Antihypertensive treatment with calcium channel blockers: pharmacological pornography or useful intervention?

More than 40 years after verapamil, the first substance of a new class of drugs, later called calcium antagonists or calcium channel blockers (CCBs) [1], appeared on the cardiovascular stage, these agents are still a matter of extensive debate and never-ending discussions. Originally designed as selective coronary vasodilators, these substances became the best-selling antihypertensive drugs during the late 1980s and early 1990s, without being tested for that indication in a single major cardiovascular trial. I deeply remember the words of Curd Furberg ‘In God we trust, the rest must show data’, when debating the issue of CCBs during a famous session at the congress of the American Heart Association 1995; he finally showed an empty slide with the headline ‘RCTs with CCBs in hypertension’. And we all had to admit, there were no data for CCBs at that time. Meanwhile, after a period of 8 years, a substantial number of randomized controlled trials (RCTs) have been presented and published (Table 1), summarized finally in two large meta-analyses [2,3] and several substantial reviews. Therefore, the database is now what it should be for a class of drugs used for primary prevention of cardiovascular, cerebrovascular and renal disease. RCTs with CCBs aNot fulfilling demands of modern statistics or adequately powered for morbidity and mortality issues. RCTs with CCBs aNot fulfilling demands of modern statistics or adequately powered for morbidity and mortality issues. The CCBs are a heterogeneous class of drugs: there is verapamil, a phenylalkylamine, the benzothiazepine diltiazem, and the large group of dihydropyridines (DHPs) with the prototype nifedipine, and an increasing number of newer agents (e.g. nitrendipine, nisoldipine, amlodipine, felodipine, lacidipine and lercandyidipine). DHPs are primarily vasodilators, lowering blood pressure by decreasing peripheral vascular resistance at the level of the small arterioles [1]. This mode of action induces autonomic counter-regulation, which can be substantial, if a DHP drug has a rapid onset of action, like immediate-release nifedipine (capsules). In that case, unfavourable side effects like tachycardia and an increase in serum catecholamines can be observed. With modern DHPs, like amlodipine or lacidipine, or extended-release formulations of felodipine or nifedipine, autonomic counter-regulation is markedly reduced, but can still be observed [4]. In patients with acute coronary syndrome and acute myocardial infarction, DHPs must not be used in monotherapy, since they can increase the level of myocardial ischaemia (via tachycardia and reduced coronary perfusion pressure). This does not hold true for verapamil and diltiazem, which do additionally block the sinuatrial and AV-node. At the kidney level, DHPs mostly dilate the affer-ent glomerular artery, thereby increasing the intraglomerular pressure. While DHPs do not compromise glomerular filtration rate in the short term, there are several reports of an increase in proteinuria in patients with nephropathy and despite blood pressure reduction, long-term kidney function may be adversely affected [5]. Since the very beginning of treatment of hypertension with CCBs, these agents became known as very effective antihypertensive agents, with substantial blood pressure reduction in all age groups and races [1]. The blood pressure reduction can be seen already after the first dose or at least after a few days, which often improves patient compliance and both patient and doctor satisfaction. In various experimental settings, CCBs improve endothelial function, and they may positively influence atherosclerosis in coronary and carotid arteries, which is, however, still a matter of debate [6]. CCBs reduce left ventricular hypertrophy [7] and hypertrophy of the resistance vessels (‘vascular remodelling’), they improve arterial compliance, and they do not adversely affect lipids and serum glucose. Despite well known side effects, mostly at the initiation of treatment, like flush, headache or palpitations with DHPs and constipation with verapamil, the CCBs are overall well tolerated; CCBs do not compromise exercise performance and only ankle oedema with higher doses of DHPs can in a substantial proportion of patients become a limiting side effect [8]. SYST-EUR was the first placebo-controlled outcome study with CCBs in hypertension. In elderly patients with isolated systolic hypertension there was a significant reduction in stroke in patients treated with nitrendipine, compared with placebo, leading to preliminary closure of the study [9]. In the diabetic subgroup there were also less cardiovascular events, and even a decrease in mortality [10]. Similar studies with quite similar results, but not fulfilling western standards of RCTs, were performed in China (Syst-China, STONE) [11]. A total of three subsequent studies (STOP-2, INSIGHT and NORDIL) compared CCBs with other forms of antihypertensive treatment in the elderly (STOP-2) [12], in patients with high risk of cardiovascular events (INSIGHT) [13], and in unselected Scandinavian patients (NORDIL) [14]. Overall, no significant differences in cardiovascular mortality or a combined endpoint of cardiovascular deaths, non-fatal stroke and non-fatal myocardial infarction could be demonstrated with the DHPs felodipine and isradipine in STOP-2 against agiotensin receptor blocker inhibitors, β-blockers or diuretics, with nifedipine gastrointestinal therapeutic system (GITS) (long-acting extended release formulation) against co-amilozide (HCT + amiloride) and with diltiazem against β-blockers or diuretics. In parallel, several smaller studies [15–17] dealing primarily with surrogate markers (e.g. intima-media-thickness, metabolic parameters) reported adverse outcomes with CCBs, despite not being powered for these secondary endpoints. MIDAS showed a higher incidence of vascular events with isradipine (compared with HCT), FACET more cardiovascular endpoints with amlodipine (compared with enalapril) and ABCD a higher incidence of myocardial infarction with nisoldipine (compared with enalapril). Finally, in December 2002 the presentation—not at a scientific meeting, but at a press conference—and publication—with express review and probably without real revision—of the ALLHAT study [18]. Overall, the study showed no difference in the primary endpoint (fatal and non-fatal myocardial infarction) and in total mortality between lisinopril, the DHP amlodipine and chlorthalidone. The conclusion of the authors focused on the superiority of the diuretic, not adequately discussing several drawbacks of the study like the high proportion of black people, the differences in achieved blood pressure and the high rate of new onset diabetes in the group treated with the diuretic. The message of ALLHAT was therefore mostly a political one: diuretics are affordable to everyone, and therefore they should be best for everyone. With less rumour, but no less important, the results of INVEST were presented during the American College of Cardiology meeting in Spring 2003 (C. Pepine, personal communication)—the comparison of a beta blocker based treatment regimen and a verapamil regimen in patients with both hypertension and coronary artery disease. Overall, the two regimens were fairly similar in primary outcome (death, non-fatal myocardial infarction, non-fatal stroke), but the verapamil based regimen induced significantly less cases of new onset diabetes. Finally, the authors of IDNT—an endpoint study primarily showing better renal protection with irbesartan than with amlodipine or placebo—published their analysis on cardiovascular events in these patients with type 2 diabetes and overt nephropathy, showing no overall difference between the treatment groups (based on irbesartane, amlodipine and placebo) [19]. The crucial question remains: why were CCBs so intensively used before we had all these endpoint data, and will the results of now available RCTs influence the worldwide use in the future? CCBs were and are mainly very effective antihypertensive agents, and especially in the elderly, they have been shown not only to reduce blood pressure, but also to prevent cardiovascular events, mainly stroke. And no study, hitherto, could demonstrate that reduction of blood pressure—or even normalization, i.e. control of hypertension—was less important than any intrinsic action of a specific antihypertensive drug. Therefore, despite the worldwide campaign against CCBs in the late 1990s, the CCB amlodipine became the number one selling drug in the world, mainly due to good efficacy in a very broad range of patients. JNC VII [20], heavily discussed, because of advocating diuretics as a unique first-line treatment for the majority of hypertensives, also claims—this time unequivocal—for more and earlier use of combinations in the treatment of hypertension: this is the second potent field for CCBs, since they are ideal combination partners for beta blockers (here only DHPs), ACE inhibitors or AT1 blockers, and diuretics (here mostly verapamil), tested in studies like HOT [21], SYST-EUR or, recently, INVEST. What CCBs never could demonstrate is a clear-cut superiority compared with other drugs in dealing with this very complex hypertensive state (‘the disease behind blood pressure’). They also have certain haemodynamic cons, mainly activation of the renin angiotensin system and the sympathetic nervous system, but also the increase in intraglomerular pressure. These, in my opinion, important cons can be overcome by logical combination treatment, which is a must for the majority of our patients; the necessity of combination treatment will hopefully limit the never-ending discussion about the very best drug for starting treatment. In cases where the haemodynamic cons play a dominant role, CCBs should not be used as primary treatment, e.g. in symptomatic congestive heart failure (all CCBs), in acute coronary syndromes and in diabetic nephropathy (only DHPs) [22]. But there are hypertensive patient groups, too, where I would prefer to have a CCB early on board, like in the elderly, especially those with isolated systolic hypertension and a high risk of stroke, in patients with asthma and chronic obstructive pulmonary disease, and in those with massive left ventricular hypertrophy (including diastolic heart failure) or with Raynaud's syndrome (and other spasmic disorders). Forty years after the launch of verapamil, CCBs have come of age. After a decade of large-scale studies these drugs now exhibit an extensive efficacy and safety profile. CCBs are far away from being the ideal antihypertensive drug, but they are important contributors in our constant effort to control human hypertension. Conflict of interest statement. The author conducted and participated in studies with various CCBs and received speaker's honoraria from Abboth, Astrazeneca, Boehringer Ingelheim, Aventis, Ricordati, Pfizer and Merck.