Clinical Trial Commentary

1. Clinical Trial Commentary Calcium channel blockers: the debate continues Dr Eric Topol Chairman and Professor, Department of Cardiology Director of the Joseph J Jacobs Center for Thrombosis and Vascular Biology at the Cleveland Clinic Dr Robert Califf Professor of Cardiology Associate Vice Chancellor for Clinical Research at Duke University

2. Essence of the argument • We are accruing a large amount of data about long term outcomes in patients with hypertension treated with various therapies in a randomized fashion. • The essence of the argument has changed from a situation where the short-acting CCBs (calcium channel blockers) are going in the wrong direction to the situation that longer-acting CCBs appear to have a benefit. • The magnitude of this benefit is not as profound.

3. Seminal realization • The argument that drugs that lower blood pressure (BP) by the same amount will have the same impact on human health is no longer tenable. • Doing direct comparative studies is a human health issue. • We need to know what the best treatments are for our patients • This discussion has implications far beyond the specifics of CCBs.

4. Key points of the analysis • There were 28 000 patients in trials with a 26% increase in MI and a 25-26% increase in heart failure (HF). • Though many different CCBs were looked at, no heterogeneity was seen. • The problem is in trying to castigate the whole class of CCBs when it’s not clear that they’re all the same and there may be agent-specific benefit. • “a meta-analysis is much like a bouillabaisse, no matter how much fresh sea food is added, one rotten fish will make it stink” 1 1. Messerli FH. Ann Intern Med 1995;123:888-889

5. Meta-analysis: design • Dr Furberg’s meta-analysis involved 9 clinical trials: • ABCD Appropriate blood pressure control in diabetes • CASTELCardiovascular study in the elderly • FACETFosinopril versus amlodipine cardiovascular events trial • INSIGHTIntervention as a goal in hypertension treatment • MIDASMulticenter isradipine diuretic atherosclerosis study • NICS-EHNational intervention cooperative study in elderly hypertensives • NORDILNordic diltiazem study • STOP2Swedish trial in old patients with hypertension-2 • VHASVerapamil in hypertension and atherosclerosis study • and the calcium channel blockers: • diltiazem, verapamil, felodipine, amlodipine, isradipine, nifedipine, nisoldipine, and nicardipine

6. PREVENT trial • Chlorthalidone 60$/yr vs amlodipine 1000$/yr • In this meta-analysis, amlodipine was only used by 190 total patients. • The PREVENT trial showed amlodipine to have a favourable effect in lowering events. • Amlodipine is still being studied for its potential therapeutic and preventive effects in vascular biology.

7. Meta-analysis: results heartwire / Aug 30, 2000 / Calcium channel blockers “should not be used first-line therapy”: inferior to other antihypertensives

8. ALLHAT • CCB’s as a class of antihypertensives is branded by Dr Furberg as detrimental, not to be used as front-line therapy. • One of the arms of ALLHAT (antihypertensive and lipid-lowering treatment to prevent heart attack trial) uses amlodipine. • Dr Furberg is the chairman of the NIH funded ALLHAT trial. • If CCBs are dangerous it would be difficult to continue the active treatment of those patients in the ALLHAT trial.

9. CCBs protective? • CAMELOT compares amlodipine vs ACE inhibition vs placebo in terms of the reduction of secondary events in patients with coronary disease. • Data from other trials such as PREVENT suggest that CCBs could be protective, in much the same way that ramipril or ACE inhibitors have been shown to be protective.

10. The market and CCBs • Antihypertensive drugs are a 25 billion-dollar market. • CCBs are a 6 billion-dollar market. • Amlodipine is a market of a few billion dollars. • It’s a source of major concern when there are less expensive alternatives. • If CCBs are protective then their cost may well be worth it.

11. Change in practice? • Hypertension treatment starts with a diuretic then an ACE inhibitor for most patients, and if necessary a CCB. • This meta-analysis does not change our standard approach for managing hypertension. • Many patients receive CCBs due to intolerance or a poor response to the other medications.

12. Short acting agents • Data from the short-acting agents was correct. Early work showed a reflex tachycardia and some untoward effects of nifedipine. • To say that amlodipine is culpable of the effect is out of bounds. • “I don’t know how you can just brand the whole class as MI and heart failure generating.” • … Dr Eric Topol

13. Quandary • How do you increase the rates of MI and HF and not do anything to mortality? • - mortality is dead-on • - stroke rate reduced by 9% • - a lot of asymmetry • Nifedipine and some of the short-acting drugs are carrying the meta-analysis.

14. The data • getting the data quantitatively • vs • a mental meta-analysis • “rational scientific thinking”

15. Public policy issue • There is a difficult public policy issue in studies which have enormous implications for the public. • The normal human tendency is to be more strident when a less than scientific approach is used to oppose your point of view. • The data are not worrisome, but the strong interpretation is.

16. NORDIL and INSIGHT • How do NORDIL and INSIGHT fit into this discussion? • These studies reinforce the finding that with the right combinations and the right type of CCB the results could be different. • Today, most of what we do has a small effect compared to what we used to think about therapeutics.

17. Conclusion • This analysis is provocative. • The data are not as easy to interpret and not as definitive as Curt Furberg is claiming. • There is marked asymmetry of the results in addition to some overinterpretation. • It is hard to show statistically that the data are heterogeneous unless you’ve got enough sampling.