was seen in VALUE but there was some divergence in favor of the CCB at about halfway through the trial. In VALUE, the majority of patients also received a diuretic.

The larger the reduction in systolic blood pressure, the greater the reduction in risk for stroke, CHD, and heart failure. This was shown from an evaluation of the relation between differences in blood pressure reduction and risk reduction in the BPLTTC meta-analysis. MacMahon also stated that there appeared to be a beneficial reduction in stroke with CCBs that is more than can be attributed solely to reduction in blood pressure.

MacMahon concluded that the current evidence shows that with CCBs:

  • Reduced risks of stroke and coronary disease, and the effects are consistent with the size of the BP reduction, and CCBs more effective than ACE inhibitors for stroke.
  • Reduced risks of total major vascular events, with similar effects to diuretic- and ACE inhibitor-based therapy.
  • Uncertainty about the effects on heart failure, appear to be less effective than diuretics and ACE inhibitors, and effects may be neutral, beneficial, or harmful. Whether or not using objective or hospitalization criteria for HF to exclude peripheral edema would make a difference in the results is arguable, MacMahon stated. Certain combinations may be more beneficial for heart failure, for example in ASCOT the combination of an ACE inhibitor and CCB gave a clear benefit and in VALUE no clear excess in HF with CCB and diuretic.

Testing subclinical atherosclerosis for early prevention strategy in asymptomatic people

In persons with existing cardiovascular (CV) disease, the annual risk for coronary heart disease (CHD) events is 3-8% and for asymptomatic persons with major risk factors it is less than 1% annually. However, because CV disease actually begins long before manifestations, the question is whether subclinical atherosclerosis will prevent CV disease better than risk factors.

Noninvasive tests for subclinical atherosclerosis include carotid intima media thickening (CIMT) and coronary calcium, “which is attractive because it quantifies total coronary atherosclerotic burden,” stated Prof. Alain Simon from Paris, France. He and his colleagues published a meta-analysis that evaluated the incidence of coronary heart disease (CHD) events on the basis of absence or presence of subclinical atherosclerosis in asymptomatic people.

The meta-analysis showed higher CIMT was associated with an annual incidence of 1.2-1.6% for CHD and lesser CIMT with an annual incidence ≤0.4%. A high coronary calcium score was associated with a 2% annual incidence of CHD and a low score with ≤0.6%. Similar results were found for carotid plaque and carotid index. A dose-response relationship was also found between atherosclerosis burden and the incidence of events.

In the CLAS study, a parallel increase in CIMT and myocardial infarction (MI) and death was found in men with coronary artery disease treated with colestipol and niacin or placebo. Progression of coronary calcium has also been clearly associated with an increase in coronary events. Yet, Simon stated there is a lack of prospective studies in asymptomatic people to establish the prognostic usefulness of CIMT and coronary calcium.

However, five treatment trials have included serial testing of subclinical atherosclerosis, primarily CIMT. Of these, three trials clearly showed that CCBs retarded the progression of CIMT. ELSA compared lacidipine and atenolol; INSIGHT compared nifedipine and co-amilozide; and PREVENT compared amlodipine and placebo.

In the INSIGHT study, in the nifedipine GITS group (n=115) there was clear regression (-0.0007) and in the co-amilozide group (n=127) clear progression (0.0077; p=0.002) over 4 years. Simon stated this was a direct effect of the CCB’s anti-proliferative and anti-atherosclerotic properties, not the blood pressure reduction. INSIGHT also showed regression of coronary calcium over 3 years with the CCB which progressed with co-amilozide. Nifedipine, and probably CCBs, retards progression of subclinical atherosclerosis, he stated. However, there was no parallel reduction in CV events, perhaps because of other factors such as thrombosis, the follow-up was not long enough, or unknown mechanisms at work.

Simon concluded that it may be useful to screen patients with moderate Framingham risk. A positive test would indicate incremental risk and reinforces risk reduction treatments and therapeutic goals. A negative test may identify low risk patients who do not need further cardiac drug treatment, he proposed. However, serial testing is not yet a management tool, he stated, and the clinical significance of progression and regression of subclinical disease is unclear.