Longterm Safety of CalciumChannel Blockers

1
Long-term Safety ofCalcium-Channel Blockers
2
Historical Background

• Introduced in the late 1970s
• became the most commonly prescribed
  antihypertensive drug in the U.S.
• approved for hypertension or anginabased on
  short-term studies with no long term data on
  morbidity and mortality

Arch Intern Med 1995155829-37
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Calcium-channel blockers

• Short-acting
• nifedipine, dilatiazem, verapamil
• Long-acting
• amlodipine, felodipine, isradipine, nicardipine,
  nisoldipine,

4
CCB Controversy

• Reports of adverse outcome started in 1991
• Increased risk of myocardial infarction
• higher total mortality
• association with cancer
• association with GI bleeding

J Hypertens 1997151197-1200
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WHO-ISHWorld Health OrganizationInternational
Society of Hypertension

• Effects of calcium antagonist on the risks of
  coronary heart disease, cancer , and
  bleedingDue to the limitation and
  inconsistency of the available evidence the
  risks of CAD, cancer, and bleeding remains
  unproven.

J Hypertension 199715105-115
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Meta-analysison calcium-channel blockers

• 31 trials on short-acting CCB16 trials in which
  only nifedipine was used
• Conclusion
• short-acting nifedipine probably increases the
  risk of reinfarction or death, in a
  dose-dependent way
• non-dihydropyridines do not increase mortality
  and may reduce reinfarction

Am J Cardiol 1991671295-7
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Clinical TrialsInvolving Long-acting CCB

• Hypertension
• MIDAS 1996 isradipine ? CV events
• Syst-Euro 1997 nitrendipine ? CVA, CV
• Diabetes
• ABCD 1998 nisoldipine ? MI
• FACET 1998 amlodipine ? CV events
• Heart Failure
• PRAISE 1996 amlodipine safe in HF
• V-HeFT III 1997 felodipine safe in HF

8
MIDASMulticenter Isradipine Diuretic
Atherosclerosis Study

• Isradipine (an intermediate-acting
  dihydropyridine) vs HCTZ
• strong adverse trend was observed with respect to
  major cardiovascular events in patients receiving
  isradipine
• relative risk of 1.78
• diabetic patients did better with HCTZ

JAMA 1996276785-91
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Syst-EurSystolic Hypertension in Europe

• 4695 patients gt60 yrs old SBP 160-219, DBP lt95
• Drugs
• Nitrendipine 10-40 mg qd
• Enalopril 5-20 mg qd, HCTZ 12.5-25 mg qd
• Conclusion
• Nitrendipine reduced the incidence of stroke
  (?42) and cardiovascular (?26) complications

Lancet 1997350757-64
10
ABCD TrialAppropriate Blood Pressure Control in
Diabetes

• Nisoldipine (long-acting dihydropyridine)
• effect of BP control on renal function
• effect compared with enalapril
• study terminated early due to increased incidence
  of MI (25 vs 5) in group treated with nisoldipine

N Engl J Med 1998338645-52
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FACET TrialFosinopril vs Amlodipine
Cardiovascular Events Randomized Trial in
Patients with HTN and NIDDM

• Objective ACEI and CCB may favorably affect
  serum lipids and glucose metabolism. FACET
  compared the effects of fosinopril and amlodipine
  in NIDDM patients with HTN.
• Results No difference in total-C, HDL-C, HbA1C,
  FBS, plasma insulin fosinopril amlodipineMI
  , stroke, angina admission 14/189 27/191
• hazard ratio 0.49

Diabetic Care 199821597-603
12
ALLHATAntihypertensive and Lipid Lowering
Treatment to Prevent Heart Attack Trial

• amlodipine (CCB)
• lisinopril (ACE)
• doxazosin (alpha-blocker)
• chlorthalidone (diuretic)

N
13
CCB in Heart Failure
14
PRAISE-1Prospective Randomized Amlodipine
Survival Evaluation Study

• Background Calcium-channel blockers increase
  mobidity and mortality in patients with chronic
  heart failure. Eval the effect of amlodipine in
  severe CHF.
• Methods 1153 pts with severe CHF, EF lt30,
  randomized to receive amlodipine (n571) or
  placebo (n582) for 6-33 months, while receiving
  usual therapy
• Primary end point All-cause mortality and
  hospitalization for major cardiovascular events

N Engl J Med 19963351107-1452
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PRAISE-1Prospective Randomized Amlodipine
Survival Evaluation Study

• Placebo Amlodipine
• Primary End Point 42 39 P0.31
• Death 38 33 P0.07
• Pulmonary edema 10 15 Plt0.05
• Peripheral edema 18 27 Plt0.05
• Ischemic cardiomyopathy no difference between
  groups
• Nonischemic cardiomyopathy amlodipine reduced
  primary events by 31 (P0.04) and risk of death
  by 46 (Plt0.001)

N Engl J Med 19963351107-1452
16
PRAISE-1Prospective Randomized Amlodipine
Survival Evaluation Study

• Conclusions
• Amlodipine did not increase cardiovascular
  morbidity and mortality
• May be used relatively safely in patients with
  combined angina, HTN, and severe heart failure
• Reduction in mortality in patient with
  nonischemic cardiomyopathy requires confirmation
  by the ongoing PRAISE-2 trial.

N Engl J Med 19963351107-1452
17
V-HeFT IIIVasodilator-Heart Failure Trial

• Background mortality remains high with
  conventional HF therapy (diuretics, enalopril,
  digoxin) additional vasodilator therapy with
  felodipine (2.5-5.0 mg bid) may be beneficial
• Results placebo felodipine mortality
  12.8 13.8 NS hospitalization 42
  43 NS ? EF at 3 months - 0.1 2.1 P.001
• Conclusion felodipine appears to be safe but not
  clearly efficacious in patients with heart
  failure.

Circulation 199796856-863
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VHA Recommendations

• Diuretics and ß-blockers remain the preferred
  therapy for treating patients with HTN - based on
  reduction in morbidity and mortality
• ß-blockers and/or nitrates are the preferred
  treatment for patients with angina
• ACE inhibitors are preferred for the treatment of
  HTN in patients with diabetes proteinuria

www.dppm.med.va.gov
19
VHA RecommendationsCCB for HTN

• CCB may be considered if diuretics or ß-blockers
  are contraindicated or ineffective
• nondihydropyridine CCB (verapamil, diltiazem) are
  preferred, unless the patient is already
  receiving a ß-blocker
• verapamil should be considered for Stage-1 HTN
• long-acting DHP CCB (felodipine, amlodipine) may
  be considered for Stage 2 or 3 HTN

www.dppm.med.va.gov
20
VHA RecommendationsCCB for Angina

• Long-acting CCB may be used
• if ß-blocker is ineffective or contraindicated
• if long-acting nitrates are not tolerated
• for additional blood pressure control
• in patients with variant angina
• Nondihydropyridine CCB (verapamil, diltiazem) are
  preferred

www.dppm.med.va.gov
21
VHA RecommendationsCCB for Heart Failure

• Felodipine
• may be used for the treatment of HTN and/or
  angina in patients being treated with standard
  therapy for heart failure
• diuretics
• anagiotensin-converting enzyme inhibitor
• digoxin

www.dppm.med.va.gov
22
VHA RecommendationsCCB for Heart Failure

• Amlodipine may be used
• for the treatment of HTN and/or angina AND the
  patient has documented adverse reaction to
  felodipine AND long-acting nifedipine
• for the treatment of HTN and/or angina in
  patients with advanced heart failure
• as a last line agent in the treatment of advanced
  heart failure due to non-ischemic cardiomyopathy

www.dppm.med.va.gov
23
SHEPSystolic HTN in the Elderly Program

• Reduced incidence of
• stroke
• coronary events
• Beneficial effect seen in both diabetic and
  non-diabetics

JAMA 19912653255-64JAMA 1996 2761886-1892