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Healthy Scepticism New Zealand

Delaying the Complications of Hypertension. Part 2


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This edition:
Delaying the Complications of Hypertension. Part 2:
Healthy Scepticism about Calcium Channel Blockers (CCBs)

Delaying the Complications of Hypertension. Part 2
The debate about CCBs ............................................................. 1
Be aware of experts and conflict of interest .............................. 1
Observational studies vs RCTs .................................................. 1
CCBs on trial .............................................................................. 1
Conclusions about CCBs ........................................................... 3
Advertising of CCBs for hypertension ...................................... 3
Isoptin (verapamil, Knoll) .................................................... 3
Norvasc (amlodipine, Pfizer) ............................................... 3
Plendil ER (felodipine, Astra) .............................................. 4
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Delaying the Complications of Hypertension. Part 2:
The debate about Calcium Channel Blockers (CCBs)
In 1995 a controversy erupted following publication of two case control studies and a meta-analysis raising concerns about CCBs.1,2,3 Bandolier has published a good summary of two of those studies.4 A survey of the subsequent debate identified 30 publications supportive of CCBs, 17 neutral and 23 critical of CCBs.5 Of respondents to the survey, 96% of supportive authors
had received funding from manufacturers of CCBs. This was significantly more than the authors of neutral publications (60%) or of critical publications (37%).

Be aware of experts and conflict of interest
Drug promotion often uses expert endorsement because it is an effective way to influence behaviour. Following experts’ recommendations can be good or bad. If the “expert” is competent, unbiased, has carefully considered the evidence andhas relevant experience then we can feel confident in his or her advice. If we do not feel confident, then it is better to examine the evidence ourselves.
It appears that the debate about CCBs has been influenced by bias. There are at least three possible mechanisms:
1. When there is a range of opinions, a drug company is likely to fund those “experts” whose opinions are most supportive of maximizing the company’s sales. This gives the supportive experts a louder voice.
2. Experts may have become more supportive of CCBs after receiving funding from manufacturers because of the reciprocal obligation that may consciously or subconsciously follow receiving a gift.
3. Experts may act to maintain consistency with the statements they have made in the past when less information was available. They may maintain consistency by being more critical of new evidence that is inconsistent with their earlier beliefs than they are of new evidence that supports their earlier judgement and thus may sometimes even be perceived as supporting their claim to expertise. (However, the best experts are able to change their minds in response to new evidence.)
Disclosure of “competing interests” is important.6

Observational vs international studies
The initial evidence suggesting that CCBs increase the risks of cardiovascular events,1,2,3 gastrointestinal haemorrhage,7 cancer,8,9 and suicide10 compared to alternative antihypertensives, came mostly from observational studies. A study is observational if there is no active intervention by the investigator. Observational studies produce correlations but are not conclusive about causation.11 For example, the inferior outcomes seen with CCBs may have been due to CCBs being inferior or may have been due to CCBs being prescribed more often to people who were sicker from the start. One recent observational study has contradicted the others by finding no clear difference in mortality among subjects with hypertension using a CCB compared with those who were not.12 Good observational studies should not be disregarded nor treated as conclusive. The hypotheses raised by observational studies need to be confirmed or denied by adequate interventional studies such as sufficiently powered and properly designed and conducted Randomised Controlled Trials (RCTs).

CCBs on trial
In this section we have attempted to summarise the key RCTs of CCBs to enable you to make your own decisions. This has not
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CCBs vs other drugs for hypertension
MIDAS: This trial found a higher rate of cardiovascular events in hypertensives on isradipine than on hydrochlorothiazide (HCT).19 However, cardiovascular events were secondary
endpoints (ie not the primary focus of the trial). This was because the investigators had not expected to find any difference. Differences in secondary endpoints are less convincing because the more things you measure the higher the probability of finding a “statistically significant” difference by chance.

FACET: This trial found a higher rate of major cardiovascular events in hypertensive non-insulin dependent diabetics on amlodipine than on fosinopril.20 However, this trial was not
double blind. Also, extrapolation from this trial or from ABCD to non-diabetics may not be justified. Again, there was no placebo group.

ABCD: This trial found a higher rate of fatal and non-fatal myocardial infarcts in hypertensive non-insulin dependent diabetics on nisoldipine than on enalapril.21 The hypertensive
diabetics component of the trial was terminated early on the recommendation of the trial’s safety committee.

VHAS: Unlike the other CCBs studied in the trials summarised in this edition, verapamil is not a dihydropyridine. It may be different from the others. VHAS found no difference in the rate
of cardiovascular events or the rate of adverse effects in hypertensives on chlorthalidone vs verapamil. However, the therapy duration was only two years.

Combined data
Wright (1998) has combined data from the MIDAS, FACET, ABCD and VHAS trials with GLANT (delapril vs dihydropyridine CCBs) and CASTEL (chlorthalidone with
atenolol vs nifedipine).22 He found that the relative risk of cardiovascular events with non-CCB drugs was around half that seen with CCBs. The odds ratio was 0.50 (99% Confidence Interval 0.35 to 0.72). However, relative risk can be misleading because it appears more dramatic than differences in absolute risk. Also, relative risk may be better or worse with longer duration of therapy.

Conclusions about CCBs
There is a range of interpretations of the currently available evidence regarding the use of CCBs for hypertension. One view is that CCBs are likely to be inferior to Thiazides, Beta-Blockers
and ACE inhibitors.22 Another view is that there is still uncertainty because of the limitations of the available studies.23
The Australian Medicines Handbook (AMH) recommends that:
“Pending results of ongoing large controlled trials, calcium channel blockers should be used for hypertension only when diuretics, beta-blockers and ACE inhibitors are contraindicated, poorly tolerated or inadequately effective.“24
Please contact us if you have any reason(s) for disagreeing with the AMH’s recommendation.

Advertising of CCBs for hypertension
Below is an analysis of advertisements for CCBs for hypertension published in New Zealand Doctor or NZ GP during 1998. We call attention to the appeals, which we believe
are being used in those advertisements, to enable you to decide for yourself whether or not you should be influenced by them.
Advertising appeals are often open to different interpretations.
Consequently for each advertisement we have tried to clarify the appeals by writing “possible interpretations”. We do not claim that our “possible interpretations” are necessarily what
the advertiser intended. However, in our opinion, they would be reasonable interpretations for readers to make if they were relying on the advertisement.
“Possible interpretations” which, in our opinion, are:
• unjustified are indicated with: x
• justified are indicated with: a tick
• borderline are indicated with: ?

Advertisement 1: Isoptin (verapril, Knoll)
Headlines: “Isoptin SR keeping watch”
Key copy: …“and protecting patients from the hazards of hypertension.”
Images: Paintings of lighthouses.

Second Opinion
Appeals: Doctor’s desire to be alert and to protect our patients.
Possible interpretations:
1. x Verapamil “protects” patients from complications of hypertension.
How good is the evidence?
1. Knoll have not cited any evidence to support their claim.
To our knowledge, verapamil has not been shown to delay the complications of hypertension. See VHAS above.

Advertisement 2: Norvasc (amiodipine, Pfizer)
Headlines: “A simple solution for your difficult to treat patients – Elderly, Polypharmacy, Concurrent CHF, Coexisting Diabetes,
Hypertension and Angina, Coexisting gout, Concurrent renal disease.” “Norvasc distinctly different. “
Images: Smiling middle-aged male GP juggling.

Second Opinion
Appeals: Simplicity – Advertisers often try to persuade us that use of their product is simple. If we believe a choice is simple then we may decide immediately without further thought.
Possible interpretations:
1. x Amlodipine is a “solution” for reducing morbidity and mortality.
2. x Using amlodipine is simple because it does not have negative drug-disease interactions with the conditions listed.
3. ? Amlodipine is “distinctly different” from all other antihypertensives.
How good is the evidence?
1. Amlodipine has not been shown to reduce morbidity or mortality. Allegedly, the yet to be fully published PREVENT trial in 825 patients with atherosclerosis has found that amlodipine is significantly better than placebo for angina.25 The amlodipine group had higher rates of cancer (21 vs 11) and bleeding (40 vs 28) but those differences were not statistically significant. Nonsignificant trends in a small study may or may not be due to a type II error.
Until the ALLHAT trial is completed, no one knows if amlodipine for hypertension does more or less good than alternative antihypertensives.
2. Amlodipine may increase the risk of pulmonary oedema in CHF.26 Evidence from all the relevant trials available to us suggests that CCBs are inferior to alternatives for diabetics.
3. CCBs may be distinctly inferior to some of the alternatives.

Advertisement 3: Plendil ER (felodipine, Astra)
Headlines: “Lowering BP to the HOT target reduces the risk.”
Key copy: …“lowering blood pressure to 80-85 reduces the risk of a major cardiovascular event by 30%. Plendil was selected as the basis of therapy for it’s proven effectiveness.”
Images: The comedian, Laurel, bending low to avoid being hit by a ladder carried by Hardy.

Second Opinion
Possible interpretations:
1. 7 If felodipine is used to reduce diastolic BP to 80-85 then the relative risk of cardiovascular events will be reduced by 30%.
How good is the evidence?
Use of relative risk reductions out of context can be misleading.27 To our knowledge felodipine has not been shown to reduce the risk of cardiovascular events.
Reducing diastolic BP to 80-85 may be beneficial for diabetics, but is unlikely to be beneficial overall for non-diabetics and may be harmful. See HOT above.


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