This remarkable monograph by Professor Philip Poole-Wilson, eminent cardiologist, medical scientist, and thought-leader, is actually a very new look at a very old symptom of serious heart disease. It begins with Heberden’s masterly description of angina, now nearly 200 years old, namely the “strong and peculiar” effort-induced “disorder of the breast.” Poole-Wilson then proceeds to illustrate angina’s seriousness and fatality. In 1674, the Chancellor of the University of Oxford, often “seized by a pain in the left arm,” met his end as follows: “the pain in this arm seizing him, he fell down dead without the least motion of any limb” [1].
Thereafter follow masterly and thorough reviews of several major topics relating to current concepts in angina. First, the author asks what is the natural history of angina pectoris, a common and disabling symptom persisting even in the present era of statins and frequent coronary intervention. Next, a new insight is given into the current optimal medical therapy for angina. The discussion focuses on new drugs such as ivabridine, nicorandil, ranolazine, and trimetazidine, but returns to the major role that the calcium antagonists play—in particular, an established old favorite among this category, namely nifedipine. In fact, the remarkable results of the ACTION (A Coronary disease Trial Investigating Outcome with Nifedipine) study show beyond a doubt that a long-acting calcium antagonist of the dihydropyridine (DHP) category is valuable and safe in the treatment of angina pectoris, and combines extremely well with a beta blocker.
My first introduction to the calcium antagonist drugs was in 1969 in Gargano, Italy, when that great researcher Fleckenstein presented his data on another calcium antagonist that had already been discovered, namely verapamil, and showed its ability to protect the myocardium from calcium overload. Clinically, however, the major interest lay in verapamil as a coronary vasodilator and anti-anginal drug. In 1970, Fleckenstein reviewed his findings in detail and mentioned Bay-a-1040 as a new type of non-verapamil calcium antagonist [2], the emerging clinical properties of which were fully reviewed in 1975 in the First International Nifedipine Adalat Symposium [3]. The remarkable coronary vasodilator and anti-anginal capacity of nifedipine was soon followed by descriptions of major antihypertensive benefit.
That was the era when coronary spasm was emphasized as the cause not only of Prinzmetal’s “variant angina,” but of the usual type of unstable angina. High doses of nifedipine capsules were given, up to 40 mg daily, but much more in some studies. This takes us through to the erroneous findings of Curt Furberg, who in an influential article in Circulation in 1995 [4] proposed that such extremely high doses of (short-acting) nifedipine could kill patients with angina and, especially, unstable angina. This article was open to serious editorial criticism [5]. Specifically, the statistics in the meta-analysis were partly in error (by Furberg’s own admission in the correspondence columns of Circulation). Nonetheless, the negative impact remained. Later, he extrapolated the claims concerning the danger of calcium antagonists in general to the treatment of hypertension and, again, suggested that serious side effects were increased by the use of calcium antagonists. These adverse concepts prevailed for a while, but were in part dispelled by a thorough review of 100 studies [6].
The real answer on the safety and efficacy of calcium antagonists, however, is now clearly evident following the very positive results of a series of well-designed outcome studies. Initially, there were several smaller but positive studies, such as PREVENT (Prevention of Recurrent Venous Thromboembolism) [7] in which amlodipine reduced the rate of carotid artery atherosclerosis and also reduced unstable angina and revascularization. The ACTION study then followed, which clearly demonstrated the safety and efficacy of treating patients with angina by long-acting nifedipine. The CAMELOT (Comparison of Amlodipine vs Enalapril to Limit Occurrences of Thrombosis) trial [8] especially began to turn the tide in favor of the DHP calcium antagonists in patients with angiographic-defined coronary disease when amlodipine was as effective as enalapril in blood pressure reduction but was much better at decreasing clinical events (angina, hospitalization, revascularization). Thereafter came the ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial) study [9], which gave a resounding benefit to antihypertensive therapy initiated with a DHP calcium antagonist. This was better able than a beta-blocker to reduce not only cardiovascular complications, including unstable angina, heart failure, and stroke, but all-cause mortality. Often in this study, but not always, the calcium antagonist was combined with an angiotensin-converting enzyme (ACE) inhibitor and the beta-blocker with a diuretic. Of note, the mechanism for the superiority of DHP over a beta-blocker was clear—the calcium antagonist reduced central aortic blood pressure better than did the beta-blocker [10].
We have thus gone full circle from the initial enthusiasm for the prime use of calcium antagonists for angina at a time when coronary spasm was thought to be a dominant mechanism, to the intervening time when various messages of doom and gloom were perpetuated, and now to the modern era where we have studies such as ACTION and ASCOT. These studies not only show safety, but also the extreme efficacy and, in the case of hypertension, the superiority of the calcium antagonist over a beta-blocker as first-line therapy. Furthermore, as the author demonstrates, modern therapy with calcium antagonists advances into the same category of preventative benefit for coronary artery disease that is currently afforded the ACE inhibitors. This monograph is timely, useful, and carries important messages.


 

 

 

REFERENCES

1. Major RH: Classic descriptions of disease. Illinois: Charles C Thomas, 1945.
2. Fleckenstein A. Specific inhibitors and promoters of calcium action in the excitation-contraction coupling of the heart muscle and their role in the prevention or production of myocardial lesions. In: Harris P, Opie LH, eds. Calcium and the heart. London: Academic Press, 1971:135-188.
3. Hashimoto K, Kimura E, Kobayashi T, eds. First International Nifedipine Adalat Symposium. A new theory of ischemic heart disease. Tokyo: University of Tokyo Press, 1975.
4. Furberg CD, Psaty BM, Meyer JV. Nifedipine. Dose-related increase in mortality in patients with coronary heart disease. Circulation 1995;92:1326-1331.
5. Opie LH, Messerli FH. Nifedipine and mortality. Grave defects in the dossier. Circulation 1995;92:1068-1073.
6. Opie LH, Yusuf S, Kubler W. Current status of safety and efficacy of calcium channel blockers in cardiovascular diseases: a critical analysis based on 100 studies. Prog Cardiovasc Dis 2000;43:171-196.
7. Pitt B, et al, for the PREVENT investigators. Effect of amlodipine on the progression of atherosclerosis and the occurrence of clinical events. Circulation 2000;102:1503–1510.
8. Nissen SE, et al, for the CAMELOT Investigators. Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure: the CAMELOT study: a randomized controlled trial. JAMA 2004;292:2217-2225.
9. Dahlof B, et al, for the ASCOT investigators. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet 2005;366:895-906.
10. The CAFE Investigators, for the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) Investigators, CAFE Steering Committee and Writing Committee, Williams B et al. Differential Impact of Blood Pressure–Lowering Drugs on Central Aortic Pressure and Clinical Outcomes: Principal Results of the Conduit Artery Function Evaluation (CAFE) Study. Circulation 2006;113:1213–1225.