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To the Editor:

The risk of stroke is reduced by calcium channel blockers (CCBs), including amlodipine, and the size of the blood pressure (BP) reductions is an important determinant of the size of this treatment effect.1 It remains uncertain, however, whether mechanisms independent of BP also affect the size of the treatment benefit to stroke, and there have been few formal attempts to investigate any such drug-specific effects. In their meta-regression analysis of amlodipine, Wang and associates2 plotted only 5 odds ratios (ORs) for stroke from two individual trials3,4 and three “pooled trials” with reference treatment of the same class: placebo,5–7 angiotensin-converting enzyme inhibitors (ACEIs),3,5 and angiotensin receptor blockers (ARBs).7–9The Cochrane Handbook for Systematic Review of Intervention,10 however, recommends that meta-regression should generally not be considered when there are fewer than 10 studies in a meta-analysis. We conducted re-analyses to determine the relative contribution of BP-dependent and independent mechanisms to the reduction in risk of stroke produced by amlodipine.

Methods

  1. Top of page
  2. Methods
  3. Results
  4. Comment
  5. References

From the most comprehensive meta-analysis1 published in 2009, we identified 10 ORs in 7 trials of amlodipine.3–9 The BP difference was assigned a positive value when the follow-up BP level was higher in the control compared with amlodipine. Percentage reductions in risk were estimated as [(1 − OR) × 100]. The association between the difference in follow-up systolic BP levels and the log OR for stroke was investigated using unrestricted maximum likelihood meta-regression analysis with inverse variance weighting. The intercept of the regression line estimated the value of the log OR when the difference in BP reduction is zero. The slope of the regression line estimated the log OR for a unit change in follow-up systolic BP difference. Both were reported with 95% confidence intervals (CIs). Analyses were carried out using Comprehensive Meta-Analysis version 2 (Biostat, Englewood, NJ).

Results

  1. Top of page
  2. Methods
  3. Results
  4. Comment
  5. References

The magnitude of the risk reduction achieved for stroke was positively associated with the size of BP reduction. Treatment with amlodipine achieved a 6.1% (95% CI, 1.1–10.8; P=.01817) reduction in the risk of stroke for each 1-mm Hg reduction in BP (slope of the regression line, −0.06241; 95% CI, −0.11420 to −0.01063; Figure). For stroke, amlodipine conferred additional protection beyond that conferred by BP reduction alone. At zero BP reduction, the estimated relative risk reduction for stroke was 10.3% (95% CI, 2.9–17.2; P=.00754) (intercept of the regression line, −0.10867; 95% CI, −0.18838 to −0.02896; Figure).

image

Figure FIGURE.  Meta-regression analysis between achieved difference in systolic blood pressure (BP [mm Hg]) and logs of odds ratios for stroke. The regression line with its 95% confidence interval (CI, dotted curve) was drawn and weighted by the inverse of the variance of the individual odds ratios. The slope of the regression line was −0.06241 (95% CI, −0.11420 to −0.01063; P=.01817) and its intercept was −0.10867 (95% CI, −0.18838 to −0.02896; P=.00754), which meant that the reduction in the risk of stroke for each 1-mm Hg reduction in BP was 6.1% (95% CI, 1.1–10.8) and the estimated relative risk reduction for stroke at zero BP reduction was 10.3% (95% CI, 2.9–17.2).

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Comment

  1. Top of page
  2. Methods
  3. Results
  4. Comment
  5. References

The present analyses, based on 10 ORs from 7 trials, confirm that the size of the reduction in BP achieved with amlodipine is a major determinant of the size of the reduction in stroke. In addition, these analyses have identified a potentially important BP-independent protective effect of amlodipine on the risk of stroke. In particular, there was clear evidence of protection against stroke with amlodipine even in the absence of any reduction in BP. This BP-independent effect was equivalent to the estimated effect of an additional 1.7-mm Hg reduction in systolic BP.

A meta-regression analysis1 found the significant relationship between BP reduction and a favorable effect of CCBs (not limiting to amlodipine) for cardiovascular death, major cardiovascular events, heart failure, and stroke. Although Wang and collaborators2 showed BP-dependent and -independent effects of amlodipine on the risk of stroke in their meta-regression analysis, they plotted only 5 ORs. Therefore, we re-analyzed 10 ORs from 7 trials and confirmed BP-dependent and -independent effects with amlodipine for the risk of stroke.

References

  1. Top of page
  2. Methods
  3. Results
  4. Comment
  5. References
  • 1
    Costanzo P, Perrone-Filardi P, Petretta M, et al. Calcium channel blockers and cardiovascular outcomes: a meta-analysis of 175,634 patients. J Hypertens. 2009;27:11361151.
  • 2
    Wang JG, Li Y, Franklin SS, et al. Prevention of stroke and myocardial infarction by amlodipine and angiotensin receptor blockers: a quantitative overview. Hypertension. 2007;50:181188.
  • 3
    ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002;288:29812997 Erratum in: JAMA. 2004;291:2196. JAMA 2003;289:178.
  • 4
    Dahlöf B, Sever PS, Poulter NR, et al. 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-BP Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet. 2005;366:895906.
  • 5
    Nissen SE, Tuzcu EM, Libby P, et al. Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal BP: the CAMELOT study: a randomized controlled trial. JAMA. 2004;292:22172225.
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    Pitt B, Byington RP, Furberg CD, et al. Effect of amlodipine on the progression of atherosclerosis and the occurrence of clinical events. Circulation. 2000;102:15031510.
  • 7
    Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345:851860.
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    Julius S, Kjeldsen SE, Weber M, et al. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet. 2004;363:20222031.
  • 9
    Ogihara T, Nakao K, Fukui T, et al. Effects of candesartan compared with amlodipine in hypertensive patients with high cardiovascular risks: candesartan antihypertensive survival evaluation in Japan trial. Hypertension. 2008;51:393398.
  • 10
    Deeks JJ, Higgins JP, Altman DG, eds. Chapter 9: Analysing data and undertaking meta-analyses. In: Higgins JP, Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.1 (updated September 2008). The Cochrane Collaboration, 2008. http://www.cochrane-handbook.org. Accessed March 1, 2011.