Combination Therapy Options

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An Indian study, led by Sanjay Kalra from Dept of Endocrinology, Bharti Hospital, Karnal, India, and published in the journal Diabetology & Metabolic Syndrome reviewed the effective options in combination therapy for hypertension.

They found the following:
  • Beta blockers with diuretics – ‘Beta-blockers showed high cardiovascular risk, increased risk for stroke, and mortality in majority of the studies as compared to other anti-hypertensives’. So, this combination should be avoided in cardiovascular therapy and could be used to treat hypertension with anxiety or fast heart rate.
  • ACE Inhibitors / ARBs with Diuretics – Studies have shown that combination of ARB (irbesartan) and diuretic (Hydrochlorothiazide) is safe and effective in patients with moderate to severe hypertension irrespective of their age, baseline blood pressure level, and the metabolic syndrome status. The results also confirm that this combination is far more effective than monotherapies in reducing blood pressure.
  • Renin-angiotensin-aldosterone system (RAAS) blocker with CCB – In this combination, ‘negative sodium balance caused by CCBs adds to the antihypertensive effect of RAAS blocker and dose-dependent CCB induced peripheral edema may be minimized in the presence of an RAAS blocker’.
  • ACE Inhibitors with CCB – The FACET study showed that the chances of getting a major cardiovascular event reduced by approximately 50 percent in the hypertensive patients with diabetes who received fosinopril than those who received amlodipine. The chances of cardiovascular event further reduced in those who received the ACE Inhibitor-CCB combination. Another study showed that initial combination therapy of 5mg amlodipine besylate and quinapril 20mg was more effective in reducing blood pressure in diabetic patients as compared with increasing the dose of quinapril to 40 mg.
  • ARB with CCB – According to a study, ‘telmisartan 80 mg plus amlodipine 10 mg is the most effective combination and the telmisartan and amlodipine combinations offer a very effective and tolerable option particularly in susceptible patients that require combination therapy’.
  • ACE Inhibitors with ARB – Studies have demonstrated that this combination therapy shows ‘significant improvement with regard to target organ damage, specifically heart failure and proteinuria’. However, such combinations often worsen hyperkalemia (higher than normal levels of potassium in the blood) and reduce hematocrit levels in chronic renal failure patients. Elderly salt depleted patients, anemic patients and those receiving concomitant cyclooxygenase inhibitors also should be monitored when using this combination.
The authors also reviewed the use of combination therapies in special situations. For example:
  • In hypertensive patients with heart failure, treatment with ACE Inhibitor-beta blockers has been shown to improve symptoms and reduce mortality and hospitalization for worsening heart failure.
  • In hypertensive patients with chronic renal failure, high-dose telmisartan /low-dose amlodipine combination was as effective in reducing BP values during the 48-week study period without affecting glycemic control or plasma electrolyte levels.
  • In patients with thyroid disorders, the systolic blood pressure (upper reading) is typically elevated and diastolic blood pressure (lower reading) is often low resulting in a widened pulse pressure. Studies have shown that ACE Inhibitor / ARB combination does not always reduce blood pressure.
  • Mono-therapy or combination therapy with thiazide diuretics, ACE Inhibitors and CCBs were found to be favorable for hypertension in the elderly patients.
  • Drugs preferred during the pregnancy are: Ist line - Methyl dopa, Beta blocker (propranolol) and Labetalol; IInd line - Metoprolol, atenolol and Calcium channel blocker (nifedipine); IIIrd line agents-clonidine, diuretics.
They suggested the following contraindications and conditions requiring special care -

ACE Inhibitors - Pregnancy, angioneurotic edema, hyperkalemia, renal artery stenosis

Diuretics - Gout, hypokalemia, pregnancy, impaired glucose tolerance

Beta blockers - Asthma, marked bradycardia, abnormal glucose tolerance, obstructive pulmonary disease, peripheral artery disease

ARB - Pregnancy, hyperkalemia, renal artery stenosis

CCB - Heart failure, bradyarrythmias

In conclusion they said ‘Choice of combination therapy depends upon the risk factors, presence of comorbidities like diabetes, renal dysfunction and the adverse effects and tailored according to individual patient’.

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